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Mechanisms of Action of Royal Jelly, Bee Pollen, and Propolis in Sarcopenia\nRelatively few studies have explored the mechanism through which royal jelly, bee pollen, and propolis may be beneficial for sarcopenia. In vivo and in vitro studies included in this review uncovered a number of inter-related cellular and molecular events that underlie the effect of these bee products on skeletal muscle including suppression of catabolic genes, counteracting metabolic abnormalities, inflammation, and oxidative damages as well as enhancement of motor neuronal regeneration, promotion of stem cell function, and correction of the structure of gut microbiome (Figure 1, Panel D). These mechanisms are exclusively described in the coming paragraphs.\n\n4.1. Modulating Inflammatory Responses in Skeletal Muscle\nThe role that inflammation plays in skeletal muscle is not quite clear as it looks. Inflammatory mediators behave in a dual fashion in muscle cells. During injury, cytokines and chemokines stimulate muscle repair and regeneration via activation of myoblasts, a core event in muscle remodeling [108]. Similarly, serum and muscle levels of IL-6 temporarily increase following physical exercise, and IL-6 blocks the activity of catabolic cytokines such as TNF-α. On the other hand, chronic inflammation in muscle cells, which correlates with persistent mitochondrial dysfunction and metabolic dysregulation, pathologically activates muscle fiber transformation and atrophy, eventually resulting in the development of sarcopenia [23,114]. It seems that bee products also act dually in skeletal muscle: they support the activity of cytokines that promote muscle remodeling [108] and suppress muscle-consuming cytokines [38,101,108]. In this regard, treating undifferentiated C2C12 myoblasts with ethanolic extracts of Brazilian propolis (100 μg/mL for 8 h) triggered the migration of RAW264 macrophage and increased their production of angiogenic factors (e.g., vascular endothelial growth factor A (VEGF-A) and metalloproteinase-12 (MMP-12)), chemokines (e.g., CCL-2 and CCL-5), and cytokines (e.g., IL-6, which increased by 40-folds). Propolis inhibited the expression of IL-1β and TNF-α at 4, 8, and 12 h of incubation. These effects were nuclear factor kappa B (NF-κB)-dependent given that propolis simultaneously increased nuclear translocation of p65 and p50 NF-κB proteins 3 h after treatment. Meanwhile, inhibiting IκB kinase (IKK) by BMS-345541 profoundly hindered the effect of propolis on the expression of CCL-2, CCL-5, and IL-6 by 66%, 81%, and 69%, respectively. Propolis also enhanced the expression of MAIL/IκBζ. This molecule modulates chromatin and selectively induces the production of IL-6, leukemia inhibitory factor (LIF), and CCL-2 [108].\nChronic muscle tissue infiltration by inflammatory cells (e.g., leukocytes, neutrophils, and monocytes) activates oxidative and inflammatory signaling cascades that degrade cellular structures and promote necrosis such as inducible nitric oxide synthase (iNOS) and NF-kB [90,101,115]. CAPE and high levels (200 and 300 mg/kg) of crude and processed bee pollen reduced inflammatory cell infiltration into the gastrocnemius muscle of rats with muscle injury induced by eccentric exercise and ischemia reperfusion [90,101,102]. This effect was revealed by lower activity of myeloperoxidase, an indicator of neutrophil sequestration [101,102]. As such, CAPE and bee pollen not only suppressed lipid peroxidation (lower levels of malondialdehyde, MDA) but also inhibited the activity of myostatin and the production of muscle depleting cytokines and chemokines such as IL-1β, α2-macroglobulin, and monocyte chemotactic protein 1 (MCP-1) [36,38,90,101]. The underlying mechanism entailed downregulation of nuclear p65NF-κB and blockage of its consensus binding sites in skeletal muscle [101]. As a result, bee products increased muscle mass both in sarcopenic obese rat and malnourished old rats [36] and restored the structure of myofibers (despite the persistence of necrosis) compared with untreated eccentric exercising animals, which demonstrated necrotic and fragmented myofibers [90].\nRoyal jelly downregulated the activity of tumor necrosis factor receptor 1 (TNFR1) in the adipose tissue of aged obese rats receiving HFD [100]. TNFR1 interacts with TNFR2 to negatively regulate toll-like receptors (TLR) and Nod-like receptor signaling and stimulate excessive release of cytokines via activation of key inflammatory pathways such as NF-κB [107]. Mitigation of TNFR1 was associated with a significant increase of the weight of hind limb muscle and reductions in insulin levels, homeostatic model assessment of insulin resistance (HOMA-IR), serum lipids, muscle triglyceride levels, body weight gain, and abdominal fat weight. Therefore, royal jelly may protect against muscle loss in conditions involving impairment of the adipokine profile mainly through suppression of inflammatory responses associated with high fat mass, which is followed by correction of metabolic irregularities [100].\n\n4.2. Counteracting Oxidative Stress in Skeletal Muscle\nHigh production of reactive oxygen species (ROS) in skeletal muscle tissues has serious destructive effects, which alter the integrity of skeletal muscle resulting into fatigue, muscle wasting, and muscle weakness [90,101]. Sources of intramuscular ROS are numerous including mitochondrial dysfunction (e.g., alteration of mitochondrial enzymes in the respiratory chain as well as enzymes responsible for β-oxidation), neutrophil infiltration, and the activity of cytokines and major muscle degrading molecules such as myostatin [21,36,38,101,102,118]. Oxidative and nitrosative damages in skeletal muscle tissues are mediated by the activity of numerous pro-oxidant enzymes that are associated with inflammatory processes such as cyclooxygenase-2 (COX-2) and iNOS [101]. ROS triggers the activity of corrosive molecules such as poly (ADP-ribose) polymerase (PARP), xanthine oxidase, and adenosine deaminase, which contribute to DNA damage, lipid peroxidation (e.g., increased MDA), and protein nitrotyrosylation as well as ATP catabolism in muscle tissues [101,102].\nRoyal jelly enhanced the activity of antioxidant enzymes and suppressed lipid peroxidation in a d-galactose induced model of aging [95]. Two weeks of propolis treatment in rats undergoing hind limb unloading significantly reduced nuclear ROS levels and numbers of apoptotic endothelial cells in the soleus muscle to levels similar to normal rats [110]. Moreover, propolis significantly suppressed MDA activity in skeletal muscle and increased liver levels of SOD as well as gastrocnemius muscle levels of SOD, glutathione peroxidase and catalase in rats on eccentric exercise training (70% VO2max treadmill running exercise for 60 min) compared with rats receiving exercise alone or no treatment [109]. In addition, intraperitoneal pre-administration of CAPE (60 min before induction of ischemia reperfusion) significantly ameliorated the effects associated with high ROS levels, which accompany acute ischemia such as protein peroxidation and ATP catabolism in the gastrocnemius muscle [102].\nBee products probably reduced ROS production via regulation of the activity of mitochondrial enzymes. Royal jelly increased the maximal activity of citrate synthase (CS) and β-hydroxyacyl coenzyme A dehydrogenase (β-HAD) in the soleus muscle of rats on endurance training [106]. Bee pollen restored mitochondrial complex-I, -II, -III, and -IV enzyme activity to normal, increased SOD and glutathione, and reduced MDA, NO, and total protein content in the gastrocnemius muscle of rats on exhaustive exercise [90]. It also increased the activity of CS and complex IV in malnourished old rats via a mechanism that involved activation of mTOR [36]. mTOR is a major signaling pathway that regulates various signaling cascades involved in metabolism and autophagy such nuclear respiratory factor 2 (NRF2) [2]. Therefore, it is possible that the antioxidant activity demonstrated by bee products, particularly that expressed in the mitochondria, is associated with their metabolic and hypoglycemic activities. For instance, 10-HDA increased expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) in skeletal muscle of diabetic mice [112,119]. Similarly, aged mice treated with amino acids similar to those found in royal jelly demonstrated improved size of muscle fiber by increasing PGC-1α mRNA levels. PGC-1α functions as a key regulator of sirtuin 1, which limits ROS production through stimulation of mitochondrial biogenesis and ROS defense system, thus protecting metabolically active tissues against oxidative damage [120]. Mechanistically, when PGC-1α gets activated, it interacts with other bioactive molecules such as muscle-specific transcription factors to stimulate the expression of genes that induce mitochondrial oxidative metabolism in brown fat and fiber-type switching in skeletal muscle [121].\nThe antioxidant activity of royal jelly and CAPE might be related to their strong capacity to activate the master redox-active NRF2 signaling pathway [73,122], which stimulates the production of internal antioxidants such as heme oxygenase-1 (HO-1), which scavenge free radicals [123]. Meanwhile, NRF2 and HO-1 block ROS production indirectly via suppression of inflammatory reactions [122]. In this context, CAPE reduced degenerative myopathy in rats on eccentric exercise via a complex mechanism that involved inhibition of NF-κB and its downstream pro-oxidant COX-2 and iNOS [101]. Correspondingly, CAPE decreased markers of oxidative cellular damages (protein carbonyl, protein nitrosylation, xanthine oxidase, and adenosine deaminase) associated with ischemia reperfusion and eccentric exercise in the gastrocnemius muscle [101,102,103]. In this regard, CAPE operated via a mechanism that involved inhibition of neutrophil and leukocyte infiltration into the gastrocnemius muscle, which was associated with decreased levels of myeloperoxidase. Myeloperoxidase contributes to excessive production of ROS and oxidative organ damage through a mechanism that embroils increased synthesis of hypochlorous acid [101,102]. Furthermore, CAPE accelerated purine salvage for ATP synthesis and inhibited ROS-induced lipid peroxidation via attenuation of the activity of adenosine deaminase [102].\nIn summary, the reported antioxidant effects of bee products were multifaceted involving increased production of antioxidant enzymes [90,95,109,110], and decreased ROS production [90,101,102,103,110] (secondary to reduction of inflammatory cell infiltration into skeletal muscle) [90,101,102,103], and restoration of mitochondrial activity [36,90,106].\n\n4.3. Metabolic Regulation\nSkeletal muscle is the main tissue that utilizes insulin for glucose uptake. Insulin regulates mitochondrial oxidative phosphorylation of proteins in human skeletal muscle and contributes to calcium mobilization from the sarcoplasmic-endoplasmic reticulum to mitochondria to stimulate the translocation of glucose transporter 4 (GLUT4) to the cell surface for glucose uptake. This process improves muscle protein synthesis in healthy people when the delivery of amino acids to skeletal muscle is increased, eventually leading to increased muscular mass [124,125,126]. Insulin resistance and glucose intolerance increase with old age evoking muscle loss. In this respect, hypoglycemic agents such as metformin can improve skeletal muscle metabolism via activation of adenosine monophosphate activated protein kinase (AMPK) [21].\nAMPK, a heterotrimeric complex that consists of a catalytic subunit and two regulatory subunits, is an intracellular energy sensor that regulates glucose and lipid metabolism. It gets activated when cellular energy is depleted through allosteric binding of AMP or phosphorylation by AMPK kinase at Thr172 of the catalytic subunit by AMPK kinase. Upregulated AMPK activates signaling pathways that generate ATP from glucose and fatty acid oxidation, and it simultaneously blocks signaling that contributes to the synthesis of cholesterol, fatty acid, and triacylglycerol [111]. In addition, AMPK masters numerous signaling cascades such as Forkhead Box O transcription factor (FOXO) and AKT/mTOR, which regulate the expression of genes associated with inflammation, oxidative stress, mitochondrial function, autophagy, metabolism, and apoptosis [127,128].\nThe molecular events involved in the effect of bee products on catabolic genes and anabolic resistance in skeletal muscle could be much related to their hypoglycemic effects, which positively affect the quality of skeletal muscle. Evidence signifies a positive effect of royal jelly acid (10-HDA) on inflammation and autophagy via upregulation of AMPK, which subsequently alters NF-κB and NLRP3 inflammasome-IL1β signaling [129]. Positive effects of whole royal jelly on skeletal muscle are associated with improved insulin signaling [96,100]. In one study, royal jelly improved serum IGF-1 levels in aged rats and increased AKT signaling in satellite cells extracted from aged rats in a separate in vitro investigation [96]. In another study, royal jelly decreased fat mass and improved anabolic resistance in the skeletal muscle of old obese rats on HFD via downregulation of inflammatory responses in adipose tissue as indicated by downregulation of TNFR1. This effect was associated with enhanced sensitivity to insulin—portrayed by reduction of serum insulin level and HOMA-IR [100].\nJapanese researchers proved that oral consumption of royal jelly and 10-HDA induced mitochondrial adaptation in the soleus muscle when accompanied with endurance training. These compounds also enhanced glucose uptake in skeletal muscle by inducing the phosphorylation of AMPK [106,112], an effect that was mediated by the upstream kinase Ca²⁺/calmodulin-dependent kinaseβ—independently of changes in AMP:ATP ratio and the liver kinase B1 pathway. Activation of AMPK was followed by translocation of GLUT4 to the plasma membrane of L6 myotubes [106]. It is note-worthy that effects of royal jelly on mitochondrial biogenesis under endurance training were muscle-specific. In this respect, neither endurance training nor royal jelly alone had an effect on the maximal activities of CS and β-HAD—the enzyme that catalyzes the rate-limiting step of β-oxidation of long-chain fatty acids—in the soleus muscle, which comprises type I fiber (around 35–45%) and type IIa (around 35–50%). On the other hand, royal jelly enhanced the activity of these enzymes in the soleus muscle of mice on endurance training. Of interest, endurance training increased the activity of CS and β-HAD in the plantaris and tibialis anterior muscles (which are mainly type II fiber with a total percentage of type IIb and type IIx fiber types of 90%) while royal jelly failed to exert an effect on these muscles in sedentary mice [106]. Nonetheless, the observed effects of royal jelly in the soleus muscle represent a merit. This is mainly because the oxidative type I fibers (e.g., soleus muscle) naturally undergo higher protein turnover (especially degradation), which makes them unable to grow in size or respond properly to insufficient nutrient intake [130].\nSeveral lines of evidence indicate that propolis may affect muscle quality through the regulation of glucose metabolism [69,70,109,111]. This effect was vividly depicted in vivo by increased glycogen level in skeletal muscle and reduced serum levels of glucose and insulin [109]. Same as insulin, ethanolic extracts of propolis and CAPE induced glucose uptake [69,70,111] and potentiated insulin-mediated AKT activation and glucose uptake in differentiated L6 myoblast cells [111]. Likewise, Italian propolis at concentrations of 0.1 and 1 mg/mL as well as 4-geranyloxyferulic acid and auraptene (2 oxyprenylated phenylpropanoids, which are abundant in propolis) remarkably increased GLUT4 translocation to the plasma membrane and accelerated GLUT4-mediated glucose uptake in L6 skeletal myoblasts. The effect of propolis at a concentration of 11 mg/mL was significantly superior to the effect of insulin (0.1 μM), which was used as a positive control [69].\nSimilar to royal jelly, the effects of propolis (1 μg/mL), CAPE (10 μM), artepillin C, coumaric acid, and kaempferide on glucose metabolism occurred via activation of AMPK. These effects were comparable to those of 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), a potent AMPK activator. In the meantime, co-treatment with inhibitors of AMPK (e.g., compound C) and of phosphatidylinositol 3-kinase (PI3K) (e.g., LY-294002) blocked the effects of CAPE [70,111]. Phosphorylation of AMPK results in activation of the insulin receptor (IR) and subsequent phosphorylation of PI3K followed by activation of AKT and protein kinase C (PKC) leading to GLUT4 translocation and subsequent activation of several molecules that modulate insulin-stimulated glucose transport, eventually leading to glucose influx into cells of several tissues such as skeletal muscle and adipose tissue [69,70,111]. It is worth noting that the effects of CAPE on AMPK and AKT were quick (within 1 h and 3 min, respectively), and they vanished quickly (both molecules returned back to their basal levels within 12 h and 30 min, respectively) [111].\n\n4.4. Enhancement of Muscle Protein Synthesis\nImbalance between muscle protein synthesis and degradation is associated with low protein intake and altered efficiency of the GI tract in old age, which triggers skeletal muscle loss and poor physical performance [36,40], given that proteins are the main building blocks of muscle myofibers. Moreover, transmembrane proteins and micro-peptides (e.g., myomixer and myomaker/Tmem8c) contribute to the formation of myofibers by promoting myoblast fusion via a mechanism that involves appropriate localization of Tmem8c at the plasma membrane of myoblasts allowing trafficking related to palmitoylation of C-terminal cysteine residues and C-terminal leucine [17]. Amino acid supplements (e.g., leucine, a master dietary regulator of muscle protein turnover, and its metabolite β-hydroxy β-methylbutyrate) and early refeeding with high protein diet (especially fast digestive proteins) can preserve muscle mass and function, revert sarcopenia, and enhance mobility and quality of life (QoL) by correcting age-related nutritional deficiencies, muscle protein turnover, and immune dysregulation—these effects are even greater when combined with other nutrients like vitamin D or omega 3 fatty acids as well as with physical exercise [6,131,132,133,134,135,136,137,138].\nResearch indicates that age-related skeletal muscle wasting results mainly from insufficient delivery of amino acids to skeletal muscle due to dysregulations in the activity of mTORC1- and activating transcription factor-4 (ATF4)-mediated amino acid sensing pathways. Meanwhile, interventions that ameliorate age-related damages in skeletal muscle operate primarily by reversing alterations in the delivery of amino acids to skeletal muscle via upregulation of mTORC1 and/or ATF4 [139]. mTORC1 is a nutrient sensing protein that acts as a core regulator of protein metabolism. It is sensitive to amino acids, energy status (ATP), stress (e.g., oxidative stress), and growth factors (e.g., insulin), which all can regulate its signaling [2,136]. Nevertheless, bioavailability of amino acids is necessary for growth factors to effectively activate mTORC1. Even more, amino acids on their own can adequately activate mTORC1 [136]. Evidence from preclinical and human studies confirms that ingestion of essential amino acids (similar to those found in royal jelly and bee pollen such as valine) increases cellular bioavailability of amino acids, which is associated with activation of the endothelial nitric oxide synthase (eNOs) pathway. eNOs further upregulates mTORC1 kinase. Translocation of mTORC1 from the cytosol to the surface of lysosomes is associated with improved mitochondrial biogenesis and cellular oxidative capacity in skeletal muscle due to activation of its substrates: P70 ribosomal proteins S6 kinase (S6K) and eukaryotic translation initiation 4E-binding protein 1 (eIF4E, also known as 4eBP1) [120,135,136].\nAs shown in Table 1, royal jelly and 10-HDA significantly increased muscle mass [54,96,100] and improved motor performance in aged rats [95,98,99]. In addition, dietary supplementation with monofloral bee pollen significantly improved the rate of muscle protein synthesis and restored muscle mass in emaciated old rats via upregulation of mTOR and two related downstream controllers of protein translation: p70S6k and 4eBP1, which were suppressed in malnourished old rats [36]. Although propolis improved various muscle-related parameters, its effect on muscle mass in rodents was limited—relative to royal jelly and bee pollen. However, it fostered muscle protein deposition in post-larva Nile tilapia [104]. Moreover, milk naturally enriched with PUFA and polyphenols from propolis remarkably increased the weight of the gastrocnemius muscle of growing obese rats while whole milk and milk enriched with PUFA only could not express any effect on skeletal muscle [105]. Therefore, this finding denotes that propolis could have enhanced the delivery of amino acids available in milk to skeletal muscle leading to its growth. Altogether, it is likely that the observed anabolic effects of royal jelly and bee pollen are associated with their high content of proteins and amino acids [32,36,83,84,85,86].\n\n4.5. Suppression of Catabolic Activity in Skeletal Muscle\nSkeletal muscle tissues represent the largest protein store in the human body (30–45% of total protein). Muscular mass, strength, and functions are greatly governed by the rates of muscle protein synthesis and turnover [124]. Muscle protein metabolism is regulated by the interaction of a wide range of genes. Aging is associated with various stresses, which increase the expression of catabolic genes such as E3 ubiquitin ligases MuRF1 and atrogin-1 (MAFbx). These genes heighten the occurrence of age-related muscular atrophy [97]. Oral consumption of royal jelly by aged HET mice resulted in lower levels of catabolic genes (e.g., MuRF1 and MAFbx), which were similar to those in young mice. In the meantime, the expression of these genes in the control mice was high indicating that royal jelly can delay age-related muscular apoptosis by suppressing the activity of catabolic genes [97]. Two other studies reported that CAPE suppressed catabolism that contributed to degenerative myopathy in the gastrocnemius muscle of rats undergoing eccentric exercising or femoral artery ligation as reflected by decreased serum levels of creatine kinase, a marker of muscular proteolysis [101,102,103]. Apart from skeletal muscle, CAPE was reported to protect heart muscle against age-related deteriorations such as accumulation of lipofuscin, nuclear irregularity, mitochondrial degeneration, and myofilament disorganization and disruption [33].\nThe molecular mechanism underling blockage of muscle proteolysis by bee products in sarcopenic rodents involves an interplay of various signaling pathways. Royal jelly and bee pollen activated mTOR and its substrate AKT, which are suggested to inhibit muscular proteolysis [36,96]. Similar to the effect of royal jelly on catabolic genes in HET mice, treating both L6 myoblasts and rats with propolis, CAPE, and kaempferide resulted in potent activation of AKT in a PI3K-dependent manner [111], in addition to phosphorylation of IR, PI3K, and AMPK [70]. AKT, a key substrate of mTORC2, is a conserved serine/threonine nutrient sensing protein kinase that belongs to the PI3k-related protein kinase family. Upon presence of growth factors, PI3k gets activated by IR substrate resulting in stimulation of a series of signaling cascades that involve activation of AKT, which leads to further activation of mTORC1. mTORC1 activates the phosphorylation of two main regulators of cap-dependent protein synthesis: S6K and eIF4E [2,140]. In addition, mTORC1 contributes to autophagy—a turnover process that involves clearance of dysfunctional organelles and long-lived protein aggregations with provision of energy and macromolecular precursors in return—by binding with AMPK resulting in phosphorylation of autophagy genes such as Unc51-like kinase 1 at different sites [140]. In fact, royal jelly is reported to fine-tune the transcriptional activity of the FOXO through modulating the activity of insulin/IGF-1 signaling [141]. FOXO plays a major role in the activation of AKT pathway, which implicates regulation of multiple stress–response pathways such as ROS detoxification and DNA repair and translation. In addition, the FOXOs family exerts a direct effect on certain muscle atrophy genes such as MUSA1 and a formerly uncharacterized ligase known as Specific of Muscle Atrophy and Regulated by Transcription (SMART) [142].\n\n4.6. Enhancement of Stem Cell Function\nReduction of the number and functional capacity of the muscle satellite cells is considered a core contributor to the development of age-related muscular dysfunction [96]. Induction of myogenesis via in vivo reprogramming of muscle satellite cells is a currently studied strategy that has not been successfully used for sarcopenia treatment yet [143]. On the other hand, treating sarcopenic rats with both royal jelly and pRJ was reported to increase the number of Pax7-positive satellite cells in vivo and in vitro (pRJ only). pRJ induced self-renewal of satellite cells via activation of AKT signaling [96,97]. AKT activity was associated with activation of IGF-1 as indicated by increased serum levels of IGF-1. IGF-1 plays a crucial rule in the activation of various signaling pathways; it is believed to be a major mediator of muscle growth and repair that functions by stimulating the proliferation and differentiation of satellite cells into myotubes, albeit the exact mechanism is not clear yet [96]. Similarly, pRJ activated AKT-signaling pathway in satellite cells culture, which was associated with increased proliferation of myosatellite cells and their differentiation into myotubes—an effect that is contradictory to muscle loss. AKT is thought to contribute to the synthesis of muscular proteins and inhibition of muscle proteolysis [96].\n\n4.7. Counteracting Glycation Stress\nOxidative stress, inflammation, and insensitivity to insulin, which accompany advanced age, contribute to the production of advanced glycation end products (AGEs) via enhancement of the activity of the Receptor for Advanced Glycation End products (RAGE) [144,145]. AGEs destroy the protein and lipid ingredients of muscle tissues by promoting the production of destructive molecules such as free radicals and inflammatory cytokines [101,102,113]. Thanks to their potent antioxidant properties, polyphenolic compounds exert multifaceted anti-glycation functions. On one hand, they scavenge free-radicals and chelate transition metals that are involved in the synthesis of dicarbonyl intermediates subsequently resulting in inhibition of the formation of AGEs. On the other hand, polyphenolic compounds antagonize AGE receptors, mainly RAGE, and facilitate the removal of already formed a,b-dicarbonyl intermediates such as methylglyoxal, promoting the degradation of AGEs [37,38,146]. Royal jelly is reported to downregulate the activity of RAGE, the main receptor for AGEs, in an aged model of cognitive impairment [147]. However, its anti-glycation effect has not been investigated in skeletal muscle yet. Propolis exhibits strong anti-AGE properties, which are superior to those of quercetin or chlorogenic acid, well-known natural AGE inhibitors. Its flavonoid fraction potently impedes the synthesis of AGEs by trapping dicarbonyl intermediates [37]. Table 1 shows that propolis accelerated AGEs clearance in a model of muscle aging induced by administration of a precursor of AGEs (methylglyoxal) via activation of glyoxalase 1, an enzyme that eliminates dicarbonyl compounds (key elements of AGEs) [38]. CAPE inhibited the production of AGEs-related molecules such as protein carbonyl in the gastrocnemius muscle of rats via blockage of the activity of xanthine oxidase and adenosine deaminase [101,102,103]. The latter negatively affects insulin signaling and promotes the development of hyperglycemia, which represents a favorable condition for the production of AGEs [148]. However, propolis could not counteract the wasting effects of AGEs that already occurred in the extensor digitorum longus muscle though it tended to restore soleus muscle mass. This finding denotes that different muscle tissues respond differently to treatment, probably based on their ratio of type I to type II fibers. It also signifies the importance of early use of bee products (e.g., propolis) for the prevention of AGEs formation in skeletal muscle in people with high risk for AGEs formation such as diabetics [38].\n\n4.8. Neuronal Regeneration\nNeuronal denervation is a key factor that contributes to skeletal muscle loss, and it is related to a plethora of pathological conditions [3,149]. Experimental induction of oxidative stress and inflammation results in skeletal muscle atrophy through induction of denervation e.g., of sciatic nerve [150]. Injuries of peripheral nerves (e.g., sciatic nerve) interrupt mechanical transmission and microvasculation of the nerve and induce reperfusion. Reperfusion involves pooling of oxygen and nutrients promoting high emission of free radicals, which attack protein and lipid contents surrounding the injury site resulting in excessive tissue loss [113]. Likewise, alterations in gut microbiome in aged rats are associated with alterations in serum level of vitamin B12 and fat metabolism as well as reductions in the gastrocnemius muscle mass and sciatic response amplitude [151]. Furthermore, dysregulation of insulin-mediated GLUT4 activity in certain areas of the central nervous system impairs neuronal metabolism and plasticity [69]. Meanwhile, activation of PGC-1α, a core regulator of mitochondrial content and oxidative metabolism, increases muscle fiber resistance to denervation and atrophy through downregulation of two ubiquitin-ligases involved in the ubiquitin-proteasome pathway: MuRF1 and Atrogin-1 [1,152].\nPropolis treatment for four weeks restored gastrocnemius muscle weight and improved functional performance (e.g., walking) in rats with crush injury of the sciatic nerve. Effects of propolis were associated with increased nerve healing and regeneration as depicted by faster healing of the myelin sheath and ultra-structurally normal unmyelinated axons and Schwann cells. Investigations of motor conduction from the sciatic nerve to the gastrocnemius muscle indicated that nerve recovery induced by propolis treatment promoted optimal physical functioning by allowing motor conduction to reach the gastrocnemius muscle [113]. Neuroprotective effects of propolis in motor neurons are documented in the literature. Both kaempferide and kaempferol protected motor neurons against atrophy induced by the toxic copper-zinc superoxide dismutase in amyotrophic lateral sclerosis—a serious neurodegenerative disease that involves selective and progressive loss of motor neurons [65]. In addition, orally administered chrysin (a flavonoid that is copious in propolis) to rats intoxicated by 6-hydroxidopamine showed neuroprotective effects by mitigating neuroinflammation, enhancing levels of neurotrophins and neuronal recovery factors (e.g., brain derived neurotrophic factor and glial cell line-derived neurotrophic factor), and maintaining integrity of dopaminergic neurons resulting in better motor performance [72].\nThe release of acetylcholine (a neurotransmitter that regulates cognition) at the synaptic cleft of the neuromuscular junction is essential for motor neurotransmission, which controls excitation-contraction coupling and cell size. However, free radicals, cytokines, and AGEs impair neurotransmission by altering the production of acetylcholine [6,21,149,153]. On the other hand, upregulation of acetylcholine receptors improves neurotransmission [154]. Treatment with royal jelly may correct acetylcholine neurotransmission given its high content of acetylcholine (4–8 mM) [60]. In addition, royal jelly, propolis, and bee pollen are rich in antioxidant elements that have a potential to scavenge ROS and mitigate other pathologies that contribute to acetylcholine deficiency (e.g., neuroinflammation) [73,101,102,103]. In this respect, treatment of experimental models of carrageenan-induced hind paw edema with hydroalcoholic extract of red propolis and its biomarker, formononetin, is reported to inhibit leukocyte migration and ameliorate inflammatory neurogenic pain induced by injections of formalin and glutamate [115]. However, investigations of the action of bee products on neurotransmission are very scarce.\n\n4.9. Improving Muscular Blood Supply\nAging is associated with higher onset of atherosclerosis and restenosis, which involve vascular and microvascular damages that result from hyperproliferation of vascular smooth muscle cells (VSMCs) [155]. Muscle unloading (e.g., in sedentary lifestyle) involves chronic neuromuscular inactivity, which results in reductions in capillary number, luminal diameter, and capillary volume as well as heightened production of anti-angiogenic factors, such as p53 and TSP-1 in skeletal muscle [110]. Microvascular alterations and impaired nitric oxide (NO) production are key causes of decreased blood flow to the skeletal muscle. Poor muscular blood supply induces muscle wasting via a mechanism that entails impaired glucose metabolism and suboptimal protein anabolism [156,157]. In addition, ischemic injury in skeletal muscle is associated with high ROS release from polymorphonuclear leukocytes, which infiltrate muscle tissues. Free radicals alter cellular structure and function by attacking lipid and protein biomolecules that exist in the structure of biological membranes, enzymes, and transport proteins [102]. Therefore, improving vascularization and blood supply to skeletal muscle is a possible mechanism for the prevention of muscle wasting.\nMitchell and colleagues examined changes in microvascular blood volume, microvascular flow velocity, and microvascular blood flow in the quadriceps muscle following treatment with 15 g of amino acids in young and old subjects (20–70 years old). They detected improvements in all the 3 parameters only in young groups, and those effects were associated with proper insulin activity. Thus, the authors suggested that refeeding effects on muscular blood supply may be hindered by dysfunctions in postprandial circulation and glucose dysregulation [157]. Bee products such as bee pollen and propolis have a potential to boost microcirculation and correct pathologies that contribute to vascular dysfunction such as hyperglycemia and dyslipidemia [36,155]. In this context, CAPE, one of the basic constituents of propolis, was reported to combat vascular damages by counteracting the proliferative activity of platelet-derived growth factor. The molecular mechanism involved inducing cell-cycle arrest in VSMCs via activation of p38mitogen-activated protein kinase (MAPK), which was associated with accumulation of hypoxia-inducible factor (HIF)-1α—mainly due to inhibition of HIF prolylhydroxylase, a key contributor to proteasomal degradation of HIF-1α—and subsequent induction of HO-1 [155]. In the same regard, supplementing rats undergoing capillary regression (resulting from two weeks of hind limb unloading) in the soleus muscle with two daily intragastric doses of propolis for two weeks restored capillary number, capillary structure, capillary volume, and capillary to muscle fiber ratio through a mechanism that involves inhibition of anti-angiogenic factors and activation of pro-angiogenic factors (e.g., VEGF). The relative muscle-to-body weight in treated animals was higher than in the unloaded control animals, and the number of TUNEL-positive apoptotic endothelial cells in the soleus muscle was similar to that in the normal control animals [110]. Likewise, bee pollen (both neat and processed) increased blood vessels in the gastrocnemius muscle of rats undergoing muscle injury because of vigorous exercise [90]. Treating C2C12 myoblasts with propolis ethanolic extract increased VEGF production [108]. VEGF is a pro-angiogenic factor that contributes to angiogenesis by recruiting endothelial cells and promoting their differentiation to form new vascular networks. VEGF protects skeletal muscle undergoing unloading against the progression of capillary regression [110]. Its expression in skeletal muscle and associated angiogenic response increase following exercise due to change in the activity of HIF-1α and AMPK. It promotes the generation of ATP following mitochondrial biogenesis in order to meet oxygen demand [158]. Altogether, these reports signify that bee products and endurance exercise share common mechanisms to produce their vitality effects in skeletal muscle.\n\n4.10. Improving the Composition of Gut Microbiome\nBee products such as royal jelly and propolis display potent antifungal, bactericidal, microbicidal, anti-inflammatory, antioxidant, and healing effects [2,66]. Most bee products investigated in this review were administered orally. Therefore, it is likely that their therapeutic effects may start locally within the GI tract, which frequently undergoes propagation of harmful endobacteria, inflammation, aberrations, and permeability in advanced age [10,24,152]. In this respect, Roquetto and colleagues [116] supplemented C57BL/6 mice on HFD with crude propolis (0.2%) for two and five weeks. HFD increased the proportion of the phylum Firmicutes as well as levels of circulating lipopolysaccharide (LPS) and inflammatory biomarkers. DNA sequencing for the 16S rRNA of the gut microbiota revealed that five weeks of propolis treatment rendered the microbiota profile almost normal. Compared with untreated mice, propolis-supplemented animals demonstrated lower levels of serum triacylglycerols, glucose, and circulating LPS, along with reduced expression of TLR4 and inflammatory cytokines in skeletal muscle [116].\nLactic acid bacteria profusely exist in bee saliva and all bee products [36,83,84]. Various species of lactic acid bacteria have been experimentally used to correct GI dysbiosis and related muscle wasting [159,160]. Moreover, oligosaccharides have been chemically isolated from bee products [32,161]. These api-materials are classified as prebiotics, fermented non-digestible compounds that promote the proliferative activity of health-promoting bacteria [24,161]. Supplementing frail old adults with fructooligosaccharides expressed positive effects on skeletal muscle strength (handgrip) and endurance (exhaustion) [162]. On the other side, microbiome of the gut can affect the biological activity of bee products. The literature shows that certain endobacteria transform dietary polyphenols into phenolic acids, which can easily access the circulation and then cross the blood brain barrier to produce therapeutic effects [163]. 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Mechanisms of Action of Royal Jelly, Bee Pollen, and Propolis in Sarcopenia\nRelatively few studies have explored the mechanism through which royal jelly, bee pollen, and propolis may be beneficial for sarcopenia. In vivo and in vitro studies included in this review uncovered a number of inter-related cellular and molecular events that underlie the effect of these bee products on skeletal muscle including suppression of catabolic genes, counteracting metabolic abnormalities, inflammation, and oxidative damages as well as enhancement of motor neuronal regeneration, promotion of stem cell function, and correction of the structure of gut microbiome (Figure 1, Panel D). These mechanisms are exclusively described in the coming paragraphs.\n\n4.1. Modulating Inflammatory Responses in Skeletal Muscle\nThe role that inflammation plays in skeletal muscle is not quite clear as it looks. Inflammatory mediators behave in a dual fashion in muscle cells. During injury, cytokines and chemokines stimulate muscle repair and regeneration via activation of myoblasts, a core event in muscle remodeling [108]. Similarly, serum and muscle levels of IL-6 temporarily increase following physical exercise, and IL-6 blocks the activity of catabolic cytokines such as TNF-α. On the other hand, chronic inflammation in muscle cells, which correlates with persistent mitochondrial dysfunction and metabolic dysregulation, pathologically activates muscle fiber transformation and atrophy, eventually resulting in the development of sarcopenia [23,114]. It seems that bee products also act dually in skeletal muscle: they support the activity of cytokines that promote muscle remodeling [108] and suppress muscle-consuming cytokines [38,101,108]. In this regard, treating undifferentiated C2C12 myoblasts with ethanolic extracts of Brazilian propolis (100 μg/mL for 8 h) triggered the migration of RAW264 macrophage and increased their production of angiogenic factors (e.g., vascular endothelial growth factor A (VEGF-A) and metalloproteinase-12 (MMP-12)), chemokines (e.g., CCL-2 and CCL-5), and cytokines (e.g., IL-6, which increased by 40-folds). Propolis inhibited the expression of IL-1β and TNF-α at 4, 8, and 12 h of incubation. These effects were nuclear factor kappa B (NF-κB)-dependent given that propolis simultaneously increased nuclear translocation of p65 and p50 NF-κB proteins 3 h after treatment. Meanwhile, inhibiting IκB kinase (IKK) by BMS-345541 profoundly hindered the effect of propolis on the expression of CCL-2, CCL-5, and IL-6 by 66%, 81%, and 69%, respectively. Propolis also enhanced the expression of MAIL/IκBζ. This molecule modulates chromatin and selectively induces the production of IL-6, leukemia inhibitory factor (LIF), and CCL-2 [108].\nChronic muscle tissue infiltration by inflammatory cells (e.g., leukocytes, neutrophils, and monocytes) activates oxidative and inflammatory signaling cascades that degrade cellular structures and promote necrosis such as inducible nitric oxide synthase (iNOS) and NF-kB [90,101,115]. CAPE and high levels (200 and 300 mg/kg) of crude and processed bee pollen reduced inflammatory cell infiltration into the gastrocnemius muscle of rats with muscle injury induced by eccentric exercise and ischemia reperfusion [90,101,102]. This effect was revealed by lower activity of myeloperoxidase, an indicator of neutrophil sequestration [101,102]. As such, CAPE and bee pollen not only suppressed lipid peroxidation (lower levels of malondialdehyde, MDA) but also inhibited the activity of myostatin and the production of muscle depleting cytokines and chemokines such as IL-1β, α2-macroglobulin, and monocyte chemotactic protein 1 (MCP-1) [36,38,90,101]. The underlying mechanism entailed downregulation of nuclear p65NF-κB and blockage of its consensus binding sites in skeletal muscle [101]. As a result, bee products increased muscle mass both in sarcopenic obese rat and malnourished old rats [36] and restored the structure of myofibers (despite the persistence of necrosis) compared with untreated eccentric exercising animals, which demonstrated necrotic and fragmented myofibers [90].\nRoyal jelly downregulated the activity of tumor necrosis factor receptor 1 (TNFR1) in the adipose tissue of aged obese rats receiving HFD [100]. TNFR1 interacts with TNFR2 to negatively regulate toll-like receptors (TLR) and Nod-like receptor signaling and stimulate excessive release of cytokines via activation of key inflammatory pathways such as NF-κB [107]. Mitigation of TNFR1 was associated with a significant increase of the weight of hind limb muscle and reductions in insulin levels, homeostatic model assessment of insulin resistance (HOMA-IR), serum lipids, muscle triglyceride levels, body weight gain, and abdominal fat weight. Therefore, royal jelly may protect against muscle loss in conditions involving impairment of the adipokine profile mainly through suppression of inflammatory responses associated with high fat mass, which is followed by correction of metabolic irregularities [100].\n\n4.2. Counteracting Oxidative Stress in Skeletal Muscle\nHigh production of reactive oxygen species (ROS) in skeletal muscle tissues has serious destructive effects, which alter the integrity of skeletal muscle resulting into fatigue, muscle wasting, and muscle weakness [90,101]. Sources of intramuscular ROS are numerous including mitochondrial dysfunction (e.g., alteration of mitochondrial enzymes in the respiratory chain as well as enzymes responsible for β-oxidation), neutrophil infiltration, and the activity of cytokines and major muscle degrading molecules such as myostatin [21,36,38,101,102,118]. Oxidative and nitrosative damages in skeletal muscle tissues are mediated by the activity of numerous pro-oxidant enzymes that are associated with inflammatory processes such as cyclooxygenase-2 (COX-2) and iNOS [101]. ROS triggers the activity of corrosive molecules such as poly (ADP-ribose) polymerase (PARP), xanthine oxidase, and adenosine deaminase, which contribute to DNA damage, lipid peroxidation (e.g., increased MDA), and protein nitrotyrosylation as well as ATP catabolism in muscle tissues [101,102].\nRoyal jelly enhanced the activity of antioxidant enzymes and suppressed lipid peroxidation in a d-galactose induced model of aging [95]. Two weeks of propolis treatment in rats undergoing hind limb unloading significantly reduced nuclear ROS levels and numbers of apoptotic endothelial cells in the soleus muscle to levels similar to normal rats [110]. Moreover, propolis significantly suppressed MDA activity in skeletal muscle and increased liver levels of SOD as well as gastrocnemius muscle levels of SOD, glutathione peroxidase and catalase in rats on eccentric exercise training (70% VO2max treadmill running exercise for 60 min) compared with rats receiving exercise alone or no treatment [109]. In addition, intraperitoneal pre-administration of CAPE (60 min before induction of ischemia reperfusion) significantly ameliorated the effects associated with high ROS levels, which accompany acute ischemia such as protein peroxidation and ATP catabolism in the gastrocnemius muscle [102].\nBee products probably reduced ROS production via regulation of the activity of mitochondrial enzymes. Royal jelly increased the maximal activity of citrate synthase (CS) and β-hydroxyacyl coenzyme A dehydrogenase (β-HAD) in the soleus muscle of rats on endurance training [106]. Bee pollen restored mitochondrial complex-I, -II, -III, and -IV enzyme activity to normal, increased SOD and glutathione, and reduced MDA, NO, and total protein content in the gastrocnemius muscle of rats on exhaustive exercise [90]. It also increased the activity of CS and complex IV in malnourished old rats via a mechanism that involved activation of mTOR [36]. mTOR is a major signaling pathway that regulates various signaling cascades involved in metabolism and autophagy such nuclear respiratory factor 2 (NRF2) [2]. Therefore, it is possible that the antioxidant activity demonstrated by bee products, particularly that expressed in the mitochondria, is associated with their metabolic and hypoglycemic activities. For instance, 10-HDA increased expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) in skeletal muscle of diabetic mice [112,119]. Similarly, aged mice treated with amino acids similar to those found in royal jelly demonstrated improved size of muscle fiber by increasing PGC-1α mRNA levels. PGC-1α functions as a key regulator of sirtuin 1, which limits ROS production through stimulation of mitochondrial biogenesis and ROS defense system, thus protecting metabolically active tissues against oxidative damage [120]. Mechanistically, when PGC-1α gets activated, it interacts with other bioactive molecules such as muscle-specific transcription factors to stimulate the expression of genes that induce mitochondrial oxidative metabolism in brown fat and fiber-type switching in skeletal muscle [121].\nThe antioxidant activity of royal jelly and CAPE might be related to their strong capacity to activate the master redox-active NRF2 signaling pathway [73,122], which stimulates the production of internal antioxidants such as heme oxygenase-1 (HO-1), which scavenge free radicals [123]. Meanwhile, NRF2 and HO-1 block ROS production indirectly via suppression of inflammatory reactions [122]. In this context, CAPE reduced degenerative myopathy in rats on eccentric exercise via a complex mechanism that involved inhibition of NF-κB and its downstream pro-oxidant COX-2 and iNOS [101]. Correspondingly, CAPE decreased markers of oxidative cellular damages (protein carbonyl, protein nitrosylation, xanthine oxidase, and adenosine deaminase) associated with ischemia reperfusion and eccentric exercise in the gastrocnemius muscle [101,102,103]. In this regard, CAPE operated via a mechanism that involved inhibition of neutrophil and leukocyte infiltration into the gastrocnemius muscle, which was associated with decreased levels of myeloperoxidase. Myeloperoxidase contributes to excessive production of ROS and oxidative organ damage through a mechanism that embroils increased synthesis of hypochlorous acid [101,102]. Furthermore, CAPE accelerated purine salvage for ATP synthesis and inhibited ROS-induced lipid peroxidation via attenuation of the activity of adenosine deaminase [102].\nIn summary, the reported antioxidant effects of bee products were multifaceted involving increased production of antioxidant enzymes [90,95,109,110], and decreased ROS production [90,101,102,103,110] (secondary to reduction of inflammatory cell infiltration into skeletal muscle) [90,101,102,103], and restoration of mitochondrial activity [36,90,106].\n\n4.3. Metabolic Regulation\nSkeletal muscle is the main tissue that utilizes insulin for glucose uptake. Insulin regulates mitochondrial oxidative phosphorylation of proteins in human skeletal muscle and contributes to calcium mobilization from the sarcoplasmic-endoplasmic reticulum to mitochondria to stimulate the translocation of glucose transporter 4 (GLUT4) to the cell surface for glucose uptake. This process improves muscle protein synthesis in healthy people when the delivery of amino acids to skeletal muscle is increased, eventually leading to increased muscular mass [124,125,126]. Insulin resistance and glucose intolerance increase with old age evoking muscle loss. In this respect, hypoglycemic agents such as metformin can improve skeletal muscle metabolism via activation of adenosine monophosphate activated protein kinase (AMPK) [21].\nAMPK, a heterotrimeric complex that consists of a catalytic subunit and two regulatory subunits, is an intracellular energy sensor that regulates glucose and lipid metabolism. It gets activated when cellular energy is depleted through allosteric binding of AMP or phosphorylation by AMPK kinase at Thr172 of the catalytic subunit by AMPK kinase. Upregulated AMPK activates signaling pathways that generate ATP from glucose and fatty acid oxidation, and it simultaneously blocks signaling that contributes to the synthesis of cholesterol, fatty acid, and triacylglycerol [111]. In addition, AMPK masters numerous signaling cascades such as Forkhead Box O transcription factor (FOXO) and AKT/mTOR, which regulate the expression of genes associated with inflammation, oxidative stress, mitochondrial function, autophagy, metabolism, and apoptosis [127,128].\nThe molecular events involved in the effect of bee products on catabolic genes and anabolic resistance in skeletal muscle could be much related to their hypoglycemic effects, which positively affect the quality of skeletal muscle. Evidence signifies a positive effect of royal jelly acid (10-HDA) on inflammation and autophagy via upregulation of AMPK, which subsequently alters NF-κB and NLRP3 inflammasome-IL1β signaling [129]. Positive effects of whole royal jelly on skeletal muscle are associated with improved insulin signaling [96,100]. In one study, royal jelly improved serum IGF-1 levels in aged rats and increased AKT signaling in satellite cells extracted from aged rats in a separate in vitro investigation [96]. In another study, royal jelly decreased fat mass and improved anabolic resistance in the skeletal muscle of old obese rats on HFD via downregulation of inflammatory responses in adipose tissue as indicated by downregulation of TNFR1. This effect was associated with enhanced sensitivity to insulin—portrayed by reduction of serum insulin level and HOMA-IR [100].\nJapanese researchers proved that oral consumption of royal jelly and 10-HDA induced mitochondrial adaptation in the soleus muscle when accompanied with endurance training. These compounds also enhanced glucose uptake in skeletal muscle by inducing the phosphorylation of AMPK [106,112], an effect that was mediated by the upstream kinase Ca²⁺/calmodulin-dependent kinaseβ—independently of changes in AMP:ATP ratio and the liver kinase B1 pathway. Activation of AMPK was followed by translocation of GLUT4 to the plasma membrane of L6 myotubes [106]. It is note-worthy that effects of royal jelly on mitochondrial biogenesis under endurance training were muscle-specific. In this respect, neither endurance training nor royal jelly alone had an effect on the maximal activities of CS and β-HAD—the enzyme that catalyzes the rate-limiting step of β-oxidation of long-chain fatty acids—in the soleus muscle, which comprises type I fiber (around 35–45%) and type IIa (around 35–50%). On the other hand, royal jelly enhanced the activity of these enzymes in the soleus muscle of mice on endurance training. Of interest, endurance training increased the activity of CS and β-HAD in the plantaris and tibialis anterior muscles (which are mainly type II fiber with a total percentage of type IIb and type IIx fiber types of 90%) while royal jelly failed to exert an effect on these muscles in sedentary mice [106]. Nonetheless, the observed effects of royal jelly in the soleus muscle represent a merit. This is mainly because the oxidative type I fibers (e.g., soleus muscle) naturally undergo higher protein turnover (especially degradation), which makes them unable to grow in size or respond properly to insufficient nutrient intake [130].\nSeveral lines of evidence indicate that propolis may affect muscle quality through the regulation of glucose metabolism [69,70,109,111]. This effect was vividly depicted in vivo by increased glycogen level in skeletal muscle and reduced serum levels of glucose and insulin [109]. Same as insulin, ethanolic extracts of propolis and CAPE induced glucose uptake [69,70,111] and potentiated insulin-mediated AKT activation and glucose uptake in differentiated L6 myoblast cells [111]. Likewise, Italian propolis at concentrations of 0.1 and 1 mg/mL as well as 4-geranyloxyferulic acid and auraptene (2 oxyprenylated phenylpropanoids, which are abundant in propolis) remarkably increased GLUT4 translocation to the plasma membrane and accelerated GLUT4-mediated glucose uptake in L6 skeletal myoblasts. The effect of propolis at a concentration of 11 mg/mL was significantly superior to the effect of insulin (0.1 μM), which was used as a positive control [69].\nSimilar to royal jelly, the effects of propolis (1 μg/mL), CAPE (10 μM), artepillin C, coumaric acid, and kaempferide on glucose metabolism occurred via activation of AMPK. These effects were comparable to those of 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), a potent AMPK activator. In the meantime, co-treatment with inhibitors of AMPK (e.g., compound C) and of phosphatidylinositol 3-kinase (PI3K) (e.g., LY-294002) blocked the effects of CAPE [70,111]. Phosphorylation of AMPK results in activation of the insulin receptor (IR) and subsequent phosphorylation of PI3K followed by activation of AKT and protein kinase C (PKC) leading to GLUT4 translocation and subsequent activation of several molecules that modulate insulin-stimulated glucose transport, eventually leading to glucose influx into cells of several tissues such as skeletal muscle and adipose tissue [69,70,111]. It is worth noting that the effects of CAPE on AMPK and AKT were quick (within 1 h and 3 min, respectively), and they vanished quickly (both molecules returned back to their basal levels within 12 h and 30 min, respectively) [111].\n\n4.4. Enhancement of Muscle Protein Synthesis\nImbalance between muscle protein synthesis and degradation is associated with low protein intake and altered efficiency of the GI tract in old age, which triggers skeletal muscle loss and poor physical performance [36,40], given that proteins are the main building blocks of muscle myofibers. Moreover, transmembrane proteins and micro-peptides (e.g., myomixer and myomaker/Tmem8c) contribute to the formation of myofibers by promoting myoblast fusion via a mechanism that involves appropriate localization of Tmem8c at the plasma membrane of myoblasts allowing trafficking related to palmitoylation of C-terminal cysteine residues and C-terminal leucine [17]. Amino acid supplements (e.g., leucine, a master dietary regulator of muscle protein turnover, and its metabolite β-hydroxy β-methylbutyrate) and early refeeding with high protein diet (especially fast digestive proteins) can preserve muscle mass and function, revert sarcopenia, and enhance mobility and quality of life (QoL) by correcting age-related nutritional deficiencies, muscle protein turnover, and immune dysregulation—these effects are even greater when combined with other nutrients like vitamin D or omega 3 fatty acids as well as with physical exercise [6,131,132,133,134,135,136,137,138].\nResearch indicates that age-related skeletal muscle wasting results mainly from insufficient delivery of amino acids to skeletal muscle due to dysregulations in the activity of mTORC1- and activating transcription factor-4 (ATF4)-mediated amino acid sensing pathways. Meanwhile, interventions that ameliorate age-related damages in skeletal muscle operate primarily by reversing alterations in the delivery of amino acids to skeletal muscle via upregulation of mTORC1 and/or ATF4 [139]. mTORC1 is a nutrient sensing protein that acts as a core regulator of protein metabolism. It is sensitive to amino acids, energy status (ATP), stress (e.g., oxidative stress), and growth factors (e.g., insulin), which all can regulate its signaling [2,136]. Nevertheless, bioavailability of amino acids is necessary for growth factors to effectively activate mTORC1. Even more, amino acids on their own can adequately activate mTORC1 [136]. Evidence from preclinical and human studies confirms that ingestion of essential amino acids (similar to those found in royal jelly and bee pollen such as valine) increases cellular bioavailability of amino acids, which is associated with activation of the endothelial nitric oxide synthase (eNOs) pathway. eNOs further upregulates mTORC1 kinase. Translocation of mTORC1 from the cytosol to the surface of lysosomes is associated with improved mitochondrial biogenesis and cellular oxidative capacity in skeletal muscle due to activation of its substrates: P70 ribosomal proteins S6 kinase (S6K) and eukaryotic translation initiation 4E-binding protein 1 (eIF4E, also known as 4eBP1) [120,135,136].\nAs shown in Table 1, royal jelly and 10-HDA significantly increased muscle mass [54,96,100] and improved motor performance in aged rats [95,98,99]. In addition, dietary supplementation with monofloral bee pollen significantly improved the rate of muscle protein synthesis and restored muscle mass in emaciated old rats via upregulation of mTOR and two related downstream controllers of protein translation: p70S6k and 4eBP1, which were suppressed in malnourished old rats [36]. Although propolis improved various muscle-related parameters, its effect on muscle mass in rodents was limited—relative to royal jelly and bee pollen. However, it fostered muscle protein deposition in post-larva Nile tilapia [104]. Moreover, milk naturally enriched with PUFA and polyphenols from propolis remarkably increased the weight of the gastrocnemius muscle of growing obese rats while whole milk and milk enriched with PUFA only could not express any effect on skeletal muscle [105]. Therefore, this finding denotes that propolis could have enhanced the delivery of amino acids available in milk to skeletal muscle leading to its growth. Altogether, it is likely that the observed anabolic effects of royal jelly and bee pollen are associated with their high content of proteins and amino acids [32,36,83,84,85,86].\n\n4.5. Suppression of Catabolic Activity in Skeletal Muscle\nSkeletal muscle tissues represent the largest protein store in the human body (30–45% of total protein). Muscular mass, strength, and functions are greatly governed by the rates of muscle protein synthesis and turnover [124]. Muscle protein metabolism is regulated by the interaction of a wide range of genes. Aging is associated with various stresses, which increase the expression of catabolic genes such as E3 ubiquitin ligases MuRF1 and atrogin-1 (MAFbx). These genes heighten the occurrence of age-related muscular atrophy [97]. Oral consumption of royal jelly by aged HET mice resulted in lower levels of catabolic genes (e.g., MuRF1 and MAFbx), which were similar to those in young mice. In the meantime, the expression of these genes in the control mice was high indicating that royal jelly can delay age-related muscular apoptosis by suppressing the activity of catabolic genes [97]. Two other studies reported that CAPE suppressed catabolism that contributed to degenerative myopathy in the gastrocnemius muscle of rats undergoing eccentric exercising or femoral artery ligation as reflected by decreased serum levels of creatine kinase, a marker of muscular proteolysis [101,102,103]. Apart from skeletal muscle, CAPE was reported to protect heart muscle against age-related deteriorations such as accumulation of lipofuscin, nuclear irregularity, mitochondrial degeneration, and myofilament disorganization and disruption [33].\nThe molecular mechanism underling blockage of muscle proteolysis by bee products in sarcopenic rodents involves an interplay of various signaling pathways. Royal jelly and bee pollen activated mTOR and its substrate AKT, which are suggested to inhibit muscular proteolysis [36,96]. Similar to the effect of royal jelly on catabolic genes in HET mice, treating both L6 myoblasts and rats with propolis, CAPE, and kaempferide resulted in potent activation of AKT in a PI3K-dependent manner [111], in addition to phosphorylation of IR, PI3K, and AMPK [70]. AKT, a key substrate of mTORC2, is a conserved serine/threonine nutrient sensing protein kinase that belongs to the PI3k-related protein kinase family. Upon presence of growth factors, PI3k gets activated by IR substrate resulting in stimulation of a series of signaling cascades that involve activation of AKT, which leads to further activation of mTORC1. mTORC1 activates the phosphorylation of two main regulators of cap-dependent protein synthesis: S6K and eIF4E [2,140]. In addition, mTORC1 contributes to autophagy—a turnover process that involves clearance of dysfunctional organelles and long-lived protein aggregations with provision of energy and macromolecular precursors in return—by binding with AMPK resulting in phosphorylation of autophagy genes such as Unc51-like kinase 1 at different sites [140]. In fact, royal jelly is reported to fine-tune the transcriptional activity of the FOXO through modulating the activity of insulin/IGF-1 signaling [141]. FOXO plays a major role in the activation of AKT pathway, which implicates regulation of multiple stress–response pathways such as ROS detoxification and DNA repair and translation. In addition, the FOXOs family exerts a direct effect on certain muscle atrophy genes such as MUSA1 and a formerly uncharacterized ligase known as Specific of Muscle Atrophy and Regulated by Transcription (SMART) [142].\n\n4.6. Enhancement of Stem Cell Function\nReduction of the number and functional capacity of the muscle satellite cells is considered a core contributor to the development of age-related muscular dysfunction [96]. Induction of myogenesis via in vivo reprogramming of muscle satellite cells is a currently studied strategy that has not been successfully used for sarcopenia treatment yet [143]. On the other hand, treating sarcopenic rats with both royal jelly and pRJ was reported to increase the number of Pax7-positive satellite cells in vivo and in vitro (pRJ only). pRJ induced self-renewal of satellite cells via activation of AKT signaling [96,97]. AKT activity was associated with activation of IGF-1 as indicated by increased serum levels of IGF-1. IGF-1 plays a crucial rule in the activation of various signaling pathways; it is believed to be a major mediator of muscle growth and repair that functions by stimulating the proliferation and differentiation of satellite cells into myotubes, albeit the exact mechanism is not clear yet [96]. Similarly, pRJ activated AKT-signaling pathway in satellite cells culture, which was associated with increased proliferation of myosatellite cells and their differentiation into myotubes—an effect that is contradictory to muscle loss. AKT is thought to contribute to the synthesis of muscular proteins and inhibition of muscle proteolysis [96].\n\n4.7. Counteracting Glycation Stress\nOxidative stress, inflammation, and insensitivity to insulin, which accompany advanced age, contribute to the production of advanced glycation end products (AGEs) via enhancement of the activity of the Receptor for Advanced Glycation End products (RAGE) [144,145]. AGEs destroy the protein and lipid ingredients of muscle tissues by promoting the production of destructive molecules such as free radicals and inflammatory cytokines [101,102,113]. Thanks to their potent antioxidant properties, polyphenolic compounds exert multifaceted anti-glycation functions. On one hand, they scavenge free-radicals and chelate transition metals that are involved in the synthesis of dicarbonyl intermediates subsequently resulting in inhibition of the formation of AGEs. On the other hand, polyphenolic compounds antagonize AGE receptors, mainly RAGE, and facilitate the removal of already formed a,b-dicarbonyl intermediates such as methylglyoxal, promoting the degradation of AGEs [37,38,146]. Royal jelly is reported to downregulate the activity of RAGE, the main receptor for AGEs, in an aged model of cognitive impairment [147]. However, its anti-glycation effect has not been investigated in skeletal muscle yet. Propolis exhibits strong anti-AGE properties, which are superior to those of quercetin or chlorogenic acid, well-known natural AGE inhibitors. Its flavonoid fraction potently impedes the synthesis of AGEs by trapping dicarbonyl intermediates [37]. Table 1 shows that propolis accelerated AGEs clearance in a model of muscle aging induced by administration of a precursor of AGEs (methylglyoxal) via activation of glyoxalase 1, an enzyme that eliminates dicarbonyl compounds (key elements of AGEs) [38]. CAPE inhibited the production of AGEs-related molecules such as protein carbonyl in the gastrocnemius muscle of rats via blockage of the activity of xanthine oxidase and adenosine deaminase [101,102,103]. The latter negatively affects insulin signaling and promotes the development of hyperglycemia, which represents a favorable condition for the production of AGEs [148]. However, propolis could not counteract the wasting effects of AGEs that already occurred in the extensor digitorum longus muscle though it tended to restore soleus muscle mass. This finding denotes that different muscle tissues respond differently to treatment, probably based on their ratio of type I to type II fibers. It also signifies the importance of early use of bee products (e.g., propolis) for the prevention of AGEs formation in skeletal muscle in people with high risk for AGEs formation such as diabetics [38].\n\n4.8. Neuronal Regeneration\nNeuronal denervation is a key factor that contributes to skeletal muscle loss, and it is related to a plethora of pathological conditions [3,149]. Experimental induction of oxidative stress and inflammation results in skeletal muscle atrophy through induction of denervation e.g., of sciatic nerve [150]. Injuries of peripheral nerves (e.g., sciatic nerve) interrupt mechanical transmission and microvasculation of the nerve and induce reperfusion. Reperfusion involves pooling of oxygen and nutrients promoting high emission of free radicals, which attack protein and lipid contents surrounding the injury site resulting in excessive tissue loss [113]. Likewise, alterations in gut microbiome in aged rats are associated with alterations in serum level of vitamin B12 and fat metabolism as well as reductions in the gastrocnemius muscle mass and sciatic response amplitude [151]. Furthermore, dysregulation of insulin-mediated GLUT4 activity in certain areas of the central nervous system impairs neuronal metabolism and plasticity [69]. Meanwhile, activation of PGC-1α, a core regulator of mitochondrial content and oxidative metabolism, increases muscle fiber resistance to denervation and atrophy through downregulation of two ubiquitin-ligases involved in the ubiquitin-proteasome pathway: MuRF1 and Atrogin-1 [1,152].\nPropolis treatment for four weeks restored gastrocnemius muscle weight and improved functional performance (e.g., walking) in rats with crush injury of the sciatic nerve. Effects of propolis were associated with increased nerve healing and regeneration as depicted by faster healing of the myelin sheath and ultra-structurally normal unmyelinated axons and Schwann cells. Investigations of motor conduction from the sciatic nerve to the gastrocnemius muscle indicated that nerve recovery induced by propolis treatment promoted optimal physical functioning by allowing motor conduction to reach the gastrocnemius muscle [113]. Neuroprotective effects of propolis in motor neurons are documented in the literature. Both kaempferide and kaempferol protected motor neurons against atrophy induced by the toxic copper-zinc superoxide dismutase in amyotrophic lateral sclerosis—a serious neurodegenerative disease that involves selective and progressive loss of motor neurons [65]. In addition, orally administered chrysin (a flavonoid that is copious in propolis) to rats intoxicated by 6-hydroxidopamine showed neuroprotective effects by mitigating neuroinflammation, enhancing levels of neurotrophins and neuronal recovery factors (e.g., brain derived neurotrophic factor and glial cell line-derived neurotrophic factor), and maintaining integrity of dopaminergic neurons resulting in better motor performance [72].\nThe release of acetylcholine (a neurotransmitter that regulates cognition) at the synaptic cleft of the neuromuscular junction is essential for motor neurotransmission, which controls excitation-contraction coupling and cell size. However, free radicals, cytokines, and AGEs impair neurotransmission by altering the production of acetylcholine [6,21,149,153]. On the other hand, upregulation of acetylcholine receptors improves neurotransmission [154]. Treatment with royal jelly may correct acetylcholine neurotransmission given its high content of acetylcholine (4–8 mM) [60]. In addition, royal jelly, propolis, and bee pollen are rich in antioxidant elements that have a potential to scavenge ROS and mitigate other pathologies that contribute to acetylcholine deficiency (e.g., neuroinflammation) [73,101,102,103]. In this respect, treatment of experimental models of carrageenan-induced hind paw edema with hydroalcoholic extract of red propolis and its biomarker, formononetin, is reported to inhibit leukocyte migration and ameliorate inflammatory neurogenic pain induced by injections of formalin and glutamate [115]. However, investigations of the action of bee products on neurotransmission are very scarce.\n\n4.9. Improving Muscular Blood Supply\nAging is associated with higher onset of atherosclerosis and restenosis, which involve vascular and microvascular damages that result from hyperproliferation of vascular smooth muscle cells (VSMCs) [155]. Muscle unloading (e.g., in sedentary lifestyle) involves chronic neuromuscular inactivity, which results in reductions in capillary number, luminal diameter, and capillary volume as well as heightened production of anti-angiogenic factors, such as p53 and TSP-1 in skeletal muscle [110]. Microvascular alterations and impaired nitric oxide (NO) production are key causes of decreased blood flow to the skeletal muscle. Poor muscular blood supply induces muscle wasting via a mechanism that entails impaired glucose metabolism and suboptimal protein anabolism [156,157]. In addition, ischemic injury in skeletal muscle is associated with high ROS release from polymorphonuclear leukocytes, which infiltrate muscle tissues. Free radicals alter cellular structure and function by attacking lipid and protein biomolecules that exist in the structure of biological membranes, enzymes, and transport proteins [102]. Therefore, improving vascularization and blood supply to skeletal muscle is a possible mechanism for the prevention of muscle wasting.\nMitchell and colleagues examined changes in microvascular blood volume, microvascular flow velocity, and microvascular blood flow in the quadriceps muscle following treatment with 15 g of amino acids in young and old subjects (20–70 years old). They detected improvements in all the 3 parameters only in young groups, and those effects were associated with proper insulin activity. Thus, the authors suggested that refeeding effects on muscular blood supply may be hindered by dysfunctions in postprandial circulation and glucose dysregulation [157]. Bee products such as bee pollen and propolis have a potential to boost microcirculation and correct pathologies that contribute to vascular dysfunction such as hyperglycemia and dyslipidemia [36,155]. In this context, CAPE, one of the basic constituents of propolis, was reported to combat vascular damages by counteracting the proliferative activity of platelet-derived growth factor. The molecular mechanism involved inducing cell-cycle arrest in VSMCs via activation of p38mitogen-activated protein kinase (MAPK), which was associated with accumulation of hypoxia-inducible factor (HIF)-1α—mainly due to inhibition of HIF prolylhydroxylase, a key contributor to proteasomal degradation of HIF-1α—and subsequent induction of HO-1 [155]. In the same regard, supplementing rats undergoing capillary regression (resulting from two weeks of hind limb unloading) in the soleus muscle with two daily intragastric doses of propolis for two weeks restored capillary number, capillary structure, capillary volume, and capillary to muscle fiber ratio through a mechanism that involves inhibition of anti-angiogenic factors and activation of pro-angiogenic factors (e.g., VEGF). The relative muscle-to-body weight in treated animals was higher than in the unloaded control animals, and the number of TUNEL-positive apoptotic endothelial cells in the soleus muscle was similar to that in the normal control animals [110]. Likewise, bee pollen (both neat and processed) increased blood vessels in the gastrocnemius muscle of rats undergoing muscle injury because of vigorous exercise [90]. Treating C2C12 myoblasts with propolis ethanolic extract increased VEGF production [108]. VEGF is a pro-angiogenic factor that contributes to angiogenesis by recruiting endothelial cells and promoting their differentiation to form new vascular networks. VEGF protects skeletal muscle undergoing unloading against the progression of capillary regression [110]. Its expression in skeletal muscle and associated angiogenic response increase following exercise due to change in the activity of HIF-1α and AMPK. It promotes the generation of ATP following mitochondrial biogenesis in order to meet oxygen demand [158]. Altogether, these reports signify that bee products and endurance exercise share common mechanisms to produce their vitality effects in skeletal muscle.\n\n4.10. Improving the Composition of Gut Microbiome\nBee products such as royal jelly and propolis display potent antifungal, bactericidal, microbicidal, anti-inflammatory, antioxidant, and healing effects [2,66]. Most bee products investigated in this review were administered orally. Therefore, it is likely that their therapeutic effects may start locally within the GI tract, which frequently undergoes propagation of harmful endobacteria, inflammation, aberrations, and permeability in advanced age [10,24,152]. In this respect, Roquetto and colleagues [116] supplemented C57BL/6 mice on HFD with crude propolis (0.2%) for two and five weeks. HFD increased the proportion of the phylum Firmicutes as well as levels of circulating lipopolysaccharide (LPS) and inflammatory biomarkers. DNA sequencing for the 16S rRNA of the gut microbiota revealed that five weeks of propolis treatment rendered the microbiota profile almost normal. Compared with untreated mice, propolis-supplemented animals demonstrated lower levels of serum triacylglycerols, glucose, and circulating LPS, along with reduced expression of TLR4 and inflammatory cytokines in skeletal muscle [116].\nLactic acid bacteria profusely exist in bee saliva and all bee products [36,83,84]. Various species of lactic acid bacteria have been experimentally used to correct GI dysbiosis and related muscle wasting [159,160]. Moreover, oligosaccharides have been chemically isolated from bee products [32,161]. These api-materials are classified as prebiotics, fermented non-digestible compounds that promote the proliferative activity of health-promoting bacteria [24,161]. Supplementing frail old adults with fructooligosaccharides expressed positive effects on skeletal muscle strength (handgrip) and endurance (exhaustion) [162]. On the other side, microbiome of the gut can affect the biological activity of bee products. The literature shows that certain endobacteria transform dietary polyphenols into phenolic acids, which can easily access the circulation and then cross the blood brain barrier to produce therapeutic effects [163]. Hence, it is important that future investigations of bee products among sarcopenic subjects examine the effect of these products on the composition of GI microbial population and its association with muscle-related outcomes."}

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Mechanisms of Action of Royal Jelly, Bee Pollen, and Propolis in Sarcopenia\nRelatively few studies have explored the mechanism through which royal jelly, bee pollen, and propolis may be beneficial for sarcopenia. In vivo and in vitro studies included in this review uncovered a number of inter-related cellular and molecular events that underlie the effect of these bee products on skeletal muscle including suppression of catabolic genes, counteracting metabolic abnormalities, inflammation, and oxidative damages as well as enhancement of motor neuronal regeneration, promotion of stem cell function, and correction of the structure of gut microbiome (Figure 1, Panel D). These mechanisms are exclusively described in the coming paragraphs.\n\n4.1. Modulating Inflammatory Responses in Skeletal Muscle\nThe role that inflammation plays in skeletal muscle is not quite clear as it looks. Inflammatory mediators behave in a dual fashion in muscle cells. During injury, cytokines and chemokines stimulate muscle repair and regeneration via activation of myoblasts, a core event in muscle remodeling [108]. Similarly, serum and muscle levels of IL-6 temporarily increase following physical exercise, and IL-6 blocks the activity of catabolic cytokines such as TNF-α. On the other hand, chronic inflammation in muscle cells, which correlates with persistent mitochondrial dysfunction and metabolic dysregulation, pathologically activates muscle fiber transformation and atrophy, eventually resulting in the development of sarcopenia [23,114]. It seems that bee products also act dually in skeletal muscle: they support the activity of cytokines that promote muscle remodeling [108] and suppress muscle-consuming cytokines [38,101,108]. In this regard, treating undifferentiated C2C12 myoblasts with ethanolic extracts of Brazilian propolis (100 μg/mL for 8 h) triggered the migration of RAW264 macrophage and increased their production of angiogenic factors (e.g., vascular endothelial growth factor A (VEGF-A) and metalloproteinase-12 (MMP-12)), chemokines (e.g., CCL-2 and CCL-5), and cytokines (e.g., IL-6, which increased by 40-folds). Propolis inhibited the expression of IL-1β and TNF-α at 4, 8, and 12 h of incubation. These effects were nuclear factor kappa B (NF-κB)-dependent given that propolis simultaneously increased nuclear translocation of p65 and p50 NF-κB proteins 3 h after treatment. Meanwhile, inhibiting IκB kinase (IKK) by BMS-345541 profoundly hindered the effect of propolis on the expression of CCL-2, CCL-5, and IL-6 by 66%, 81%, and 69%, respectively. Propolis also enhanced the expression of MAIL/IκBζ. This molecule modulates chromatin and selectively induces the production of IL-6, leukemia inhibitory factor (LIF), and CCL-2 [108].\nChronic muscle tissue infiltration by inflammatory cells (e.g., leukocytes, neutrophils, and monocytes) activates oxidative and inflammatory signaling cascades that degrade cellular structures and promote necrosis such as inducible nitric oxide synthase (iNOS) and NF-kB [90,101,115]. CAPE and high levels (200 and 300 mg/kg) of crude and processed bee pollen reduced inflammatory cell infiltration into the gastrocnemius muscle of rats with muscle injury induced by eccentric exercise and ischemia reperfusion [90,101,102]. This effect was revealed by lower activity of myeloperoxidase, an indicator of neutrophil sequestration [101,102]. As such, CAPE and bee pollen not only suppressed lipid peroxidation (lower levels of malondialdehyde, MDA) but also inhibited the activity of myostatin and the production of muscle depleting cytokines and chemokines such as IL-1β, α2-macroglobulin, and monocyte chemotactic protein 1 (MCP-1) [36,38,90,101]. The underlying mechanism entailed downregulation of nuclear p65NF-κB and blockage of its consensus binding sites in skeletal muscle [101]. As a result, bee products increased muscle mass both in sarcopenic obese rat and malnourished old rats [36] and restored the structure of myofibers (despite the persistence of necrosis) compared with untreated eccentric exercising animals, which demonstrated necrotic and fragmented myofibers [90].\nRoyal jelly downregulated the activity of tumor necrosis factor receptor 1 (TNFR1) in the adipose tissue of aged obese rats receiving HFD [100]. TNFR1 interacts with TNFR2 to negatively regulate toll-like receptors (TLR) and Nod-like receptor signaling and stimulate excessive release of cytokines via activation of key inflammatory pathways such as NF-κB [107]. Mitigation of TNFR1 was associated with a significant increase of the weight of hind limb muscle and reductions in insulin levels, homeostatic model assessment of insulin resistance (HOMA-IR), serum lipids, muscle triglyceride levels, body weight gain, and abdominal fat weight. Therefore, royal jelly may protect against muscle loss in conditions involving impairment of the adipokine profile mainly through suppression of inflammatory responses associated with high fat mass, which is followed by correction of metabolic irregularities [100].\n\n4.2. Counteracting Oxidative Stress in Skeletal Muscle\nHigh production of reactive oxygen species (ROS) in skeletal muscle tissues has serious destructive effects, which alter the integrity of skeletal muscle resulting into fatigue, muscle wasting, and muscle weakness [90,101]. Sources of intramuscular ROS are numerous including mitochondrial dysfunction (e.g., alteration of mitochondrial enzymes in the respiratory chain as well as enzymes responsible for β-oxidation), neutrophil infiltration, and the activity of cytokines and major muscle degrading molecules such as myostatin [21,36,38,101,102,118]. Oxidative and nitrosative damages in skeletal muscle tissues are mediated by the activity of numerous pro-oxidant enzymes that are associated with inflammatory processes such as cyclooxygenase-2 (COX-2) and iNOS [101]. ROS triggers the activity of corrosive molecules such as poly (ADP-ribose) polymerase (PARP), xanthine oxidase, and adenosine deaminase, which contribute to DNA damage, lipid peroxidation (e.g., increased MDA), and protein nitrotyrosylation as well as ATP catabolism in muscle tissues [101,102].\nRoyal jelly enhanced the activity of antioxidant enzymes and suppressed lipid peroxidation in a d-galactose induced model of aging [95]. Two weeks of propolis treatment in rats undergoing hind limb unloading significantly reduced nuclear ROS levels and numbers of apoptotic endothelial cells in the soleus muscle to levels similar to normal rats [110]. Moreover, propolis significantly suppressed MDA activity in skeletal muscle and increased liver levels of SOD as well as gastrocnemius muscle levels of SOD, glutathione peroxidase and catalase in rats on eccentric exercise training (70% VO2max treadmill running exercise for 60 min) compared with rats receiving exercise alone or no treatment [109]. In addition, intraperitoneal pre-administration of CAPE (60 min before induction of ischemia reperfusion) significantly ameliorated the effects associated with high ROS levels, which accompany acute ischemia such as protein peroxidation and ATP catabolism in the gastrocnemius muscle [102].\nBee products probably reduced ROS production via regulation of the activity of mitochondrial enzymes. Royal jelly increased the maximal activity of citrate synthase (CS) and β-hydroxyacyl coenzyme A dehydrogenase (β-HAD) in the soleus muscle of rats on endurance training [106]. Bee pollen restored mitochondrial complex-I, -II, -III, and -IV enzyme activity to normal, increased SOD and glutathione, and reduced MDA, NO, and total protein content in the gastrocnemius muscle of rats on exhaustive exercise [90]. It also increased the activity of CS and complex IV in malnourished old rats via a mechanism that involved activation of mTOR [36]. mTOR is a major signaling pathway that regulates various signaling cascades involved in metabolism and autophagy such nuclear respiratory factor 2 (NRF2) [2]. Therefore, it is possible that the antioxidant activity demonstrated by bee products, particularly that expressed in the mitochondria, is associated with their metabolic and hypoglycemic activities. For instance, 10-HDA increased expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) in skeletal muscle of diabetic mice [112,119]. Similarly, aged mice treated with amino acids similar to those found in royal jelly demonstrated improved size of muscle fiber by increasing PGC-1α mRNA levels. PGC-1α functions as a key regulator of sirtuin 1, which limits ROS production through stimulation of mitochondrial biogenesis and ROS defense system, thus protecting metabolically active tissues against oxidative damage [120]. Mechanistically, when PGC-1α gets activated, it interacts with other bioactive molecules such as muscle-specific transcription factors to stimulate the expression of genes that induce mitochondrial oxidative metabolism in brown fat and fiber-type switching in skeletal muscle [121].\nThe antioxidant activity of royal jelly and CAPE might be related to their strong capacity to activate the master redox-active NRF2 signaling pathway [73,122], which stimulates the production of internal antioxidants such as heme oxygenase-1 (HO-1), which scavenge free radicals [123]. Meanwhile, NRF2 and HO-1 block ROS production indirectly via suppression of inflammatory reactions [122]. In this context, CAPE reduced degenerative myopathy in rats on eccentric exercise via a complex mechanism that involved inhibition of NF-κB and its downstream pro-oxidant COX-2 and iNOS [101]. Correspondingly, CAPE decreased markers of oxidative cellular damages (protein carbonyl, protein nitrosylation, xanthine oxidase, and adenosine deaminase) associated with ischemia reperfusion and eccentric exercise in the gastrocnemius muscle [101,102,103]. In this regard, CAPE operated via a mechanism that involved inhibition of neutrophil and leukocyte infiltration into the gastrocnemius muscle, which was associated with decreased levels of myeloperoxidase. Myeloperoxidase contributes to excessive production of ROS and oxidative organ damage through a mechanism that embroils increased synthesis of hypochlorous acid [101,102]. Furthermore, CAPE accelerated purine salvage for ATP synthesis and inhibited ROS-induced lipid peroxidation via attenuation of the activity of adenosine deaminase [102].\nIn summary, the reported antioxidant effects of bee products were multifaceted involving increased production of antioxidant enzymes [90,95,109,110], and decreased ROS production [90,101,102,103,110] (secondary to reduction of inflammatory cell infiltration into skeletal muscle) [90,101,102,103], and restoration of mitochondrial activity [36,90,106].\n\n4.3. Metabolic Regulation\nSkeletal muscle is the main tissue that utilizes insulin for glucose uptake. Insulin regulates mitochondrial oxidative phosphorylation of proteins in human skeletal muscle and contributes to calcium mobilization from the sarcoplasmic-endoplasmic reticulum to mitochondria to stimulate the translocation of glucose transporter 4 (GLUT4) to the cell surface for glucose uptake. This process improves muscle protein synthesis in healthy people when the delivery of amino acids to skeletal muscle is increased, eventually leading to increased muscular mass [124,125,126]. Insulin resistance and glucose intolerance increase with old age evoking muscle loss. In this respect, hypoglycemic agents such as metformin can improve skeletal muscle metabolism via activation of adenosine monophosphate activated protein kinase (AMPK) [21].\nAMPK, a heterotrimeric complex that consists of a catalytic subunit and two regulatory subunits, is an intracellular energy sensor that regulates glucose and lipid metabolism. It gets activated when cellular energy is depleted through allosteric binding of AMP or phosphorylation by AMPK kinase at Thr172 of the catalytic subunit by AMPK kinase. Upregulated AMPK activates signaling pathways that generate ATP from glucose and fatty acid oxidation, and it simultaneously blocks signaling that contributes to the synthesis of cholesterol, fatty acid, and triacylglycerol [111]. In addition, AMPK masters numerous signaling cascades such as Forkhead Box O transcription factor (FOXO) and AKT/mTOR, which regulate the expression of genes associated with inflammation, oxidative stress, mitochondrial function, autophagy, metabolism, and apoptosis [127,128].\nThe molecular events involved in the effect of bee products on catabolic genes and anabolic resistance in skeletal muscle could be much related to their hypoglycemic effects, which positively affect the quality of skeletal muscle. Evidence signifies a positive effect of royal jelly acid (10-HDA) on inflammation and autophagy via upregulation of AMPK, which subsequently alters NF-κB and NLRP3 inflammasome-IL1β signaling [129]. Positive effects of whole royal jelly on skeletal muscle are associated with improved insulin signaling [96,100]. In one study, royal jelly improved serum IGF-1 levels in aged rats and increased AKT signaling in satellite cells extracted from aged rats in a separate in vitro investigation [96]. In another study, royal jelly decreased fat mass and improved anabolic resistance in the skeletal muscle of old obese rats on HFD via downregulation of inflammatory responses in adipose tissue as indicated by downregulation of TNFR1. This effect was associated with enhanced sensitivity to insulin—portrayed by reduction of serum insulin level and HOMA-IR [100].\nJapanese researchers proved that oral consumption of royal jelly and 10-HDA induced mitochondrial adaptation in the soleus muscle when accompanied with endurance training. These compounds also enhanced glucose uptake in skeletal muscle by inducing the phosphorylation of AMPK [106,112], an effect that was mediated by the upstream kinase Ca²⁺/calmodulin-dependent kinaseβ—independently of changes in AMP:ATP ratio and the liver kinase B1 pathway. Activation of AMPK was followed by translocation of GLUT4 to the plasma membrane of L6 myotubes [106]. It is note-worthy that effects of royal jelly on mitochondrial biogenesis under endurance training were muscle-specific. In this respect, neither endurance training nor royal jelly alone had an effect on the maximal activities of CS and β-HAD—the enzyme that catalyzes the rate-limiting step of β-oxidation of long-chain fatty acids—in the soleus muscle, which comprises type I fiber (around 35–45%) and type IIa (around 35–50%). On the other hand, royal jelly enhanced the activity of these enzymes in the soleus muscle of mice on endurance training. Of interest, endurance training increased the activity of CS and β-HAD in the plantaris and tibialis anterior muscles (which are mainly type II fiber with a total percentage of type IIb and type IIx fiber types of 90%) while royal jelly failed to exert an effect on these muscles in sedentary mice [106]. Nonetheless, the observed effects of royal jelly in the soleus muscle represent a merit. This is mainly because the oxidative type I fibers (e.g., soleus muscle) naturally undergo higher protein turnover (especially degradation), which makes them unable to grow in size or respond properly to insufficient nutrient intake [130].\nSeveral lines of evidence indicate that propolis may affect muscle quality through the regulation of glucose metabolism [69,70,109,111]. This effect was vividly depicted in vivo by increased glycogen level in skeletal muscle and reduced serum levels of glucose and insulin [109]. Same as insulin, ethanolic extracts of propolis and CAPE induced glucose uptake [69,70,111] and potentiated insulin-mediated AKT activation and glucose uptake in differentiated L6 myoblast cells [111]. Likewise, Italian propolis at concentrations of 0.1 and 1 mg/mL as well as 4-geranyloxyferulic acid and auraptene (2 oxyprenylated phenylpropanoids, which are abundant in propolis) remarkably increased GLUT4 translocation to the plasma membrane and accelerated GLUT4-mediated glucose uptake in L6 skeletal myoblasts. The effect of propolis at a concentration of 11 mg/mL was significantly superior to the effect of insulin (0.1 μM), which was used as a positive control [69].\nSimilar to royal jelly, the effects of propolis (1 μg/mL), CAPE (10 μM), artepillin C, coumaric acid, and kaempferide on glucose metabolism occurred via activation of AMPK. These effects were comparable to those of 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), a potent AMPK activator. In the meantime, co-treatment with inhibitors of AMPK (e.g., compound C) and of phosphatidylinositol 3-kinase (PI3K) (e.g., LY-294002) blocked the effects of CAPE [70,111]. Phosphorylation of AMPK results in activation of the insulin receptor (IR) and subsequent phosphorylation of PI3K followed by activation of AKT and protein kinase C (PKC) leading to GLUT4 translocation and subsequent activation of several molecules that modulate insulin-stimulated glucose transport, eventually leading to glucose influx into cells of several tissues such as skeletal muscle and adipose tissue [69,70,111]. It is worth noting that the effects of CAPE on AMPK and AKT were quick (within 1 h and 3 min, respectively), and they vanished quickly (both molecules returned back to their basal levels within 12 h and 30 min, respectively) [111].\n\n4.4. Enhancement of Muscle Protein Synthesis\nImbalance between muscle protein synthesis and degradation is associated with low protein intake and altered efficiency of the GI tract in old age, which triggers skeletal muscle loss and poor physical performance [36,40], given that proteins are the main building blocks of muscle myofibers. Moreover, transmembrane proteins and micro-peptides (e.g., myomixer and myomaker/Tmem8c) contribute to the formation of myofibers by promoting myoblast fusion via a mechanism that involves appropriate localization of Tmem8c at the plasma membrane of myoblasts allowing trafficking related to palmitoylation of C-terminal cysteine residues and C-terminal leucine [17]. Amino acid supplements (e.g., leucine, a master dietary regulator of muscle protein turnover, and its metabolite β-hydroxy β-methylbutyrate) and early refeeding with high protein diet (especially fast digestive proteins) can preserve muscle mass and function, revert sarcopenia, and enhance mobility and quality of life (QoL) by correcting age-related nutritional deficiencies, muscle protein turnover, and immune dysregulation—these effects are even greater when combined with other nutrients like vitamin D or omega 3 fatty acids as well as with physical exercise [6,131,132,133,134,135,136,137,138].\nResearch indicates that age-related skeletal muscle wasting results mainly from insufficient delivery of amino acids to skeletal muscle due to dysregulations in the activity of mTORC1- and activating transcription factor-4 (ATF4)-mediated amino acid sensing pathways. Meanwhile, interventions that ameliorate age-related damages in skeletal muscle operate primarily by reversing alterations in the delivery of amino acids to skeletal muscle via upregulation of mTORC1 and/or ATF4 [139]. mTORC1 is a nutrient sensing protein that acts as a core regulator of protein metabolism. It is sensitive to amino acids, energy status (ATP), stress (e.g., oxidative stress), and growth factors (e.g., insulin), which all can regulate its signaling [2,136]. Nevertheless, bioavailability of amino acids is necessary for growth factors to effectively activate mTORC1. Even more, amino acids on their own can adequately activate mTORC1 [136]. Evidence from preclinical and human studies confirms that ingestion of essential amino acids (similar to those found in royal jelly and bee pollen such as valine) increases cellular bioavailability of amino acids, which is associated with activation of the endothelial nitric oxide synthase (eNOs) pathway. eNOs further upregulates mTORC1 kinase. Translocation of mTORC1 from the cytosol to the surface of lysosomes is associated with improved mitochondrial biogenesis and cellular oxidative capacity in skeletal muscle due to activation of its substrates: P70 ribosomal proteins S6 kinase (S6K) and eukaryotic translation initiation 4E-binding protein 1 (eIF4E, also known as 4eBP1) [120,135,136].\nAs shown in Table 1, royal jelly and 10-HDA significantly increased muscle mass [54,96,100] and improved motor performance in aged rats [95,98,99]. In addition, dietary supplementation with monofloral bee pollen significantly improved the rate of muscle protein synthesis and restored muscle mass in emaciated old rats via upregulation of mTOR and two related downstream controllers of protein translation: p70S6k and 4eBP1, which were suppressed in malnourished old rats [36]. Although propolis improved various muscle-related parameters, its effect on muscle mass in rodents was limited—relative to royal jelly and bee pollen. However, it fostered muscle protein deposition in post-larva Nile tilapia [104]. Moreover, milk naturally enriched with PUFA and polyphenols from propolis remarkably increased the weight of the gastrocnemius muscle of growing obese rats while whole milk and milk enriched with PUFA only could not express any effect on skeletal muscle [105]. Therefore, this finding denotes that propolis could have enhanced the delivery of amino acids available in milk to skeletal muscle leading to its growth. Altogether, it is likely that the observed anabolic effects of royal jelly and bee pollen are associated with their high content of proteins and amino acids [32,36,83,84,85,86].\n\n4.5. Suppression of Catabolic Activity in Skeletal Muscle\nSkeletal muscle tissues represent the largest protein store in the human body (30–45% of total protein). Muscular mass, strength, and functions are greatly governed by the rates of muscle protein synthesis and turnover [124]. Muscle protein metabolism is regulated by the interaction of a wide range of genes. Aging is associated with various stresses, which increase the expression of catabolic genes such as E3 ubiquitin ligases MuRF1 and atrogin-1 (MAFbx). These genes heighten the occurrence of age-related muscular atrophy [97]. Oral consumption of royal jelly by aged HET mice resulted in lower levels of catabolic genes (e.g., MuRF1 and MAFbx), which were similar to those in young mice. In the meantime, the expression of these genes in the control mice was high indicating that royal jelly can delay age-related muscular apoptosis by suppressing the activity of catabolic genes [97]. Two other studies reported that CAPE suppressed catabolism that contributed to degenerative myopathy in the gastrocnemius muscle of rats undergoing eccentric exercising or femoral artery ligation as reflected by decreased serum levels of creatine kinase, a marker of muscular proteolysis [101,102,103]. Apart from skeletal muscle, CAPE was reported to protect heart muscle against age-related deteriorations such as accumulation of lipofuscin, nuclear irregularity, mitochondrial degeneration, and myofilament disorganization and disruption [33].\nThe molecular mechanism underling blockage of muscle proteolysis by bee products in sarcopenic rodents involves an interplay of various signaling pathways. Royal jelly and bee pollen activated mTOR and its substrate AKT, which are suggested to inhibit muscular proteolysis [36,96]. Similar to the effect of royal jelly on catabolic genes in HET mice, treating both L6 myoblasts and rats with propolis, CAPE, and kaempferide resulted in potent activation of AKT in a PI3K-dependent manner [111], in addition to phosphorylation of IR, PI3K, and AMPK [70]. AKT, a key substrate of mTORC2, is a conserved serine/threonine nutrient sensing protein kinase that belongs to the PI3k-related protein kinase family. Upon presence of growth factors, PI3k gets activated by IR substrate resulting in stimulation of a series of signaling cascades that involve activation of AKT, which leads to further activation of mTORC1. mTORC1 activates the phosphorylation of two main regulators of cap-dependent protein synthesis: S6K and eIF4E [2,140]. In addition, mTORC1 contributes to autophagy—a turnover process that involves clearance of dysfunctional organelles and long-lived protein aggregations with provision of energy and macromolecular precursors in return—by binding with AMPK resulting in phosphorylation of autophagy genes such as Unc51-like kinase 1 at different sites [140]. In fact, royal jelly is reported to fine-tune the transcriptional activity of the FOXO through modulating the activity of insulin/IGF-1 signaling [141]. FOXO plays a major role in the activation of AKT pathway, which implicates regulation of multiple stress–response pathways such as ROS detoxification and DNA repair and translation. In addition, the FOXOs family exerts a direct effect on certain muscle atrophy genes such as MUSA1 and a formerly uncharacterized ligase known as Specific of Muscle Atrophy and Regulated by Transcription (SMART) [142].\n\n4.6. Enhancement of Stem Cell Function\nReduction of the number and functional capacity of the muscle satellite cells is considered a core contributor to the development of age-related muscular dysfunction [96]. Induction of myogenesis via in vivo reprogramming of muscle satellite cells is a currently studied strategy that has not been successfully used for sarcopenia treatment yet [143]. On the other hand, treating sarcopenic rats with both royal jelly and pRJ was reported to increase the number of Pax7-positive satellite cells in vivo and in vitro (pRJ only). pRJ induced self-renewal of satellite cells via activation of AKT signaling [96,97]. AKT activity was associated with activation of IGF-1 as indicated by increased serum levels of IGF-1. IGF-1 plays a crucial rule in the activation of various signaling pathways; it is believed to be a major mediator of muscle growth and repair that functions by stimulating the proliferation and differentiation of satellite cells into myotubes, albeit the exact mechanism is not clear yet [96]. Similarly, pRJ activated AKT-signaling pathway in satellite cells culture, which was associated with increased proliferation of myosatellite cells and their differentiation into myotubes—an effect that is contradictory to muscle loss. AKT is thought to contribute to the synthesis of muscular proteins and inhibition of muscle proteolysis [96].\n\n4.7. Counteracting Glycation Stress\nOxidative stress, inflammation, and insensitivity to insulin, which accompany advanced age, contribute to the production of advanced glycation end products (AGEs) via enhancement of the activity of the Receptor for Advanced Glycation End products (RAGE) [144,145]. AGEs destroy the protein and lipid ingredients of muscle tissues by promoting the production of destructive molecules such as free radicals and inflammatory cytokines [101,102,113]. Thanks to their potent antioxidant properties, polyphenolic compounds exert multifaceted anti-glycation functions. On one hand, they scavenge free-radicals and chelate transition metals that are involved in the synthesis of dicarbonyl intermediates subsequently resulting in inhibition of the formation of AGEs. On the other hand, polyphenolic compounds antagonize AGE receptors, mainly RAGE, and facilitate the removal of already formed a,b-dicarbonyl intermediates such as methylglyoxal, promoting the degradation of AGEs [37,38,146]. Royal jelly is reported to downregulate the activity of RAGE, the main receptor for AGEs, in an aged model of cognitive impairment [147]. However, its anti-glycation effect has not been investigated in skeletal muscle yet. Propolis exhibits strong anti-AGE properties, which are superior to those of quercetin or chlorogenic acid, well-known natural AGE inhibitors. Its flavonoid fraction potently impedes the synthesis of AGEs by trapping dicarbonyl intermediates [37]. Table 1 shows that propolis accelerated AGEs clearance in a model of muscle aging induced by administration of a precursor of AGEs (methylglyoxal) via activation of glyoxalase 1, an enzyme that eliminates dicarbonyl compounds (key elements of AGEs) [38]. CAPE inhibited the production of AGEs-related molecules such as protein carbonyl in the gastrocnemius muscle of rats via blockage of the activity of xanthine oxidase and adenosine deaminase [101,102,103]. The latter negatively affects insulin signaling and promotes the development of hyperglycemia, which represents a favorable condition for the production of AGEs [148]. However, propolis could not counteract the wasting effects of AGEs that already occurred in the extensor digitorum longus muscle though it tended to restore soleus muscle mass. This finding denotes that different muscle tissues respond differently to treatment, probably based on their ratio of type I to type II fibers. It also signifies the importance of early use of bee products (e.g., propolis) for the prevention of AGEs formation in skeletal muscle in people with high risk for AGEs formation such as diabetics [38].\n\n4.8. Neuronal Regeneration\nNeuronal denervation is a key factor that contributes to skeletal muscle loss, and it is related to a plethora of pathological conditions [3,149]. Experimental induction of oxidative stress and inflammation results in skeletal muscle atrophy through induction of denervation e.g., of sciatic nerve [150]. Injuries of peripheral nerves (e.g., sciatic nerve) interrupt mechanical transmission and microvasculation of the nerve and induce reperfusion. Reperfusion involves pooling of oxygen and nutrients promoting high emission of free radicals, which attack protein and lipid contents surrounding the injury site resulting in excessive tissue loss [113]. Likewise, alterations in gut microbiome in aged rats are associated with alterations in serum level of vitamin B12 and fat metabolism as well as reductions in the gastrocnemius muscle mass and sciatic response amplitude [151]. Furthermore, dysregulation of insulin-mediated GLUT4 activity in certain areas of the central nervous system impairs neuronal metabolism and plasticity [69]. Meanwhile, activation of PGC-1α, a core regulator of mitochondrial content and oxidative metabolism, increases muscle fiber resistance to denervation and atrophy through downregulation of two ubiquitin-ligases involved in the ubiquitin-proteasome pathway: MuRF1 and Atrogin-1 [1,152].\nPropolis treatment for four weeks restored gastrocnemius muscle weight and improved functional performance (e.g., walking) in rats with crush injury of the sciatic nerve. Effects of propolis were associated with increased nerve healing and regeneration as depicted by faster healing of the myelin sheath and ultra-structurally normal unmyelinated axons and Schwann cells. Investigations of motor conduction from the sciatic nerve to the gastrocnemius muscle indicated that nerve recovery induced by propolis treatment promoted optimal physical functioning by allowing motor conduction to reach the gastrocnemius muscle [113]. Neuroprotective effects of propolis in motor neurons are documented in the literature. Both kaempferide and kaempferol protected motor neurons against atrophy induced by the toxic copper-zinc superoxide dismutase in amyotrophic lateral sclerosis—a serious neurodegenerative disease that involves selective and progressive loss of motor neurons [65]. In addition, orally administered chrysin (a flavonoid that is copious in propolis) to rats intoxicated by 6-hydroxidopamine showed neuroprotective effects by mitigating neuroinflammation, enhancing levels of neurotrophins and neuronal recovery factors (e.g., brain derived neurotrophic factor and glial cell line-derived neurotrophic factor), and maintaining integrity of dopaminergic neurons resulting in better motor performance [72].\nThe release of acetylcholine (a neurotransmitter that regulates cognition) at the synaptic cleft of the neuromuscular junction is essential for motor neurotransmission, which controls excitation-contraction coupling and cell size. However, free radicals, cytokines, and AGEs impair neurotransmission by altering the production of acetylcholine [6,21,149,153]. On the other hand, upregulation of acetylcholine receptors improves neurotransmission [154]. Treatment with royal jelly may correct acetylcholine neurotransmission given its high content of acetylcholine (4–8 mM) [60]. In addition, royal jelly, propolis, and bee pollen are rich in antioxidant elements that have a potential to scavenge ROS and mitigate other pathologies that contribute to acetylcholine deficiency (e.g., neuroinflammation) [73,101,102,103]. In this respect, treatment of experimental models of carrageenan-induced hind paw edema with hydroalcoholic extract of red propolis and its biomarker, formononetin, is reported to inhibit leukocyte migration and ameliorate inflammatory neurogenic pain induced by injections of formalin and glutamate [115]. However, investigations of the action of bee products on neurotransmission are very scarce.\n\n4.9. Improving Muscular Blood Supply\nAging is associated with higher onset of atherosclerosis and restenosis, which involve vascular and microvascular damages that result from hyperproliferation of vascular smooth muscle cells (VSMCs) [155]. Muscle unloading (e.g., in sedentary lifestyle) involves chronic neuromuscular inactivity, which results in reductions in capillary number, luminal diameter, and capillary volume as well as heightened production of anti-angiogenic factors, such as p53 and TSP-1 in skeletal muscle [110]. Microvascular alterations and impaired nitric oxide (NO) production are key causes of decreased blood flow to the skeletal muscle. Poor muscular blood supply induces muscle wasting via a mechanism that entails impaired glucose metabolism and suboptimal protein anabolism [156,157]. In addition, ischemic injury in skeletal muscle is associated with high ROS release from polymorphonuclear leukocytes, which infiltrate muscle tissues. Free radicals alter cellular structure and function by attacking lipid and protein biomolecules that exist in the structure of biological membranes, enzymes, and transport proteins [102]. Therefore, improving vascularization and blood supply to skeletal muscle is a possible mechanism for the prevention of muscle wasting.\nMitchell and colleagues examined changes in microvascular blood volume, microvascular flow velocity, and microvascular blood flow in the quadriceps muscle following treatment with 15 g of amino acids in young and old subjects (20–70 years old). They detected improvements in all the 3 parameters only in young groups, and those effects were associated with proper insulin activity. Thus, the authors suggested that refeeding effects on muscular blood supply may be hindered by dysfunctions in postprandial circulation and glucose dysregulation [157]. Bee products such as bee pollen and propolis have a potential to boost microcirculation and correct pathologies that contribute to vascular dysfunction such as hyperglycemia and dyslipidemia [36,155]. In this context, CAPE, one of the basic constituents of propolis, was reported to combat vascular damages by counteracting the proliferative activity of platelet-derived growth factor. The molecular mechanism involved inducing cell-cycle arrest in VSMCs via activation of p38mitogen-activated protein kinase (MAPK), which was associated with accumulation of hypoxia-inducible factor (HIF)-1α—mainly due to inhibition of HIF prolylhydroxylase, a key contributor to proteasomal degradation of HIF-1α—and subsequent induction of HO-1 [155]. In the same regard, supplementing rats undergoing capillary regression (resulting from two weeks of hind limb unloading) in the soleus muscle with two daily intragastric doses of propolis for two weeks restored capillary number, capillary structure, capillary volume, and capillary to muscle fiber ratio through a mechanism that involves inhibition of anti-angiogenic factors and activation of pro-angiogenic factors (e.g., VEGF). The relative muscle-to-body weight in treated animals was higher than in the unloaded control animals, and the number of TUNEL-positive apoptotic endothelial cells in the soleus muscle was similar to that in the normal control animals [110]. Likewise, bee pollen (both neat and processed) increased blood vessels in the gastrocnemius muscle of rats undergoing muscle injury because of vigorous exercise [90]. Treating C2C12 myoblasts with propolis ethanolic extract increased VEGF production [108]. VEGF is a pro-angiogenic factor that contributes to angiogenesis by recruiting endothelial cells and promoting their differentiation to form new vascular networks. VEGF protects skeletal muscle undergoing unloading against the progression of capillary regression [110]. Its expression in skeletal muscle and associated angiogenic response increase following exercise due to change in the activity of HIF-1α and AMPK. It promotes the generation of ATP following mitochondrial biogenesis in order to meet oxygen demand [158]. Altogether, these reports signify that bee products and endurance exercise share common mechanisms to produce their vitality effects in skeletal muscle.\n\n4.10. Improving the Composition of Gut Microbiome\nBee products such as royal jelly and propolis display potent antifungal, bactericidal, microbicidal, anti-inflammatory, antioxidant, and healing effects [2,66]. Most bee products investigated in this review were administered orally. Therefore, it is likely that their therapeutic effects may start locally within the GI tract, which frequently undergoes propagation of harmful endobacteria, inflammation, aberrations, and permeability in advanced age [10,24,152]. In this respect, Roquetto and colleagues [116] supplemented C57BL/6 mice on HFD with crude propolis (0.2%) for two and five weeks. HFD increased the proportion of the phylum Firmicutes as well as levels of circulating lipopolysaccharide (LPS) and inflammatory biomarkers. DNA sequencing for the 16S rRNA of the gut microbiota revealed that five weeks of propolis treatment rendered the microbiota profile almost normal. Compared with untreated mice, propolis-supplemented animals demonstrated lower levels of serum triacylglycerols, glucose, and circulating LPS, along with reduced expression of TLR4 and inflammatory cytokines in skeletal muscle [116].\nLactic acid bacteria profusely exist in bee saliva and all bee products [36,83,84]. Various species of lactic acid bacteria have been experimentally used to correct GI dysbiosis and related muscle wasting [159,160]. Moreover, oligosaccharides have been chemically isolated from bee products [32,161]. These api-materials are classified as prebiotics, fermented non-digestible compounds that promote the proliferative activity of health-promoting bacteria [24,161]. Supplementing frail old adults with fructooligosaccharides expressed positive effects on skeletal muscle strength (handgrip) and endurance (exhaustion) [162]. On the other side, microbiome of the gut can affect the biological activity of bee products. The literature shows that certain endobacteria transform dietary polyphenols into phenolic acids, which can easily access the circulation and then cross the blood brain barrier to produce therapeutic effects [163]. Hence, it is important that future investigations of bee products among sarcopenic subjects examine the effect of these products on the composition of GI microbial population and its association with muscle-related outcomes."}

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Mechanisms of Action of Royal Jelly, Bee Pollen, and Propolis in Sarcopenia\nRelatively few studies have explored the mechanism through which royal jelly, bee pollen, and propolis may be beneficial for sarcopenia. In vivo and in vitro studies included in this review uncovered a number of inter-related cellular and molecular events that underlie the effect of these bee products on skeletal muscle including suppression of catabolic genes, counteracting metabolic abnormalities, inflammation, and oxidative damages as well as enhancement of motor neuronal regeneration, promotion of stem cell function, and correction of the structure of gut microbiome (Figure 1, Panel D). These mechanisms are exclusively described in the coming paragraphs.\n\n4.1. Modulating Inflammatory Responses in Skeletal Muscle\nThe role that inflammation plays in skeletal muscle is not quite clear as it looks. Inflammatory mediators behave in a dual fashion in muscle cells. During injury, cytokines and chemokines stimulate muscle repair and regeneration via activation of myoblasts, a core event in muscle remodeling [108]. Similarly, serum and muscle levels of IL-6 temporarily increase following physical exercise, and IL-6 blocks the activity of catabolic cytokines such as TNF-α. On the other hand, chronic inflammation in muscle cells, which correlates with persistent mitochondrial dysfunction and metabolic dysregulation, pathologically activates muscle fiber transformation and atrophy, eventually resulting in the development of sarcopenia [23,114]. It seems that bee products also act dually in skeletal muscle: they support the activity of cytokines that promote muscle remodeling [108] and suppress muscle-consuming cytokines [38,101,108]. In this regard, treating undifferentiated C2C12 myoblasts with ethanolic extracts of Brazilian propolis (100 μg/mL for 8 h) triggered the migration of RAW264 macrophage and increased their production of angiogenic factors (e.g., vascular endothelial growth factor A (VEGF-A) and metalloproteinase-12 (MMP-12)), chemokines (e.g., CCL-2 and CCL-5), and cytokines (e.g., IL-6, which increased by 40-folds). Propolis inhibited the expression of IL-1β and TNF-α at 4, 8, and 12 h of incubation. These effects were nuclear factor kappa B (NF-κB)-dependent given that propolis simultaneously increased nuclear translocation of p65 and p50 NF-κB proteins 3 h after treatment. Meanwhile, inhibiting IκB kinase (IKK) by BMS-345541 profoundly hindered the effect of propolis on the expression of CCL-2, CCL-5, and IL-6 by 66%, 81%, and 69%, respectively. Propolis also enhanced the expression of MAIL/IκBζ. This molecule modulates chromatin and selectively induces the production of IL-6, leukemia inhibitory factor (LIF), and CCL-2 [108].\nChronic muscle tissue infiltration by inflammatory cells (e.g., leukocytes, neutrophils, and monocytes) activates oxidative and inflammatory signaling cascades that degrade cellular structures and promote necrosis such as inducible nitric oxide synthase (iNOS) and NF-kB [90,101,115]. CAPE and high levels (200 and 300 mg/kg) of crude and processed bee pollen reduced inflammatory cell infiltration into the gastrocnemius muscle of rats with muscle injury induced by eccentric exercise and ischemia reperfusion [90,101,102]. This effect was revealed by lower activity of myeloperoxidase, an indicator of neutrophil sequestration [101,102]. As such, CAPE and bee pollen not only suppressed lipid peroxidation (lower levels of malondialdehyde, MDA) but also inhibited the activity of myostatin and the production of muscle depleting cytokines and chemokines such as IL-1β, α2-macroglobulin, and monocyte chemotactic protein 1 (MCP-1) [36,38,90,101]. The underlying mechanism entailed downregulation of nuclear p65NF-κB and blockage of its consensus binding sites in skeletal muscle [101]. As a result, bee products increased muscle mass both in sarcopenic obese rat and malnourished old rats [36] and restored the structure of myofibers (despite the persistence of necrosis) compared with untreated eccentric exercising animals, which demonstrated necrotic and fragmented myofibers [90].\nRoyal jelly downregulated the activity of tumor necrosis factor receptor 1 (TNFR1) in the adipose tissue of aged obese rats receiving HFD [100]. TNFR1 interacts with TNFR2 to negatively regulate toll-like receptors (TLR) and Nod-like receptor signaling and stimulate excessive release of cytokines via activation of key inflammatory pathways such as NF-κB [107]. Mitigation of TNFR1 was associated with a significant increase of the weight of hind limb muscle and reductions in insulin levels, homeostatic model assessment of insulin resistance (HOMA-IR), serum lipids, muscle triglyceride levels, body weight gain, and abdominal fat weight. Therefore, royal jelly may protect against muscle loss in conditions involving impairment of the adipokine profile mainly through suppression of inflammatory responses associated with high fat mass, which is followed by correction of metabolic irregularities [100].\n\n4.2. Counteracting Oxidative Stress in Skeletal Muscle\nHigh production of reactive oxygen species (ROS) in skeletal muscle tissues has serious destructive effects, which alter the integrity of skeletal muscle resulting into fatigue, muscle wasting, and muscle weakness [90,101]. Sources of intramuscular ROS are numerous including mitochondrial dysfunction (e.g., alteration of mitochondrial enzymes in the respiratory chain as well as enzymes responsible for β-oxidation), neutrophil infiltration, and the activity of cytokines and major muscle degrading molecules such as myostatin [21,36,38,101,102,118]. Oxidative and nitrosative damages in skeletal muscle tissues are mediated by the activity of numerous pro-oxidant enzymes that are associated with inflammatory processes such as cyclooxygenase-2 (COX-2) and iNOS [101]. ROS triggers the activity of corrosive molecules such as poly (ADP-ribose) polymerase (PARP), xanthine oxidase, and adenosine deaminase, which contribute to DNA damage, lipid peroxidation (e.g., increased MDA), and protein nitrotyrosylation as well as ATP catabolism in muscle tissues [101,102].\nRoyal jelly enhanced the activity of antioxidant enzymes and suppressed lipid peroxidation in a d-galactose induced model of aging [95]. Two weeks of propolis treatment in rats undergoing hind limb unloading significantly reduced nuclear ROS levels and numbers of apoptotic endothelial cells in the soleus muscle to levels similar to normal rats [110]. Moreover, propolis significantly suppressed MDA activity in skeletal muscle and increased liver levels of SOD as well as gastrocnemius muscle levels of SOD, glutathione peroxidase and catalase in rats on eccentric exercise training (70% VO2max treadmill running exercise for 60 min) compared with rats receiving exercise alone or no treatment [109]. In addition, intraperitoneal pre-administration of CAPE (60 min before induction of ischemia reperfusion) significantly ameliorated the effects associated with high ROS levels, which accompany acute ischemia such as protein peroxidation and ATP catabolism in the gastrocnemius muscle [102].\nBee products probably reduced ROS production via regulation of the activity of mitochondrial enzymes. Royal jelly increased the maximal activity of citrate synthase (CS) and β-hydroxyacyl coenzyme A dehydrogenase (β-HAD) in the soleus muscle of rats on endurance training [106]. Bee pollen restored mitochondrial complex-I, -II, -III, and -IV enzyme activity to normal, increased SOD and glutathione, and reduced MDA, NO, and total protein content in the gastrocnemius muscle of rats on exhaustive exercise [90]. It also increased the activity of CS and complex IV in malnourished old rats via a mechanism that involved activation of mTOR [36]. mTOR is a major signaling pathway that regulates various signaling cascades involved in metabolism and autophagy such nuclear respiratory factor 2 (NRF2) [2]. Therefore, it is possible that the antioxidant activity demonstrated by bee products, particularly that expressed in the mitochondria, is associated with their metabolic and hypoglycemic activities. For instance, 10-HDA increased expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) in skeletal muscle of diabetic mice [112,119]. Similarly, aged mice treated with amino acids similar to those found in royal jelly demonstrated improved size of muscle fiber by increasing PGC-1α mRNA levels. PGC-1α functions as a key regulator of sirtuin 1, which limits ROS production through stimulation of mitochondrial biogenesis and ROS defense system, thus protecting metabolically active tissues against oxidative damage [120]. Mechanistically, when PGC-1α gets activated, it interacts with other bioactive molecules such as muscle-specific transcription factors to stimulate the expression of genes that induce mitochondrial oxidative metabolism in brown fat and fiber-type switching in skeletal muscle [121].\nThe antioxidant activity of royal jelly and CAPE might be related to their strong capacity to activate the master redox-active NRF2 signaling pathway [73,122], which stimulates the production of internal antioxidants such as heme oxygenase-1 (HO-1), which scavenge free radicals [123]. Meanwhile, NRF2 and HO-1 block ROS production indirectly via suppression of inflammatory reactions [122]. In this context, CAPE reduced degenerative myopathy in rats on eccentric exercise via a complex mechanism that involved inhibition of NF-κB and its downstream pro-oxidant COX-2 and iNOS [101]. Correspondingly, CAPE decreased markers of oxidative cellular damages (protein carbonyl, protein nitrosylation, xanthine oxidase, and adenosine deaminase) associated with ischemia reperfusion and eccentric exercise in the gastrocnemius muscle [101,102,103]. In this regard, CAPE operated via a mechanism that involved inhibition of neutrophil and leukocyte infiltration into the gastrocnemius muscle, which was associated with decreased levels of myeloperoxidase. Myeloperoxidase contributes to excessive production of ROS and oxidative organ damage through a mechanism that embroils increased synthesis of hypochlorous acid [101,102]. Furthermore, CAPE accelerated purine salvage for ATP synthesis and inhibited ROS-induced lipid peroxidation via attenuation of the activity of adenosine deaminase [102].\nIn summary, the reported antioxidant effects of bee products were multifaceted involving increased production of antioxidant enzymes [90,95,109,110], and decreased ROS production [90,101,102,103,110] (secondary to reduction of inflammatory cell infiltration into skeletal muscle) [90,101,102,103], and restoration of mitochondrial activity [36,90,106].\n\n4.3. Metabolic Regulation\nSkeletal muscle is the main tissue that utilizes insulin for glucose uptake. Insulin regulates mitochondrial oxidative phosphorylation of proteins in human skeletal muscle and contributes to calcium mobilization from the sarcoplasmic-endoplasmic reticulum to mitochondria to stimulate the translocation of glucose transporter 4 (GLUT4) to the cell surface for glucose uptake. This process improves muscle protein synthesis in healthy people when the delivery of amino acids to skeletal muscle is increased, eventually leading to increased muscular mass [124,125,126]. Insulin resistance and glucose intolerance increase with old age evoking muscle loss. In this respect, hypoglycemic agents such as metformin can improve skeletal muscle metabolism via activation of adenosine monophosphate activated protein kinase (AMPK) [21].\nAMPK, a heterotrimeric complex that consists of a catalytic subunit and two regulatory subunits, is an intracellular energy sensor that regulates glucose and lipid metabolism. It gets activated when cellular energy is depleted through allosteric binding of AMP or phosphorylation by AMPK kinase at Thr172 of the catalytic subunit by AMPK kinase. Upregulated AMPK activates signaling pathways that generate ATP from glucose and fatty acid oxidation, and it simultaneously blocks signaling that contributes to the synthesis of cholesterol, fatty acid, and triacylglycerol [111]. In addition, AMPK masters numerous signaling cascades such as Forkhead Box O transcription factor (FOXO) and AKT/mTOR, which regulate the expression of genes associated with inflammation, oxidative stress, mitochondrial function, autophagy, metabolism, and apoptosis [127,128].\nThe molecular events involved in the effect of bee products on catabolic genes and anabolic resistance in skeletal muscle could be much related to their hypoglycemic effects, which positively affect the quality of skeletal muscle. Evidence signifies a positive effect of royal jelly acid (10-HDA) on inflammation and autophagy via upregulation of AMPK, which subsequently alters NF-κB and NLRP3 inflammasome-IL1β signaling [129]. Positive effects of whole royal jelly on skeletal muscle are associated with improved insulin signaling [96,100]. In one study, royal jelly improved serum IGF-1 levels in aged rats and increased AKT signaling in satellite cells extracted from aged rats in a separate in vitro investigation [96]. In another study, royal jelly decreased fat mass and improved anabolic resistance in the skeletal muscle of old obese rats on HFD via downregulation of inflammatory responses in adipose tissue as indicated by downregulation of TNFR1. This effect was associated with enhanced sensitivity to insulin—portrayed by reduction of serum insulin level and HOMA-IR [100].\nJapanese researchers proved that oral consumption of royal jelly and 10-HDA induced mitochondrial adaptation in the soleus muscle when accompanied with endurance training. These compounds also enhanced glucose uptake in skeletal muscle by inducing the phosphorylation of AMPK [106,112], an effect that was mediated by the upstream kinase Ca²⁺/calmodulin-dependent kinaseβ—independently of changes in AMP:ATP ratio and the liver kinase B1 pathway. Activation of AMPK was followed by translocation of GLUT4 to the plasma membrane of L6 myotubes [106]. It is note-worthy that effects of royal jelly on mitochondrial biogenesis under endurance training were muscle-specific. In this respect, neither endurance training nor royal jelly alone had an effect on the maximal activities of CS and β-HAD—the enzyme that catalyzes the rate-limiting step of β-oxidation of long-chain fatty acids—in the soleus muscle, which comprises type I fiber (around 35–45%) and type IIa (around 35–50%). On the other hand, royal jelly enhanced the activity of these enzymes in the soleus muscle of mice on endurance training. Of interest, endurance training increased the activity of CS and β-HAD in the plantaris and tibialis anterior muscles (which are mainly type II fiber with a total percentage of type IIb and type IIx fiber types of 90%) while royal jelly failed to exert an effect on these muscles in sedentary mice [106]. Nonetheless, the observed effects of royal jelly in the soleus muscle represent a merit. This is mainly because the oxidative type I fibers (e.g., soleus muscle) naturally undergo higher protein turnover (especially degradation), which makes them unable to grow in size or respond properly to insufficient nutrient intake [130].\nSeveral lines of evidence indicate that propolis may affect muscle quality through the regulation of glucose metabolism [69,70,109,111]. This effect was vividly depicted in vivo by increased glycogen level in skeletal muscle and reduced serum levels of glucose and insulin [109]. Same as insulin, ethanolic extracts of propolis and CAPE induced glucose uptake [69,70,111] and potentiated insulin-mediated AKT activation and glucose uptake in differentiated L6 myoblast cells [111]. Likewise, Italian propolis at concentrations of 0.1 and 1 mg/mL as well as 4-geranyloxyferulic acid and auraptene (2 oxyprenylated phenylpropanoids, which are abundant in propolis) remarkably increased GLUT4 translocation to the plasma membrane and accelerated GLUT4-mediated glucose uptake in L6 skeletal myoblasts. The effect of propolis at a concentration of 11 mg/mL was significantly superior to the effect of insulin (0.1 μM), which was used as a positive control [69].\nSimilar to royal jelly, the effects of propolis (1 μg/mL), CAPE (10 μM), artepillin C, coumaric acid, and kaempferide on glucose metabolism occurred via activation of AMPK. These effects were comparable to those of 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), a potent AMPK activator. In the meantime, co-treatment with inhibitors of AMPK (e.g., compound C) and of phosphatidylinositol 3-kinase (PI3K) (e.g., LY-294002) blocked the effects of CAPE [70,111]. Phosphorylation of AMPK results in activation of the insulin receptor (IR) and subsequent phosphorylation of PI3K followed by activation of AKT and protein kinase C (PKC) leading to GLUT4 translocation and subsequent activation of several molecules that modulate insulin-stimulated glucose transport, eventually leading to glucose influx into cells of several tissues such as skeletal muscle and adipose tissue [69,70,111]. It is worth noting that the effects of CAPE on AMPK and AKT were quick (within 1 h and 3 min, respectively), and they vanished quickly (both molecules returned back to their basal levels within 12 h and 30 min, respectively) [111].\n\n4.4. Enhancement of Muscle Protein Synthesis\nImbalance between muscle protein synthesis and degradation is associated with low protein intake and altered efficiency of the GI tract in old age, which triggers skeletal muscle loss and poor physical performance [36,40], given that proteins are the main building blocks of muscle myofibers. Moreover, transmembrane proteins and micro-peptides (e.g., myomixer and myomaker/Tmem8c) contribute to the formation of myofibers by promoting myoblast fusion via a mechanism that involves appropriate localization of Tmem8c at the plasma membrane of myoblasts allowing trafficking related to palmitoylation of C-terminal cysteine residues and C-terminal leucine [17]. Amino acid supplements (e.g., leucine, a master dietary regulator of muscle protein turnover, and its metabolite β-hydroxy β-methylbutyrate) and early refeeding with high protein diet (especially fast digestive proteins) can preserve muscle mass and function, revert sarcopenia, and enhance mobility and quality of life (QoL) by correcting age-related nutritional deficiencies, muscle protein turnover, and immune dysregulation—these effects are even greater when combined with other nutrients like vitamin D or omega 3 fatty acids as well as with physical exercise [6,131,132,133,134,135,136,137,138].\nResearch indicates that age-related skeletal muscle wasting results mainly from insufficient delivery of amino acids to skeletal muscle due to dysregulations in the activity of mTORC1- and activating transcription factor-4 (ATF4)-mediated amino acid sensing pathways. Meanwhile, interventions that ameliorate age-related damages in skeletal muscle operate primarily by reversing alterations in the delivery of amino acids to skeletal muscle via upregulation of mTORC1 and/or ATF4 [139]. mTORC1 is a nutrient sensing protein that acts as a core regulator of protein metabolism. It is sensitive to amino acids, energy status (ATP), stress (e.g., oxidative stress), and growth factors (e.g., insulin), which all can regulate its signaling [2,136]. Nevertheless, bioavailability of amino acids is necessary for growth factors to effectively activate mTORC1. Even more, amino acids on their own can adequately activate mTORC1 [136]. Evidence from preclinical and human studies confirms that ingestion of essential amino acids (similar to those found in royal jelly and bee pollen such as valine) increases cellular bioavailability of amino acids, which is associated with activation of the endothelial nitric oxide synthase (eNOs) pathway. eNOs further upregulates mTORC1 kinase. Translocation of mTORC1 from the cytosol to the surface of lysosomes is associated with improved mitochondrial biogenesis and cellular oxidative capacity in skeletal muscle due to activation of its substrates: P70 ribosomal proteins S6 kinase (S6K) and eukaryotic translation initiation 4E-binding protein 1 (eIF4E, also known as 4eBP1) [120,135,136].\nAs shown in Table 1, royal jelly and 10-HDA significantly increased muscle mass [54,96,100] and improved motor performance in aged rats [95,98,99]. In addition, dietary supplementation with monofloral bee pollen significantly improved the rate of muscle protein synthesis and restored muscle mass in emaciated old rats via upregulation of mTOR and two related downstream controllers of protein translation: p70S6k and 4eBP1, which were suppressed in malnourished old rats [36]. Although propolis improved various muscle-related parameters, its effect on muscle mass in rodents was limited—relative to royal jelly and bee pollen. However, it fostered muscle protein deposition in post-larva Nile tilapia [104]. Moreover, milk naturally enriched with PUFA and polyphenols from propolis remarkably increased the weight of the gastrocnemius muscle of growing obese rats while whole milk and milk enriched with PUFA only could not express any effect on skeletal muscle [105]. Therefore, this finding denotes that propolis could have enhanced the delivery of amino acids available in milk to skeletal muscle leading to its growth. Altogether, it is likely that the observed anabolic effects of royal jelly and bee pollen are associated with their high content of proteins and amino acids [32,36,83,84,85,86].\n\n4.5. Suppression of Catabolic Activity in Skeletal Muscle\nSkeletal muscle tissues represent the largest protein store in the human body (30–45% of total protein). Muscular mass, strength, and functions are greatly governed by the rates of muscle protein synthesis and turnover [124]. Muscle protein metabolism is regulated by the interaction of a wide range of genes. Aging is associated with various stresses, which increase the expression of catabolic genes such as E3 ubiquitin ligases MuRF1 and atrogin-1 (MAFbx). These genes heighten the occurrence of age-related muscular atrophy [97]. Oral consumption of royal jelly by aged HET mice resulted in lower levels of catabolic genes (e.g., MuRF1 and MAFbx), which were similar to those in young mice. In the meantime, the expression of these genes in the control mice was high indicating that royal jelly can delay age-related muscular apoptosis by suppressing the activity of catabolic genes [97]. Two other studies reported that CAPE suppressed catabolism that contributed to degenerative myopathy in the gastrocnemius muscle of rats undergoing eccentric exercising or femoral artery ligation as reflected by decreased serum levels of creatine kinase, a marker of muscular proteolysis [101,102,103]. Apart from skeletal muscle, CAPE was reported to protect heart muscle against age-related deteriorations such as accumulation of lipofuscin, nuclear irregularity, mitochondrial degeneration, and myofilament disorganization and disruption [33].\nThe molecular mechanism underling blockage of muscle proteolysis by bee products in sarcopenic rodents involves an interplay of various signaling pathways. Royal jelly and bee pollen activated mTOR and its substrate AKT, which are suggested to inhibit muscular proteolysis [36,96]. Similar to the effect of royal jelly on catabolic genes in HET mice, treating both L6 myoblasts and rats with propolis, CAPE, and kaempferide resulted in potent activation of AKT in a PI3K-dependent manner [111], in addition to phosphorylation of IR, PI3K, and AMPK [70]. AKT, a key substrate of mTORC2, is a conserved serine/threonine nutrient sensing protein kinase that belongs to the PI3k-related protein kinase family. Upon presence of growth factors, PI3k gets activated by IR substrate resulting in stimulation of a series of signaling cascades that involve activation of AKT, which leads to further activation of mTORC1. mTORC1 activates the phosphorylation of two main regulators of cap-dependent protein synthesis: S6K and eIF4E [2,140]. In addition, mTORC1 contributes to autophagy—a turnover process that involves clearance of dysfunctional organelles and long-lived protein aggregations with provision of energy and macromolecular precursors in return—by binding with AMPK resulting in phosphorylation of autophagy genes such as Unc51-like kinase 1 at different sites [140]. In fact, royal jelly is reported to fine-tune the transcriptional activity of the FOXO through modulating the activity of insulin/IGF-1 signaling [141]. FOXO plays a major role in the activation of AKT pathway, which implicates regulation of multiple stress–response pathways such as ROS detoxification and DNA repair and translation. In addition, the FOXOs family exerts a direct effect on certain muscle atrophy genes such as MUSA1 and a formerly uncharacterized ligase known as Specific of Muscle Atrophy and Regulated by Transcription (SMART) [142].\n\n4.6. Enhancement of Stem Cell Function\nReduction of the number and functional capacity of the muscle satellite cells is considered a core contributor to the development of age-related muscular dysfunction [96]. Induction of myogenesis via in vivo reprogramming of muscle satellite cells is a currently studied strategy that has not been successfully used for sarcopenia treatment yet [143]. On the other hand, treating sarcopenic rats with both royal jelly and pRJ was reported to increase the number of Pax7-positive satellite cells in vivo and in vitro (pRJ only). pRJ induced self-renewal of satellite cells via activation of AKT signaling [96,97]. AKT activity was associated with activation of IGF-1 as indicated by increased serum levels of IGF-1. IGF-1 plays a crucial rule in the activation of various signaling pathways; it is believed to be a major mediator of muscle growth and repair that functions by stimulating the proliferation and differentiation of satellite cells into myotubes, albeit the exact mechanism is not clear yet [96]. Similarly, pRJ activated AKT-signaling pathway in satellite cells culture, which was associated with increased proliferation of myosatellite cells and their differentiation into myotubes—an effect that is contradictory to muscle loss. AKT is thought to contribute to the synthesis of muscular proteins and inhibition of muscle proteolysis [96].\n\n4.7. Counteracting Glycation Stress\nOxidative stress, inflammation, and insensitivity to insulin, which accompany advanced age, contribute to the production of advanced glycation end products (AGEs) via enhancement of the activity of the Receptor for Advanced Glycation End products (RAGE) [144,145]. AGEs destroy the protein and lipid ingredients of muscle tissues by promoting the production of destructive molecules such as free radicals and inflammatory cytokines [101,102,113]. Thanks to their potent antioxidant properties, polyphenolic compounds exert multifaceted anti-glycation functions. On one hand, they scavenge free-radicals and chelate transition metals that are involved in the synthesis of dicarbonyl intermediates subsequently resulting in inhibition of the formation of AGEs. On the other hand, polyphenolic compounds antagonize AGE receptors, mainly RAGE, and facilitate the removal of already formed a,b-dicarbonyl intermediates such as methylglyoxal, promoting the degradation of AGEs [37,38,146]. Royal jelly is reported to downregulate the activity of RAGE, the main receptor for AGEs, in an aged model of cognitive impairment [147]. However, its anti-glycation effect has not been investigated in skeletal muscle yet. Propolis exhibits strong anti-AGE properties, which are superior to those of quercetin or chlorogenic acid, well-known natural AGE inhibitors. Its flavonoid fraction potently impedes the synthesis of AGEs by trapping dicarbonyl intermediates [37]. Table 1 shows that propolis accelerated AGEs clearance in a model of muscle aging induced by administration of a precursor of AGEs (methylglyoxal) via activation of glyoxalase 1, an enzyme that eliminates dicarbonyl compounds (key elements of AGEs) [38]. CAPE inhibited the production of AGEs-related molecules such as protein carbonyl in the gastrocnemius muscle of rats via blockage of the activity of xanthine oxidase and adenosine deaminase [101,102,103]. The latter negatively affects insulin signaling and promotes the development of hyperglycemia, which represents a favorable condition for the production of AGEs [148]. However, propolis could not counteract the wasting effects of AGEs that already occurred in the extensor digitorum longus muscle though it tended to restore soleus muscle mass. This finding denotes that different muscle tissues respond differently to treatment, probably based on their ratio of type I to type II fibers. It also signifies the importance of early use of bee products (e.g., propolis) for the prevention of AGEs formation in skeletal muscle in people with high risk for AGEs formation such as diabetics [38].\n\n4.8. Neuronal Regeneration\nNeuronal denervation is a key factor that contributes to skeletal muscle loss, and it is related to a plethora of pathological conditions [3,149]. Experimental induction of oxidative stress and inflammation results in skeletal muscle atrophy through induction of denervation e.g., of sciatic nerve [150]. Injuries of peripheral nerves (e.g., sciatic nerve) interrupt mechanical transmission and microvasculation of the nerve and induce reperfusion. Reperfusion involves pooling of oxygen and nutrients promoting high emission of free radicals, which attack protein and lipid contents surrounding the injury site resulting in excessive tissue loss [113]. Likewise, alterations in gut microbiome in aged rats are associated with alterations in serum level of vitamin B12 and fat metabolism as well as reductions in the gastrocnemius muscle mass and sciatic response amplitude [151]. Furthermore, dysregulation of insulin-mediated GLUT4 activity in certain areas of the central nervous system impairs neuronal metabolism and plasticity [69]. Meanwhile, activation of PGC-1α, a core regulator of mitochondrial content and oxidative metabolism, increases muscle fiber resistance to denervation and atrophy through downregulation of two ubiquitin-ligases involved in the ubiquitin-proteasome pathway: MuRF1 and Atrogin-1 [1,152].\nPropolis treatment for four weeks restored gastrocnemius muscle weight and improved functional performance (e.g., walking) in rats with crush injury of the sciatic nerve. Effects of propolis were associated with increased nerve healing and regeneration as depicted by faster healing of the myelin sheath and ultra-structurally normal unmyelinated axons and Schwann cells. Investigations of motor conduction from the sciatic nerve to the gastrocnemius muscle indicated that nerve recovery induced by propolis treatment promoted optimal physical functioning by allowing motor conduction to reach the gastrocnemius muscle [113]. Neuroprotective effects of propolis in motor neurons are documented in the literature. Both kaempferide and kaempferol protected motor neurons against atrophy induced by the toxic copper-zinc superoxide dismutase in amyotrophic lateral sclerosis—a serious neurodegenerative disease that involves selective and progressive loss of motor neurons [65]. In addition, orally administered chrysin (a flavonoid that is copious in propolis) to rats intoxicated by 6-hydroxidopamine showed neuroprotective effects by mitigating neuroinflammation, enhancing levels of neurotrophins and neuronal recovery factors (e.g., brain derived neurotrophic factor and glial cell line-derived neurotrophic factor), and maintaining integrity of dopaminergic neurons resulting in better motor performance [72].\nThe release of acetylcholine (a neurotransmitter that regulates cognition) at the synaptic cleft of the neuromuscular junction is essential for motor neurotransmission, which controls excitation-contraction coupling and cell size. However, free radicals, cytokines, and AGEs impair neurotransmission by altering the production of acetylcholine [6,21,149,153]. On the other hand, upregulation of acetylcholine receptors improves neurotransmission [154]. Treatment with royal jelly may correct acetylcholine neurotransmission given its high content of acetylcholine (4–8 mM) [60]. In addition, royal jelly, propolis, and bee pollen are rich in antioxidant elements that have a potential to scavenge ROS and mitigate other pathologies that contribute to acetylcholine deficiency (e.g., neuroinflammation) [73,101,102,103]. In this respect, treatment of experimental models of carrageenan-induced hind paw edema with hydroalcoholic extract of red propolis and its biomarker, formononetin, is reported to inhibit leukocyte migration and ameliorate inflammatory neurogenic pain induced by injections of formalin and glutamate [115]. However, investigations of the action of bee products on neurotransmission are very scarce.\n\n4.9. Improving Muscular Blood Supply\nAging is associated with higher onset of atherosclerosis and restenosis, which involve vascular and microvascular damages that result from hyperproliferation of vascular smooth muscle cells (VSMCs) [155]. Muscle unloading (e.g., in sedentary lifestyle) involves chronic neuromuscular inactivity, which results in reductions in capillary number, luminal diameter, and capillary volume as well as heightened production of anti-angiogenic factors, such as p53 and TSP-1 in skeletal muscle [110]. Microvascular alterations and impaired nitric oxide (NO) production are key causes of decreased blood flow to the skeletal muscle. Poor muscular blood supply induces muscle wasting via a mechanism that entails impaired glucose metabolism and suboptimal protein anabolism [156,157]. In addition, ischemic injury in skeletal muscle is associated with high ROS release from polymorphonuclear leukocytes, which infiltrate muscle tissues. Free radicals alter cellular structure and function by attacking lipid and protein biomolecules that exist in the structure of biological membranes, enzymes, and transport proteins [102]. Therefore, improving vascularization and blood supply to skeletal muscle is a possible mechanism for the prevention of muscle wasting.\nMitchell and colleagues examined changes in microvascular blood volume, microvascular flow velocity, and microvascular blood flow in the quadriceps muscle following treatment with 15 g of amino acids in young and old subjects (20–70 years old). They detected improvements in all the 3 parameters only in young groups, and those effects were associated with proper insulin activity. Thus, the authors suggested that refeeding effects on muscular blood supply may be hindered by dysfunctions in postprandial circulation and glucose dysregulation [157]. Bee products such as bee pollen and propolis have a potential to boost microcirculation and correct pathologies that contribute to vascular dysfunction such as hyperglycemia and dyslipidemia [36,155]. In this context, CAPE, one of the basic constituents of propolis, was reported to combat vascular damages by counteracting the proliferative activity of platelet-derived growth factor. The molecular mechanism involved inducing cell-cycle arrest in VSMCs via activation of p38mitogen-activated protein kinase (MAPK), which was associated with accumulation of hypoxia-inducible factor (HIF)-1α—mainly due to inhibition of HIF prolylhydroxylase, a key contributor to proteasomal degradation of HIF-1α—and subsequent induction of HO-1 [155]. In the same regard, supplementing rats undergoing capillary regression (resulting from two weeks of hind limb unloading) in the soleus muscle with two daily intragastric doses of propolis for two weeks restored capillary number, capillary structure, capillary volume, and capillary to muscle fiber ratio through a mechanism that involves inhibition of anti-angiogenic factors and activation of pro-angiogenic factors (e.g., VEGF). The relative muscle-to-body weight in treated animals was higher than in the unloaded control animals, and the number of TUNEL-positive apoptotic endothelial cells in the soleus muscle was similar to that in the normal control animals [110]. Likewise, bee pollen (both neat and processed) increased blood vessels in the gastrocnemius muscle of rats undergoing muscle injury because of vigorous exercise [90]. Treating C2C12 myoblasts with propolis ethanolic extract increased VEGF production [108]. VEGF is a pro-angiogenic factor that contributes to angiogenesis by recruiting endothelial cells and promoting their differentiation to form new vascular networks. VEGF protects skeletal muscle undergoing unloading against the progression of capillary regression [110]. Its expression in skeletal muscle and associated angiogenic response increase following exercise due to change in the activity of HIF-1α and AMPK. It promotes the generation of ATP following mitochondrial biogenesis in order to meet oxygen demand [158]. Altogether, these reports signify that bee products and endurance exercise share common mechanisms to produce their vitality effects in skeletal muscle.\n\n4.10. Improving the Composition of Gut Microbiome\nBee products such as royal jelly and propolis display potent antifungal, bactericidal, microbicidal, anti-inflammatory, antioxidant, and healing effects [2,66]. Most bee products investigated in this review were administered orally. Therefore, it is likely that their therapeutic effects may start locally within the GI tract, which frequently undergoes propagation of harmful endobacteria, inflammation, aberrations, and permeability in advanced age [10,24,152]. In this respect, Roquetto and colleagues [116] supplemented C57BL/6 mice on HFD with crude propolis (0.2%) for two and five weeks. HFD increased the proportion of the phylum Firmicutes as well as levels of circulating lipopolysaccharide (LPS) and inflammatory biomarkers. DNA sequencing for the 16S rRNA of the gut microbiota revealed that five weeks of propolis treatment rendered the microbiota profile almost normal. Compared with untreated mice, propolis-supplemented animals demonstrated lower levels of serum triacylglycerols, glucose, and circulating LPS, along with reduced expression of TLR4 and inflammatory cytokines in skeletal muscle [116].\nLactic acid bacteria profusely exist in bee saliva and all bee products [36,83,84]. Various species of lactic acid bacteria have been experimentally used to correct GI dysbiosis and related muscle wasting [159,160]. Moreover, oligosaccharides have been chemically isolated from bee products [32,161]. These api-materials are classified as prebiotics, fermented non-digestible compounds that promote the proliferative activity of health-promoting bacteria [24,161]. Supplementing frail old adults with fructooligosaccharides expressed positive effects on skeletal muscle strength (handgrip) and endurance (exhaustion) [162]. On the other side, microbiome of the gut can affect the biological activity of bee products. The literature shows that certain endobacteria transform dietary polyphenols into phenolic acids, which can easily access the circulation and then cross the blood brain barrier to produce therapeutic effects [163]. Hence, it is important that future investigations of bee products among sarcopenic subjects examine the effect of these products on the composition of GI microbial population and its association with muscle-related outcomes."}

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Mechanisms of Action of Royal Jelly, Bee Pollen, and Propolis in Sarcopenia\nRelatively few studies have explored the mechanism through which royal jelly, bee pollen, and propolis may be beneficial for sarcopenia. In vivo and in vitro studies included in this review uncovered a number of inter-related cellular and molecular events that underlie the effect of these bee products on skeletal muscle including suppression of catabolic genes, counteracting metabolic abnormalities, inflammation, and oxidative damages as well as enhancement of motor neuronal regeneration, promotion of stem cell function, and correction of the structure of gut microbiome (Figure 1, Panel D). These mechanisms are exclusively described in the coming paragraphs.\n\n4.1. Modulating Inflammatory Responses in Skeletal Muscle\nThe role that inflammation plays in skeletal muscle is not quite clear as it looks. Inflammatory mediators behave in a dual fashion in muscle cells. During injury, cytokines and chemokines stimulate muscle repair and regeneration via activation of myoblasts, a core event in muscle remodeling [108]. Similarly, serum and muscle levels of IL-6 temporarily increase following physical exercise, and IL-6 blocks the activity of catabolic cytokines such as TNF-α. On the other hand, chronic inflammation in muscle cells, which correlates with persistent mitochondrial dysfunction and metabolic dysregulation, pathologically activates muscle fiber transformation and atrophy, eventually resulting in the development of sarcopenia [23,114]. It seems that bee products also act dually in skeletal muscle: they support the activity of cytokines that promote muscle remodeling [108] and suppress muscle-consuming cytokines [38,101,108]. In this regard, treating undifferentiated C2C12 myoblasts with ethanolic extracts of Brazilian propolis (100 μg/mL for 8 h) triggered the migration of RAW264 macrophage and increased their production of angiogenic factors (e.g., vascular endothelial growth factor A (VEGF-A) and metalloproteinase-12 (MMP-12)), chemokines (e.g., CCL-2 and CCL-5), and cytokines (e.g., IL-6, which increased by 40-folds). Propolis inhibited the expression of IL-1β and TNF-α at 4, 8, and 12 h of incubation. These effects were nuclear factor kappa B (NF-κB)-dependent given that propolis simultaneously increased nuclear translocation of p65 and p50 NF-κB proteins 3 h after treatment. Meanwhile, inhibiting IκB kinase (IKK) by BMS-345541 profoundly hindered the effect of propolis on the expression of CCL-2, CCL-5, and IL-6 by 66%, 81%, and 69%, respectively. Propolis also enhanced the expression of MAIL/IκBζ. This molecule modulates chromatin and selectively induces the production of IL-6, leukemia inhibitory factor (LIF), and CCL-2 [108].\nChronic muscle tissue infiltration by inflammatory cells (e.g., leukocytes, neutrophils, and monocytes) activates oxidative and inflammatory signaling cascades that degrade cellular structures and promote necrosis such as inducible nitric oxide synthase (iNOS) and NF-kB [90,101,115]. CAPE and high levels (200 and 300 mg/kg) of crude and processed bee pollen reduced inflammatory cell infiltration into the gastrocnemius muscle of rats with muscle injury induced by eccentric exercise and ischemia reperfusion [90,101,102]. This effect was revealed by lower activity of myeloperoxidase, an indicator of neutrophil sequestration [101,102]. As such, CAPE and bee pollen not only suppressed lipid peroxidation (lower levels of malondialdehyde, MDA) but also inhibited the activity of myostatin and the production of muscle depleting cytokines and chemokines such as IL-1β, α2-macroglobulin, and monocyte chemotactic protein 1 (MCP-1) [36,38,90,101]. The underlying mechanism entailed downregulation of nuclear p65NF-κB and blockage of its consensus binding sites in skeletal muscle [101]. As a result, bee products increased muscle mass both in sarcopenic obese rat and malnourished old rats [36] and restored the structure of myofibers (despite the persistence of necrosis) compared with untreated eccentric exercising animals, which demonstrated necrotic and fragmented myofibers [90].\nRoyal jelly downregulated the activity of tumor necrosis factor receptor 1 (TNFR1) in the adipose tissue of aged obese rats receiving HFD [100]. TNFR1 interacts with TNFR2 to negatively regulate toll-like receptors (TLR) and Nod-like receptor signaling and stimulate excessive release of cytokines via activation of key inflammatory pathways such as NF-κB [107]. Mitigation of TNFR1 was associated with a significant increase of the weight of hind limb muscle and reductions in insulin levels, homeostatic model assessment of insulin resistance (HOMA-IR), serum lipids, muscle triglyceride levels, body weight gain, and abdominal fat weight. Therefore, royal jelly may protect against muscle loss in conditions involving impairment of the adipokine profile mainly through suppression of inflammatory responses associated with high fat mass, which is followed by correction of metabolic irregularities [100].\n\n4.2. Counteracting Oxidative Stress in Skeletal Muscle\nHigh production of reactive oxygen species (ROS) in skeletal muscle tissues has serious destructive effects, which alter the integrity of skeletal muscle resulting into fatigue, muscle wasting, and muscle weakness [90,101]. Sources of intramuscular ROS are numerous including mitochondrial dysfunction (e.g., alteration of mitochondrial enzymes in the respiratory chain as well as enzymes responsible for β-oxidation), neutrophil infiltration, and the activity of cytokines and major muscle degrading molecules such as myostatin [21,36,38,101,102,118]. Oxidative and nitrosative damages in skeletal muscle tissues are mediated by the activity of numerous pro-oxidant enzymes that are associated with inflammatory processes such as cyclooxygenase-2 (COX-2) and iNOS [101]. ROS triggers the activity of corrosive molecules such as poly (ADP-ribose) polymerase (PARP), xanthine oxidase, and adenosine deaminase, which contribute to DNA damage, lipid peroxidation (e.g., increased MDA), and protein nitrotyrosylation as well as ATP catabolism in muscle tissues [101,102].\nRoyal jelly enhanced the activity of antioxidant enzymes and suppressed lipid peroxidation in a d-galactose induced model of aging [95]. Two weeks of propolis treatment in rats undergoing hind limb unloading significantly reduced nuclear ROS levels and numbers of apoptotic endothelial cells in the soleus muscle to levels similar to normal rats [110]. Moreover, propolis significantly suppressed MDA activity in skeletal muscle and increased liver levels of SOD as well as gastrocnemius muscle levels of SOD, glutathione peroxidase and catalase in rats on eccentric exercise training (70% VO2max treadmill running exercise for 60 min) compared with rats receiving exercise alone or no treatment [109]. In addition, intraperitoneal pre-administration of CAPE (60 min before induction of ischemia reperfusion) significantly ameliorated the effects associated with high ROS levels, which accompany acute ischemia such as protein peroxidation and ATP catabolism in the gastrocnemius muscle [102].\nBee products probably reduced ROS production via regulation of the activity of mitochondrial enzymes. Royal jelly increased the maximal activity of citrate synthase (CS) and β-hydroxyacyl coenzyme A dehydrogenase (β-HAD) in the soleus muscle of rats on endurance training [106]. Bee pollen restored mitochondrial complex-I, -II, -III, and -IV enzyme activity to normal, increased SOD and glutathione, and reduced MDA, NO, and total protein content in the gastrocnemius muscle of rats on exhaustive exercise [90]. It also increased the activity of CS and complex IV in malnourished old rats via a mechanism that involved activation of mTOR [36]. mTOR is a major signaling pathway that regulates various signaling cascades involved in metabolism and autophagy such nuclear respiratory factor 2 (NRF2) [2]. Therefore, it is possible that the antioxidant activity demonstrated by bee products, particularly that expressed in the mitochondria, is associated with their metabolic and hypoglycemic activities. For instance, 10-HDA increased expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) in skeletal muscle of diabetic mice [112,119]. Similarly, aged mice treated with amino acids similar to those found in royal jelly demonstrated improved size of muscle fiber by increasing PGC-1α mRNA levels. PGC-1α functions as a key regulator of sirtuin 1, which limits ROS production through stimulation of mitochondrial biogenesis and ROS defense system, thus protecting metabolically active tissues against oxidative damage [120]. Mechanistically, when PGC-1α gets activated, it interacts with other bioactive molecules such as muscle-specific transcription factors to stimulate the expression of genes that induce mitochondrial oxidative metabolism in brown fat and fiber-type switching in skeletal muscle [121].\nThe antioxidant activity of royal jelly and CAPE might be related to their strong capacity to activate the master redox-active NRF2 signaling pathway [73,122], which stimulates the production of internal antioxidants such as heme oxygenase-1 (HO-1), which scavenge free radicals [123]. Meanwhile, NRF2 and HO-1 block ROS production indirectly via suppression of inflammatory reactions [122]. In this context, CAPE reduced degenerative myopathy in rats on eccentric exercise via a complex mechanism that involved inhibition of NF-κB and its downstream pro-oxidant COX-2 and iNOS [101]. Correspondingly, CAPE decreased markers of oxidative cellular damages (protein carbonyl, protein nitrosylation, xanthine oxidase, and adenosine deaminase) associated with ischemia reperfusion and eccentric exercise in the gastrocnemius muscle [101,102,103]. In this regard, CAPE operated via a mechanism that involved inhibition of neutrophil and leukocyte infiltration into the gastrocnemius muscle, which was associated with decreased levels of myeloperoxidase. Myeloperoxidase contributes to excessive production of ROS and oxidative organ damage through a mechanism that embroils increased synthesis of hypochlorous acid [101,102]. Furthermore, CAPE accelerated purine salvage for ATP synthesis and inhibited ROS-induced lipid peroxidation via attenuation of the activity of adenosine deaminase [102].\nIn summary, the reported antioxidant effects of bee products were multifaceted involving increased production of antioxidant enzymes [90,95,109,110], and decreased ROS production [90,101,102,103,110] (secondary to reduction of inflammatory cell infiltration into skeletal muscle) [90,101,102,103], and restoration of mitochondrial activity [36,90,106].\n\n4.3. Metabolic Regulation\nSkeletal muscle is the main tissue that utilizes insulin for glucose uptake. Insulin regulates mitochondrial oxidative phosphorylation of proteins in human skeletal muscle and contributes to calcium mobilization from the sarcoplasmic-endoplasmic reticulum to mitochondria to stimulate the translocation of glucose transporter 4 (GLUT4) to the cell surface for glucose uptake. This process improves muscle protein synthesis in healthy people when the delivery of amino acids to skeletal muscle is increased, eventually leading to increased muscular mass [124,125,126]. Insulin resistance and glucose intolerance increase with old age evoking muscle loss. In this respect, hypoglycemic agents such as metformin can improve skeletal muscle metabolism via activation of adenosine monophosphate activated protein kinase (AMPK) [21].\nAMPK, a heterotrimeric complex that consists of a catalytic subunit and two regulatory subunits, is an intracellular energy sensor that regulates glucose and lipid metabolism. It gets activated when cellular energy is depleted through allosteric binding of AMP or phosphorylation by AMPK kinase at Thr172 of the catalytic subunit by AMPK kinase. Upregulated AMPK activates signaling pathways that generate ATP from glucose and fatty acid oxidation, and it simultaneously blocks signaling that contributes to the synthesis of cholesterol, fatty acid, and triacylglycerol [111]. In addition, AMPK masters numerous signaling cascades such as Forkhead Box O transcription factor (FOXO) and AKT/mTOR, which regulate the expression of genes associated with inflammation, oxidative stress, mitochondrial function, autophagy, metabolism, and apoptosis [127,128].\nThe molecular events involved in the effect of bee products on catabolic genes and anabolic resistance in skeletal muscle could be much related to their hypoglycemic effects, which positively affect the quality of skeletal muscle. Evidence signifies a positive effect of royal jelly acid (10-HDA) on inflammation and autophagy via upregulation of AMPK, which subsequently alters NF-κB and NLRP3 inflammasome-IL1β signaling [129]. Positive effects of whole royal jelly on skeletal muscle are associated with improved insulin signaling [96,100]. In one study, royal jelly improved serum IGF-1 levels in aged rats and increased AKT signaling in satellite cells extracted from aged rats in a separate in vitro investigation [96]. In another study, royal jelly decreased fat mass and improved anabolic resistance in the skeletal muscle of old obese rats on HFD via downregulation of inflammatory responses in adipose tissue as indicated by downregulation of TNFR1. This effect was associated with enhanced sensitivity to insulin—portrayed by reduction of serum insulin level and HOMA-IR [100].\nJapanese researchers proved that oral consumption of royal jelly and 10-HDA induced mitochondrial adaptation in the soleus muscle when accompanied with endurance training. These compounds also enhanced glucose uptake in skeletal muscle by inducing the phosphorylation of AMPK [106,112], an effect that was mediated by the upstream kinase Ca²⁺/calmodulin-dependent kinaseβ—independently of changes in AMP:ATP ratio and the liver kinase B1 pathway. Activation of AMPK was followed by translocation of GLUT4 to the plasma membrane of L6 myotubes [106]. It is note-worthy that effects of royal jelly on mitochondrial biogenesis under endurance training were muscle-specific. In this respect, neither endurance training nor royal jelly alone had an effect on the maximal activities of CS and β-HAD—the enzyme that catalyzes the rate-limiting step of β-oxidation of long-chain fatty acids—in the soleus muscle, which comprises type I fiber (around 35–45%) and type IIa (around 35–50%). On the other hand, royal jelly enhanced the activity of these enzymes in the soleus muscle of mice on endurance training. Of interest, endurance training increased the activity of CS and β-HAD in the plantaris and tibialis anterior muscles (which are mainly type II fiber with a total percentage of type IIb and type IIx fiber types of 90%) while royal jelly failed to exert an effect on these muscles in sedentary mice [106]. Nonetheless, the observed effects of royal jelly in the soleus muscle represent a merit. This is mainly because the oxidative type I fibers (e.g., soleus muscle) naturally undergo higher protein turnover (especially degradation), which makes them unable to grow in size or respond properly to insufficient nutrient intake [130].\nSeveral lines of evidence indicate that propolis may affect muscle quality through the regulation of glucose metabolism [69,70,109,111]. This effect was vividly depicted in vivo by increased glycogen level in skeletal muscle and reduced serum levels of glucose and insulin [109]. Same as insulin, ethanolic extracts of propolis and CAPE induced glucose uptake [69,70,111] and potentiated insulin-mediated AKT activation and glucose uptake in differentiated L6 myoblast cells [111]. Likewise, Italian propolis at concentrations of 0.1 and 1 mg/mL as well as 4-geranyloxyferulic acid and auraptene (2 oxyprenylated phenylpropanoids, which are abundant in propolis) remarkably increased GLUT4 translocation to the plasma membrane and accelerated GLUT4-mediated glucose uptake in L6 skeletal myoblasts. The effect of propolis at a concentration of 11 mg/mL was significantly superior to the effect of insulin (0.1 μM), which was used as a positive control [69].\nSimilar to royal jelly, the effects of propolis (1 μg/mL), CAPE (10 μM), artepillin C, coumaric acid, and kaempferide on glucose metabolism occurred via activation of AMPK. These effects were comparable to those of 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), a potent AMPK activator. In the meantime, co-treatment with inhibitors of AMPK (e.g., compound C) and of phosphatidylinositol 3-kinase (PI3K) (e.g., LY-294002) blocked the effects of CAPE [70,111]. Phosphorylation of AMPK results in activation of the insulin receptor (IR) and subsequent phosphorylation of PI3K followed by activation of AKT and protein kinase C (PKC) leading to GLUT4 translocation and subsequent activation of several molecules that modulate insulin-stimulated glucose transport, eventually leading to glucose influx into cells of several tissues such as skeletal muscle and adipose tissue [69,70,111]. It is worth noting that the effects of CAPE on AMPK and AKT were quick (within 1 h and 3 min, respectively), and they vanished quickly (both molecules returned back to their basal levels within 12 h and 30 min, respectively) [111].\n\n4.4. Enhancement of Muscle Protein Synthesis\nImbalance between muscle protein synthesis and degradation is associated with low protein intake and altered efficiency of the GI tract in old age, which triggers skeletal muscle loss and poor physical performance [36,40], given that proteins are the main building blocks of muscle myofibers. Moreover, transmembrane proteins and micro-peptides (e.g., myomixer and myomaker/Tmem8c) contribute to the formation of myofibers by promoting myoblast fusion via a mechanism that involves appropriate localization of Tmem8c at the plasma membrane of myoblasts allowing trafficking related to palmitoylation of C-terminal cysteine residues and C-terminal leucine [17]. Amino acid supplements (e.g., leucine, a master dietary regulator of muscle protein turnover, and its metabolite β-hydroxy β-methylbutyrate) and early refeeding with high protein diet (especially fast digestive proteins) can preserve muscle mass and function, revert sarcopenia, and enhance mobility and quality of life (QoL) by correcting age-related nutritional deficiencies, muscle protein turnover, and immune dysregulation—these effects are even greater when combined with other nutrients like vitamin D or omega 3 fatty acids as well as with physical exercise [6,131,132,133,134,135,136,137,138].\nResearch indicates that age-related skeletal muscle wasting results mainly from insufficient delivery of amino acids to skeletal muscle due to dysregulations in the activity of mTORC1- and activating transcription factor-4 (ATF4)-mediated amino acid sensing pathways. Meanwhile, interventions that ameliorate age-related damages in skeletal muscle operate primarily by reversing alterations in the delivery of amino acids to skeletal muscle via upregulation of mTORC1 and/or ATF4 [139]. mTORC1 is a nutrient sensing protein that acts as a core regulator of protein metabolism. It is sensitive to amino acids, energy status (ATP), stress (e.g., oxidative stress), and growth factors (e.g., insulin), which all can regulate its signaling [2,136]. Nevertheless, bioavailability of amino acids is necessary for growth factors to effectively activate mTORC1. Even more, amino acids on their own can adequately activate mTORC1 [136]. Evidence from preclinical and human studies confirms that ingestion of essential amino acids (similar to those found in royal jelly and bee pollen such as valine) increases cellular bioavailability of amino acids, which is associated with activation of the endothelial nitric oxide synthase (eNOs) pathway. eNOs further upregulates mTORC1 kinase. Translocation of mTORC1 from the cytosol to the surface of lysosomes is associated with improved mitochondrial biogenesis and cellular oxidative capacity in skeletal muscle due to activation of its substrates: P70 ribosomal proteins S6 kinase (S6K) and eukaryotic translation initiation 4E-binding protein 1 (eIF4E, also known as 4eBP1) [120,135,136].\nAs shown in Table 1, royal jelly and 10-HDA significantly increased muscle mass [54,96,100] and improved motor performance in aged rats [95,98,99]. In addition, dietary supplementation with monofloral bee pollen significantly improved the rate of muscle protein synthesis and restored muscle mass in emaciated old rats via upregulation of mTOR and two related downstream controllers of protein translation: p70S6k and 4eBP1, which were suppressed in malnourished old rats [36]. Although propolis improved various muscle-related parameters, its effect on muscle mass in rodents was limited—relative to royal jelly and bee pollen. However, it fostered muscle protein deposition in post-larva Nile tilapia [104]. Moreover, milk naturally enriched with PUFA and polyphenols from propolis remarkably increased the weight of the gastrocnemius muscle of growing obese rats while whole milk and milk enriched with PUFA only could not express any effect on skeletal muscle [105]. Therefore, this finding denotes that propolis could have enhanced the delivery of amino acids available in milk to skeletal muscle leading to its growth. Altogether, it is likely that the observed anabolic effects of royal jelly and bee pollen are associated with their high content of proteins and amino acids [32,36,83,84,85,86].\n\n4.5. Suppression of Catabolic Activity in Skeletal Muscle\nSkeletal muscle tissues represent the largest protein store in the human body (30–45% of total protein). Muscular mass, strength, and functions are greatly governed by the rates of muscle protein synthesis and turnover [124]. Muscle protein metabolism is regulated by the interaction of a wide range of genes. Aging is associated with various stresses, which increase the expression of catabolic genes such as E3 ubiquitin ligases MuRF1 and atrogin-1 (MAFbx). These genes heighten the occurrence of age-related muscular atrophy [97]. Oral consumption of royal jelly by aged HET mice resulted in lower levels of catabolic genes (e.g., MuRF1 and MAFbx), which were similar to those in young mice. In the meantime, the expression of these genes in the control mice was high indicating that royal jelly can delay age-related muscular apoptosis by suppressing the activity of catabolic genes [97]. Two other studies reported that CAPE suppressed catabolism that contributed to degenerative myopathy in the gastrocnemius muscle of rats undergoing eccentric exercising or femoral artery ligation as reflected by decreased serum levels of creatine kinase, a marker of muscular proteolysis [101,102,103]. Apart from skeletal muscle, CAPE was reported to protect heart muscle against age-related deteriorations such as accumulation of lipofuscin, nuclear irregularity, mitochondrial degeneration, and myofilament disorganization and disruption [33].\nThe molecular mechanism underling blockage of muscle proteolysis by bee products in sarcopenic rodents involves an interplay of various signaling pathways. Royal jelly and bee pollen activated mTOR and its substrate AKT, which are suggested to inhibit muscular proteolysis [36,96]. Similar to the effect of royal jelly on catabolic genes in HET mice, treating both L6 myoblasts and rats with propolis, CAPE, and kaempferide resulted in potent activation of AKT in a PI3K-dependent manner [111], in addition to phosphorylation of IR, PI3K, and AMPK [70]. AKT, a key substrate of mTORC2, is a conserved serine/threonine nutrient sensing protein kinase that belongs to the PI3k-related protein kinase family. Upon presence of growth factors, PI3k gets activated by IR substrate resulting in stimulation of a series of signaling cascades that involve activation of AKT, which leads to further activation of mTORC1. mTORC1 activates the phosphorylation of two main regulators of cap-dependent protein synthesis: S6K and eIF4E [2,140]. In addition, mTORC1 contributes to autophagy—a turnover process that involves clearance of dysfunctional organelles and long-lived protein aggregations with provision of energy and macromolecular precursors in return—by binding with AMPK resulting in phosphorylation of autophagy genes such as Unc51-like kinase 1 at different sites [140]. In fact, royal jelly is reported to fine-tune the transcriptional activity of the FOXO through modulating the activity of insulin/IGF-1 signaling [141]. FOXO plays a major role in the activation of AKT pathway, which implicates regulation of multiple stress–response pathways such as ROS detoxification and DNA repair and translation. In addition, the FOXOs family exerts a direct effect on certain muscle atrophy genes such as MUSA1 and a formerly uncharacterized ligase known as Specific of Muscle Atrophy and Regulated by Transcription (SMART) [142].\n\n4.6. Enhancement of Stem Cell Function\nReduction of the number and functional capacity of the muscle satellite cells is considered a core contributor to the development of age-related muscular dysfunction [96]. Induction of myogenesis via in vivo reprogramming of muscle satellite cells is a currently studied strategy that has not been successfully used for sarcopenia treatment yet [143]. On the other hand, treating sarcopenic rats with both royal jelly and pRJ was reported to increase the number of Pax7-positive satellite cells in vivo and in vitro (pRJ only). pRJ induced self-renewal of satellite cells via activation of AKT signaling [96,97]. AKT activity was associated with activation of IGF-1 as indicated by increased serum levels of IGF-1. IGF-1 plays a crucial rule in the activation of various signaling pathways; it is believed to be a major mediator of muscle growth and repair that functions by stimulating the proliferation and differentiation of satellite cells into myotubes, albeit the exact mechanism is not clear yet [96]. Similarly, pRJ activated AKT-signaling pathway in satellite cells culture, which was associated with increased proliferation of myosatellite cells and their differentiation into myotubes—an effect that is contradictory to muscle loss. AKT is thought to contribute to the synthesis of muscular proteins and inhibition of muscle proteolysis [96].\n\n4.7. Counteracting Glycation Stress\nOxidative stress, inflammation, and insensitivity to insulin, which accompany advanced age, contribute to the production of advanced glycation end products (AGEs) via enhancement of the activity of the Receptor for Advanced Glycation End products (RAGE) [144,145]. AGEs destroy the protein and lipid ingredients of muscle tissues by promoting the production of destructive molecules such as free radicals and inflammatory cytokines [101,102,113]. Thanks to their potent antioxidant properties, polyphenolic compounds exert multifaceted anti-glycation functions. On one hand, they scavenge free-radicals and chelate transition metals that are involved in the synthesis of dicarbonyl intermediates subsequently resulting in inhibition of the formation of AGEs. On the other hand, polyphenolic compounds antagonize AGE receptors, mainly RAGE, and facilitate the removal of already formed a,b-dicarbonyl intermediates such as methylglyoxal, promoting the degradation of AGEs [37,38,146]. Royal jelly is reported to downregulate the activity of RAGE, the main receptor for AGEs, in an aged model of cognitive impairment [147]. However, its anti-glycation effect has not been investigated in skeletal muscle yet. Propolis exhibits strong anti-AGE properties, which are superior to those of quercetin or chlorogenic acid, well-known natural AGE inhibitors. Its flavonoid fraction potently impedes the synthesis of AGEs by trapping dicarbonyl intermediates [37]. Table 1 shows that propolis accelerated AGEs clearance in a model of muscle aging induced by administration of a precursor of AGEs (methylglyoxal) via activation of glyoxalase 1, an enzyme that eliminates dicarbonyl compounds (key elements of AGEs) [38]. CAPE inhibited the production of AGEs-related molecules such as protein carbonyl in the gastrocnemius muscle of rats via blockage of the activity of xanthine oxidase and adenosine deaminase [101,102,103]. The latter negatively affects insulin signaling and promotes the development of hyperglycemia, which represents a favorable condition for the production of AGEs [148]. However, propolis could not counteract the wasting effects of AGEs that already occurred in the extensor digitorum longus muscle though it tended to restore soleus muscle mass. This finding denotes that different muscle tissues respond differently to treatment, probably based on their ratio of type I to type II fibers. It also signifies the importance of early use of bee products (e.g., propolis) for the prevention of AGEs formation in skeletal muscle in people with high risk for AGEs formation such as diabetics [38].\n\n4.8. Neuronal Regeneration\nNeuronal denervation is a key factor that contributes to skeletal muscle loss, and it is related to a plethora of pathological conditions [3,149]. Experimental induction of oxidative stress and inflammation results in skeletal muscle atrophy through induction of denervation e.g., of sciatic nerve [150]. Injuries of peripheral nerves (e.g., sciatic nerve) interrupt mechanical transmission and microvasculation of the nerve and induce reperfusion. Reperfusion involves pooling of oxygen and nutrients promoting high emission of free radicals, which attack protein and lipid contents surrounding the injury site resulting in excessive tissue loss [113]. Likewise, alterations in gut microbiome in aged rats are associated with alterations in serum level of vitamin B12 and fat metabolism as well as reductions in the gastrocnemius muscle mass and sciatic response amplitude [151]. Furthermore, dysregulation of insulin-mediated GLUT4 activity in certain areas of the central nervous system impairs neuronal metabolism and plasticity [69]. Meanwhile, activation of PGC-1α, a core regulator of mitochondrial content and oxidative metabolism, increases muscle fiber resistance to denervation and atrophy through downregulation of two ubiquitin-ligases involved in the ubiquitin-proteasome pathway: MuRF1 and Atrogin-1 [1,152].\nPropolis treatment for four weeks restored gastrocnemius muscle weight and improved functional performance (e.g., walking) in rats with crush injury of the sciatic nerve. Effects of propolis were associated with increased nerve healing and regeneration as depicted by faster healing of the myelin sheath and ultra-structurally normal unmyelinated axons and Schwann cells. Investigations of motor conduction from the sciatic nerve to the gastrocnemius muscle indicated that nerve recovery induced by propolis treatment promoted optimal physical functioning by allowing motor conduction to reach the gastrocnemius muscle [113]. Neuroprotective effects of propolis in motor neurons are documented in the literature. Both kaempferide and kaempferol protected motor neurons against atrophy induced by the toxic copper-zinc superoxide dismutase in amyotrophic lateral sclerosis—a serious neurodegenerative disease that involves selective and progressive loss of motor neurons [65]. In addition, orally administered chrysin (a flavonoid that is copious in propolis) to rats intoxicated by 6-hydroxidopamine showed neuroprotective effects by mitigating neuroinflammation, enhancing levels of neurotrophins and neuronal recovery factors (e.g., brain derived neurotrophic factor and glial cell line-derived neurotrophic factor), and maintaining integrity of dopaminergic neurons resulting in better motor performance [72].\nThe release of acetylcholine (a neurotransmitter that regulates cognition) at the synaptic cleft of the neuromuscular junction is essential for motor neurotransmission, which controls excitation-contraction coupling and cell size. However, free radicals, cytokines, and AGEs impair neurotransmission by altering the production of acetylcholine [6,21,149,153]. On the other hand, upregulation of acetylcholine receptors improves neurotransmission [154]. Treatment with royal jelly may correct acetylcholine neurotransmission given its high content of acetylcholine (4–8 mM) [60]. In addition, royal jelly, propolis, and bee pollen are rich in antioxidant elements that have a potential to scavenge ROS and mitigate other pathologies that contribute to acetylcholine deficiency (e.g., neuroinflammation) [73,101,102,103]. In this respect, treatment of experimental models of carrageenan-induced hind paw edema with hydroalcoholic extract of red propolis and its biomarker, formononetin, is reported to inhibit leukocyte migration and ameliorate inflammatory neurogenic pain induced by injections of formalin and glutamate [115]. However, investigations of the action of bee products on neurotransmission are very scarce.\n\n4.9. Improving Muscular Blood Supply\nAging is associated with higher onset of atherosclerosis and restenosis, which involve vascular and microvascular damages that result from hyperproliferation of vascular smooth muscle cells (VSMCs) [155]. Muscle unloading (e.g., in sedentary lifestyle) involves chronic neuromuscular inactivity, which results in reductions in capillary number, luminal diameter, and capillary volume as well as heightened production of anti-angiogenic factors, such as p53 and TSP-1 in skeletal muscle [110]. Microvascular alterations and impaired nitric oxide (NO) production are key causes of decreased blood flow to the skeletal muscle. Poor muscular blood supply induces muscle wasting via a mechanism that entails impaired glucose metabolism and suboptimal protein anabolism [156,157]. In addition, ischemic injury in skeletal muscle is associated with high ROS release from polymorphonuclear leukocytes, which infiltrate muscle tissues. Free radicals alter cellular structure and function by attacking lipid and protein biomolecules that exist in the structure of biological membranes, enzymes, and transport proteins [102]. Therefore, improving vascularization and blood supply to skeletal muscle is a possible mechanism for the prevention of muscle wasting.\nMitchell and colleagues examined changes in microvascular blood volume, microvascular flow velocity, and microvascular blood flow in the quadriceps muscle following treatment with 15 g of amino acids in young and old subjects (20–70 years old). They detected improvements in all the 3 parameters only in young groups, and those effects were associated with proper insulin activity. Thus, the authors suggested that refeeding effects on muscular blood supply may be hindered by dysfunctions in postprandial circulation and glucose dysregulation [157]. Bee products such as bee pollen and propolis have a potential to boost microcirculation and correct pathologies that contribute to vascular dysfunction such as hyperglycemia and dyslipidemia [36,155]. In this context, CAPE, one of the basic constituents of propolis, was reported to combat vascular damages by counteracting the proliferative activity of platelet-derived growth factor. The molecular mechanism involved inducing cell-cycle arrest in VSMCs via activation of p38mitogen-activated protein kinase (MAPK), which was associated with accumulation of hypoxia-inducible factor (HIF)-1α—mainly due to inhibition of HIF prolylhydroxylase, a key contributor to proteasomal degradation of HIF-1α—and subsequent induction of HO-1 [155]. In the same regard, supplementing rats undergoing capillary regression (resulting from two weeks of hind limb unloading) in the soleus muscle with two daily intragastric doses of propolis for two weeks restored capillary number, capillary structure, capillary volume, and capillary to muscle fiber ratio through a mechanism that involves inhibition of anti-angiogenic factors and activation of pro-angiogenic factors (e.g., VEGF). The relative muscle-to-body weight in treated animals was higher than in the unloaded control animals, and the number of TUNEL-positive apoptotic endothelial cells in the soleus muscle was similar to that in the normal control animals [110]. Likewise, bee pollen (both neat and processed) increased blood vessels in the gastrocnemius muscle of rats undergoing muscle injury because of vigorous exercise [90]. Treating C2C12 myoblasts with propolis ethanolic extract increased VEGF production [108]. VEGF is a pro-angiogenic factor that contributes to angiogenesis by recruiting endothelial cells and promoting their differentiation to form new vascular networks. VEGF protects skeletal muscle undergoing unloading against the progression of capillary regression [110]. Its expression in skeletal muscle and associated angiogenic response increase following exercise due to change in the activity of HIF-1α and AMPK. It promotes the generation of ATP following mitochondrial biogenesis in order to meet oxygen demand [158]. Altogether, these reports signify that bee products and endurance exercise share common mechanisms to produce their vitality effects in skeletal muscle.\n\n4.10. Improving the Composition of Gut Microbiome\nBee products such as royal jelly and propolis display potent antifungal, bactericidal, microbicidal, anti-inflammatory, antioxidant, and healing effects [2,66]. Most bee products investigated in this review were administered orally. Therefore, it is likely that their therapeutic effects may start locally within the GI tract, which frequently undergoes propagation of harmful endobacteria, inflammation, aberrations, and permeability in advanced age [10,24,152]. In this respect, Roquetto and colleagues [116] supplemented C57BL/6 mice on HFD with crude propolis (0.2%) for two and five weeks. HFD increased the proportion of the phylum Firmicutes as well as levels of circulating lipopolysaccharide (LPS) and inflammatory biomarkers. DNA sequencing for the 16S rRNA of the gut microbiota revealed that five weeks of propolis treatment rendered the microbiota profile almost normal. Compared with untreated mice, propolis-supplemented animals demonstrated lower levels of serum triacylglycerols, glucose, and circulating LPS, along with reduced expression of TLR4 and inflammatory cytokines in skeletal muscle [116].\nLactic acid bacteria profusely exist in bee saliva and all bee products [36,83,84]. Various species of lactic acid bacteria have been experimentally used to correct GI dysbiosis and related muscle wasting [159,160]. Moreover, oligosaccharides have been chemically isolated from bee products [32,161]. These api-materials are classified as prebiotics, fermented non-digestible compounds that promote the proliferative activity of health-promoting bacteria [24,161]. Supplementing frail old adults with fructooligosaccharides expressed positive effects on skeletal muscle strength (handgrip) and endurance (exhaustion) [162]. On the other side, microbiome of the gut can affect the biological activity of bee products. The literature shows that certain endobacteria transform dietary polyphenols into phenolic acids, which can easily access the circulation and then cross the blood brain barrier to produce therapeutic effects [163]. Hence, it is important that future investigations of bee products among sarcopenic subjects examine the effect of these products on the composition of GI microbial population and its association with muscle-related outcomes."}

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Mechanisms of Action of Royal Jelly, Bee Pollen, and Propolis in Sarcopenia\nRelatively few studies have explored the mechanism through which royal jelly, bee pollen, and propolis may be beneficial for sarcopenia. In vivo and in vitro studies included in this review uncovered a number of inter-related cellular and molecular events that underlie the effect of these bee products on skeletal muscle including suppression of catabolic genes, counteracting metabolic abnormalities, inflammation, and oxidative damages as well as enhancement of motor neuronal regeneration, promotion of stem cell function, and correction of the structure of gut microbiome (Figure 1, Panel D). These mechanisms are exclusively described in the coming paragraphs.\n\n4.1. Modulating Inflammatory Responses in Skeletal Muscle\nThe role that inflammation plays in skeletal muscle is not quite clear as it looks. Inflammatory mediators behave in a dual fashion in muscle cells. During injury, cytokines and chemokines stimulate muscle repair and regeneration via activation of myoblasts, a core event in muscle remodeling [108]. Similarly, serum and muscle levels of IL-6 temporarily increase following physical exercise, and IL-6 blocks the activity of catabolic cytokines such as TNF-α. On the other hand, chronic inflammation in muscle cells, which correlates with persistent mitochondrial dysfunction and metabolic dysregulation, pathologically activates muscle fiber transformation and atrophy, eventually resulting in the development of sarcopenia [23,114]. It seems that bee products also act dually in skeletal muscle: they support the activity of cytokines that promote muscle remodeling [108] and suppress muscle-consuming cytokines [38,101,108]. In this regard, treating undifferentiated C2C12 myoblasts with ethanolic extracts of Brazilian propolis (100 μg/mL for 8 h) triggered the migration of RAW264 macrophage and increased their production of angiogenic factors (e.g., vascular endothelial growth factor A (VEGF-A) and metalloproteinase-12 (MMP-12)), chemokines (e.g., CCL-2 and CCL-5), and cytokines (e.g., IL-6, which increased by 40-folds). Propolis inhibited the expression of IL-1β and TNF-α at 4, 8, and 12 h of incubation. These effects were nuclear factor kappa B (NF-κB)-dependent given that propolis simultaneously increased nuclear translocation of p65 and p50 NF-κB proteins 3 h after treatment. Meanwhile, inhibiting IκB kinase (IKK) by BMS-345541 profoundly hindered the effect of propolis on the expression of CCL-2, CCL-5, and IL-6 by 66%, 81%, and 69%, respectively. Propolis also enhanced the expression of MAIL/IκBζ. This molecule modulates chromatin and selectively induces the production of IL-6, leukemia inhibitory factor (LIF), and CCL-2 [108].\nChronic muscle tissue infiltration by inflammatory cells (e.g., leukocytes, neutrophils, and monocytes) activates oxidative and inflammatory signaling cascades that degrade cellular structures and promote necrosis such as inducible nitric oxide synthase (iNOS) and NF-kB [90,101,115]. CAPE and high levels (200 and 300 mg/kg) of crude and processed bee pollen reduced inflammatory cell infiltration into the gastrocnemius muscle of rats with muscle injury induced by eccentric exercise and ischemia reperfusion [90,101,102]. This effect was revealed by lower activity of myeloperoxidase, an indicator of neutrophil sequestration [101,102]. As such, CAPE and bee pollen not only suppressed lipid peroxidation (lower levels of malondialdehyde, MDA) but also inhibited the activity of myostatin and the production of muscle depleting cytokines and chemokines such as IL-1β, α2-macroglobulin, and monocyte chemotactic protein 1 (MCP-1) [36,38,90,101]. The underlying mechanism entailed downregulation of nuclear p65NF-κB and blockage of its consensus binding sites in skeletal muscle [101]. As a result, bee products increased muscle mass both in sarcopenic obese rat and malnourished old rats [36] and restored the structure of myofibers (despite the persistence of necrosis) compared with untreated eccentric exercising animals, which demonstrated necrotic and fragmented myofibers [90].\nRoyal jelly downregulated the activity of tumor necrosis factor receptor 1 (TNFR1) in the adipose tissue of aged obese rats receiving HFD [100]. TNFR1 interacts with TNFR2 to negatively regulate toll-like receptors (TLR) and Nod-like receptor signaling and stimulate excessive release of cytokines via activation of key inflammatory pathways such as NF-κB [107]. Mitigation of TNFR1 was associated with a significant increase of the weight of hind limb muscle and reductions in insulin levels, homeostatic model assessment of insulin resistance (HOMA-IR), serum lipids, muscle triglyceride levels, body weight gain, and abdominal fat weight. Therefore, royal jelly may protect against muscle loss in conditions involving impairment of the adipokine profile mainly through suppression of inflammatory responses associated with high fat mass, which is followed by correction of metabolic irregularities [100].\n\n4.2. Counteracting Oxidative Stress in Skeletal Muscle\nHigh production of reactive oxygen species (ROS) in skeletal muscle tissues has serious destructive effects, which alter the integrity of skeletal muscle resulting into fatigue, muscle wasting, and muscle weakness [90,101]. Sources of intramuscular ROS are numerous including mitochondrial dysfunction (e.g., alteration of mitochondrial enzymes in the respiratory chain as well as enzymes responsible for β-oxidation), neutrophil infiltration, and the activity of cytokines and major muscle degrading molecules such as myostatin [21,36,38,101,102,118]. Oxidative and nitrosative damages in skeletal muscle tissues are mediated by the activity of numerous pro-oxidant enzymes that are associated with inflammatory processes such as cyclooxygenase-2 (COX-2) and iNOS [101]. ROS triggers the activity of corrosive molecules such as poly (ADP-ribose) polymerase (PARP), xanthine oxidase, and adenosine deaminase, which contribute to DNA damage, lipid peroxidation (e.g., increased MDA), and protein nitrotyrosylation as well as ATP catabolism in muscle tissues [101,102].\nRoyal jelly enhanced the activity of antioxidant enzymes and suppressed lipid peroxidation in a d-galactose induced model of aging [95]. Two weeks of propolis treatment in rats undergoing hind limb unloading significantly reduced nuclear ROS levels and numbers of apoptotic endothelial cells in the soleus muscle to levels similar to normal rats [110]. Moreover, propolis significantly suppressed MDA activity in skeletal muscle and increased liver levels of SOD as well as gastrocnemius muscle levels of SOD, glutathione peroxidase and catalase in rats on eccentric exercise training (70% VO2max treadmill running exercise for 60 min) compared with rats receiving exercise alone or no treatment [109]. In addition, intraperitoneal pre-administration of CAPE (60 min before induction of ischemia reperfusion) significantly ameliorated the effects associated with high ROS levels, which accompany acute ischemia such as protein peroxidation and ATP catabolism in the gastrocnemius muscle [102].\nBee products probably reduced ROS production via regulation of the activity of mitochondrial enzymes. Royal jelly increased the maximal activity of citrate synthase (CS) and β-hydroxyacyl coenzyme A dehydrogenase (β-HAD) in the soleus muscle of rats on endurance training [106]. Bee pollen restored mitochondrial complex-I, -II, -III, and -IV enzyme activity to normal, increased SOD and glutathione, and reduced MDA, NO, and total protein content in the gastrocnemius muscle of rats on exhaustive exercise [90]. It also increased the activity of CS and complex IV in malnourished old rats via a mechanism that involved activation of mTOR [36]. mTOR is a major signaling pathway that regulates various signaling cascades involved in metabolism and autophagy such nuclear respiratory factor 2 (NRF2) [2]. Therefore, it is possible that the antioxidant activity demonstrated by bee products, particularly that expressed in the mitochondria, is associated with their metabolic and hypoglycemic activities. For instance, 10-HDA increased expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) in skeletal muscle of diabetic mice [112,119]. Similarly, aged mice treated with amino acids similar to those found in royal jelly demonstrated improved size of muscle fiber by increasing PGC-1α mRNA levels. PGC-1α functions as a key regulator of sirtuin 1, which limits ROS production through stimulation of mitochondrial biogenesis and ROS defense system, thus protecting metabolically active tissues against oxidative damage [120]. Mechanistically, when PGC-1α gets activated, it interacts with other bioactive molecules such as muscle-specific transcription factors to stimulate the expression of genes that induce mitochondrial oxidative metabolism in brown fat and fiber-type switching in skeletal muscle [121].\nThe antioxidant activity of royal jelly and CAPE might be related to their strong capacity to activate the master redox-active NRF2 signaling pathway [73,122], which stimulates the production of internal antioxidants such as heme oxygenase-1 (HO-1), which scavenge free radicals [123]. Meanwhile, NRF2 and HO-1 block ROS production indirectly via suppression of inflammatory reactions [122]. In this context, CAPE reduced degenerative myopathy in rats on eccentric exercise via a complex mechanism that involved inhibition of NF-κB and its downstream pro-oxidant COX-2 and iNOS [101]. Correspondingly, CAPE decreased markers of oxidative cellular damages (protein carbonyl, protein nitrosylation, xanthine oxidase, and adenosine deaminase) associated with ischemia reperfusion and eccentric exercise in the gastrocnemius muscle [101,102,103]. In this regard, CAPE operated via a mechanism that involved inhibition of neutrophil and leukocyte infiltration into the gastrocnemius muscle, which was associated with decreased levels of myeloperoxidase. Myeloperoxidase contributes to excessive production of ROS and oxidative organ damage through a mechanism that embroils increased synthesis of hypochlorous acid [101,102]. Furthermore, CAPE accelerated purine salvage for ATP synthesis and inhibited ROS-induced lipid peroxidation via attenuation of the activity of adenosine deaminase [102].\nIn summary, the reported antioxidant effects of bee products were multifaceted involving increased production of antioxidant enzymes [90,95,109,110], and decreased ROS production [90,101,102,103,110] (secondary to reduction of inflammatory cell infiltration into skeletal muscle) [90,101,102,103], and restoration of mitochondrial activity [36,90,106].\n\n4.3. Metabolic Regulation\nSkeletal muscle is the main tissue that utilizes insulin for glucose uptake. Insulin regulates mitochondrial oxidative phosphorylation of proteins in human skeletal muscle and contributes to calcium mobilization from the sarcoplasmic-endoplasmic reticulum to mitochondria to stimulate the translocation of glucose transporter 4 (GLUT4) to the cell surface for glucose uptake. This process improves muscle protein synthesis in healthy people when the delivery of amino acids to skeletal muscle is increased, eventually leading to increased muscular mass [124,125,126]. Insulin resistance and glucose intolerance increase with old age evoking muscle loss. In this respect, hypoglycemic agents such as metformin can improve skeletal muscle metabolism via activation of adenosine monophosphate activated protein kinase (AMPK) [21].\nAMPK, a heterotrimeric complex that consists of a catalytic subunit and two regulatory subunits, is an intracellular energy sensor that regulates glucose and lipid metabolism. It gets activated when cellular energy is depleted through allosteric binding of AMP or phosphorylation by AMPK kinase at Thr172 of the catalytic subunit by AMPK kinase. Upregulated AMPK activates signaling pathways that generate ATP from glucose and fatty acid oxidation, and it simultaneously blocks signaling that contributes to the synthesis of cholesterol, fatty acid, and triacylglycerol [111]. In addition, AMPK masters numerous signaling cascades such as Forkhead Box O transcription factor (FOXO) and AKT/mTOR, which regulate the expression of genes associated with inflammation, oxidative stress, mitochondrial function, autophagy, metabolism, and apoptosis [127,128].\nThe molecular events involved in the effect of bee products on catabolic genes and anabolic resistance in skeletal muscle could be much related to their hypoglycemic effects, which positively affect the quality of skeletal muscle. Evidence signifies a positive effect of royal jelly acid (10-HDA) on inflammation and autophagy via upregulation of AMPK, which subsequently alters NF-κB and NLRP3 inflammasome-IL1β signaling [129]. Positive effects of whole royal jelly on skeletal muscle are associated with improved insulin signaling [96,100]. In one study, royal jelly improved serum IGF-1 levels in aged rats and increased AKT signaling in satellite cells extracted from aged rats in a separate in vitro investigation [96]. In another study, royal jelly decreased fat mass and improved anabolic resistance in the skeletal muscle of old obese rats on HFD via downregulation of inflammatory responses in adipose tissue as indicated by downregulation of TNFR1. This effect was associated with enhanced sensitivity to insulin—portrayed by reduction of serum insulin level and HOMA-IR [100].\nJapanese researchers proved that oral consumption of royal jelly and 10-HDA induced mitochondrial adaptation in the soleus muscle when accompanied with endurance training. These compounds also enhanced glucose uptake in skeletal muscle by inducing the phosphorylation of AMPK [106,112], an effect that was mediated by the upstream kinase Ca²⁺/calmodulin-dependent kinaseβ—independently of changes in AMP:ATP ratio and the liver kinase B1 pathway. Activation of AMPK was followed by translocation of GLUT4 to the plasma membrane of L6 myotubes [106]. It is note-worthy that effects of royal jelly on mitochondrial biogenesis under endurance training were muscle-specific. In this respect, neither endurance training nor royal jelly alone had an effect on the maximal activities of CS and β-HAD—the enzyme that catalyzes the rate-limiting step of β-oxidation of long-chain fatty acids—in the soleus muscle, which comprises type I fiber (around 35–45%) and type IIa (around 35–50%). On the other hand, royal jelly enhanced the activity of these enzymes in the soleus muscle of mice on endurance training. Of interest, endurance training increased the activity of CS and β-HAD in the plantaris and tibialis anterior muscles (which are mainly type II fiber with a total percentage of type IIb and type IIx fiber types of 90%) while royal jelly failed to exert an effect on these muscles in sedentary mice [106]. Nonetheless, the observed effects of royal jelly in the soleus muscle represent a merit. This is mainly because the oxidative type I fibers (e.g., soleus muscle) naturally undergo higher protein turnover (especially degradation), which makes them unable to grow in size or respond properly to insufficient nutrient intake [130].\nSeveral lines of evidence indicate that propolis may affect muscle quality through the regulation of glucose metabolism [69,70,109,111]. This effect was vividly depicted in vivo by increased glycogen level in skeletal muscle and reduced serum levels of glucose and insulin [109]. Same as insulin, ethanolic extracts of propolis and CAPE induced glucose uptake [69,70,111] and potentiated insulin-mediated AKT activation and glucose uptake in differentiated L6 myoblast cells [111]. Likewise, Italian propolis at concentrations of 0.1 and 1 mg/mL as well as 4-geranyloxyferulic acid and auraptene (2 oxyprenylated phenylpropanoids, which are abundant in propolis) remarkably increased GLUT4 translocation to the plasma membrane and accelerated GLUT4-mediated glucose uptake in L6 skeletal myoblasts. The effect of propolis at a concentration of 11 mg/mL was significantly superior to the effect of insulin (0.1 μM), which was used as a positive control [69].\nSimilar to royal jelly, the effects of propolis (1 μg/mL), CAPE (10 μM), artepillin C, coumaric acid, and kaempferide on glucose metabolism occurred via activation of AMPK. These effects were comparable to those of 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), a potent AMPK activator. In the meantime, co-treatment with inhibitors of AMPK (e.g., compound C) and of phosphatidylinositol 3-kinase (PI3K) (e.g., LY-294002) blocked the effects of CAPE [70,111]. Phosphorylation of AMPK results in activation of the insulin receptor (IR) and subsequent phosphorylation of PI3K followed by activation of AKT and protein kinase C (PKC) leading to GLUT4 translocation and subsequent activation of several molecules that modulate insulin-stimulated glucose transport, eventually leading to glucose influx into cells of several tissues such as skeletal muscle and adipose tissue [69,70,111]. It is worth noting that the effects of CAPE on AMPK and AKT were quick (within 1 h and 3 min, respectively), and they vanished quickly (both molecules returned back to their basal levels within 12 h and 30 min, respectively) [111].\n\n4.4. Enhancement of Muscle Protein Synthesis\nImbalance between muscle protein synthesis and degradation is associated with low protein intake and altered efficiency of the GI tract in old age, which triggers skeletal muscle loss and poor physical performance [36,40], given that proteins are the main building blocks of muscle myofibers. Moreover, transmembrane proteins and micro-peptides (e.g., myomixer and myomaker/Tmem8c) contribute to the formation of myofibers by promoting myoblast fusion via a mechanism that involves appropriate localization of Tmem8c at the plasma membrane of myoblasts allowing trafficking related to palmitoylation of C-terminal cysteine residues and C-terminal leucine [17]. Amino acid supplements (e.g., leucine, a master dietary regulator of muscle protein turnover, and its metabolite β-hydroxy β-methylbutyrate) and early refeeding with high protein diet (especially fast digestive proteins) can preserve muscle mass and function, revert sarcopenia, and enhance mobility and quality of life (QoL) by correcting age-related nutritional deficiencies, muscle protein turnover, and immune dysregulation—these effects are even greater when combined with other nutrients like vitamin D or omega 3 fatty acids as well as with physical exercise [6,131,132,133,134,135,136,137,138].\nResearch indicates that age-related skeletal muscle wasting results mainly from insufficient delivery of amino acids to skeletal muscle due to dysregulations in the activity of mTORC1- and activating transcription factor-4 (ATF4)-mediated amino acid sensing pathways. Meanwhile, interventions that ameliorate age-related damages in skeletal muscle operate primarily by reversing alterations in the delivery of amino acids to skeletal muscle via upregulation of mTORC1 and/or ATF4 [139]. mTORC1 is a nutrient sensing protein that acts as a core regulator of protein metabolism. It is sensitive to amino acids, energy status (ATP), stress (e.g., oxidative stress), and growth factors (e.g., insulin), which all can regulate its signaling [2,136]. Nevertheless, bioavailability of amino acids is necessary for growth factors to effectively activate mTORC1. Even more, amino acids on their own can adequately activate mTORC1 [136]. Evidence from preclinical and human studies confirms that ingestion of essential amino acids (similar to those found in royal jelly and bee pollen such as valine) increases cellular bioavailability of amino acids, which is associated with activation of the endothelial nitric oxide synthase (eNOs) pathway. eNOs further upregulates mTORC1 kinase. Translocation of mTORC1 from the cytosol to the surface of lysosomes is associated with improved mitochondrial biogenesis and cellular oxidative capacity in skeletal muscle due to activation of its substrates: P70 ribosomal proteins S6 kinase (S6K) and eukaryotic translation initiation 4E-binding protein 1 (eIF4E, also known as 4eBP1) [120,135,136].\nAs shown in Table 1, royal jelly and 10-HDA significantly increased muscle mass [54,96,100] and improved motor performance in aged rats [95,98,99]. In addition, dietary supplementation with monofloral bee pollen significantly improved the rate of muscle protein synthesis and restored muscle mass in emaciated old rats via upregulation of mTOR and two related downstream controllers of protein translation: p70S6k and 4eBP1, which were suppressed in malnourished old rats [36]. Although propolis improved various muscle-related parameters, its effect on muscle mass in rodents was limited—relative to royal jelly and bee pollen. However, it fostered muscle protein deposition in post-larva Nile tilapia [104]. Moreover, milk naturally enriched with PUFA and polyphenols from propolis remarkably increased the weight of the gastrocnemius muscle of growing obese rats while whole milk and milk enriched with PUFA only could not express any effect on skeletal muscle [105]. Therefore, this finding denotes that propolis could have enhanced the delivery of amino acids available in milk to skeletal muscle leading to its growth. Altogether, it is likely that the observed anabolic effects of royal jelly and bee pollen are associated with their high content of proteins and amino acids [32,36,83,84,85,86].\n\n4.5. Suppression of Catabolic Activity in Skeletal Muscle\nSkeletal muscle tissues represent the largest protein store in the human body (30–45% of total protein). Muscular mass, strength, and functions are greatly governed by the rates of muscle protein synthesis and turnover [124]. Muscle protein metabolism is regulated by the interaction of a wide range of genes. Aging is associated with various stresses, which increase the expression of catabolic genes such as E3 ubiquitin ligases MuRF1 and atrogin-1 (MAFbx). These genes heighten the occurrence of age-related muscular atrophy [97]. Oral consumption of royal jelly by aged HET mice resulted in lower levels of catabolic genes (e.g., MuRF1 and MAFbx), which were similar to those in young mice. In the meantime, the expression of these genes in the control mice was high indicating that royal jelly can delay age-related muscular apoptosis by suppressing the activity of catabolic genes [97]. Two other studies reported that CAPE suppressed catabolism that contributed to degenerative myopathy in the gastrocnemius muscle of rats undergoing eccentric exercising or femoral artery ligation as reflected by decreased serum levels of creatine kinase, a marker of muscular proteolysis [101,102,103]. Apart from skeletal muscle, CAPE was reported to protect heart muscle against age-related deteriorations such as accumulation of lipofuscin, nuclear irregularity, mitochondrial degeneration, and myofilament disorganization and disruption [33].\nThe molecular mechanism underling blockage of muscle proteolysis by bee products in sarcopenic rodents involves an interplay of various signaling pathways. Royal jelly and bee pollen activated mTOR and its substrate AKT, which are suggested to inhibit muscular proteolysis [36,96]. Similar to the effect of royal jelly on catabolic genes in HET mice, treating both L6 myoblasts and rats with propolis, CAPE, and kaempferide resulted in potent activation of AKT in a PI3K-dependent manner [111], in addition to phosphorylation of IR, PI3K, and AMPK [70]. AKT, a key substrate of mTORC2, is a conserved serine/threonine nutrient sensing protein kinase that belongs to the PI3k-related protein kinase family. Upon presence of growth factors, PI3k gets activated by IR substrate resulting in stimulation of a series of signaling cascades that involve activation of AKT, which leads to further activation of mTORC1. mTORC1 activates the phosphorylation of two main regulators of cap-dependent protein synthesis: S6K and eIF4E [2,140]. In addition, mTORC1 contributes to autophagy—a turnover process that involves clearance of dysfunctional organelles and long-lived protein aggregations with provision of energy and macromolecular precursors in return—by binding with AMPK resulting in phosphorylation of autophagy genes such as Unc51-like kinase 1 at different sites [140]. In fact, royal jelly is reported to fine-tune the transcriptional activity of the FOXO through modulating the activity of insulin/IGF-1 signaling [141]. FOXO plays a major role in the activation of AKT pathway, which implicates regulation of multiple stress–response pathways such as ROS detoxification and DNA repair and translation. In addition, the FOXOs family exerts a direct effect on certain muscle atrophy genes such as MUSA1 and a formerly uncharacterized ligase known as Specific of Muscle Atrophy and Regulated by Transcription (SMART) [142].\n\n4.6. Enhancement of Stem Cell Function\nReduction of the number and functional capacity of the muscle satellite cells is considered a core contributor to the development of age-related muscular dysfunction [96]. Induction of myogenesis via in vivo reprogramming of muscle satellite cells is a currently studied strategy that has not been successfully used for sarcopenia treatment yet [143]. On the other hand, treating sarcopenic rats with both royal jelly and pRJ was reported to increase the number of Pax7-positive satellite cells in vivo and in vitro (pRJ only). pRJ induced self-renewal of satellite cells via activation of AKT signaling [96,97]. AKT activity was associated with activation of IGF-1 as indicated by increased serum levels of IGF-1. IGF-1 plays a crucial rule in the activation of various signaling pathways; it is believed to be a major mediator of muscle growth and repair that functions by stimulating the proliferation and differentiation of satellite cells into myotubes, albeit the exact mechanism is not clear yet [96]. Similarly, pRJ activated AKT-signaling pathway in satellite cells culture, which was associated with increased proliferation of myosatellite cells and their differentiation into myotubes—an effect that is contradictory to muscle loss. AKT is thought to contribute to the synthesis of muscular proteins and inhibition of muscle proteolysis [96].\n\n4.7. Counteracting Glycation Stress\nOxidative stress, inflammation, and insensitivity to insulin, which accompany advanced age, contribute to the production of advanced glycation end products (AGEs) via enhancement of the activity of the Receptor for Advanced Glycation End products (RAGE) [144,145]. AGEs destroy the protein and lipid ingredients of muscle tissues by promoting the production of destructive molecules such as free radicals and inflammatory cytokines [101,102,113]. Thanks to their potent antioxidant properties, polyphenolic compounds exert multifaceted anti-glycation functions. On one hand, they scavenge free-radicals and chelate transition metals that are involved in the synthesis of dicarbonyl intermediates subsequently resulting in inhibition of the formation of AGEs. On the other hand, polyphenolic compounds antagonize AGE receptors, mainly RAGE, and facilitate the removal of already formed a,b-dicarbonyl intermediates such as methylglyoxal, promoting the degradation of AGEs [37,38,146]. Royal jelly is reported to downregulate the activity of RAGE, the main receptor for AGEs, in an aged model of cognitive impairment [147]. However, its anti-glycation effect has not been investigated in skeletal muscle yet. Propolis exhibits strong anti-AGE properties, which are superior to those of quercetin or chlorogenic acid, well-known natural AGE inhibitors. Its flavonoid fraction potently impedes the synthesis of AGEs by trapping dicarbonyl intermediates [37]. Table 1 shows that propolis accelerated AGEs clearance in a model of muscle aging induced by administration of a precursor of AGEs (methylglyoxal) via activation of glyoxalase 1, an enzyme that eliminates dicarbonyl compounds (key elements of AGEs) [38]. CAPE inhibited the production of AGEs-related molecules such as protein carbonyl in the gastrocnemius muscle of rats via blockage of the activity of xanthine oxidase and adenosine deaminase [101,102,103]. The latter negatively affects insulin signaling and promotes the development of hyperglycemia, which represents a favorable condition for the production of AGEs [148]. However, propolis could not counteract the wasting effects of AGEs that already occurred in the extensor digitorum longus muscle though it tended to restore soleus muscle mass. This finding denotes that different muscle tissues respond differently to treatment, probably based on their ratio of type I to type II fibers. It also signifies the importance of early use of bee products (e.g., propolis) for the prevention of AGEs formation in skeletal muscle in people with high risk for AGEs formation such as diabetics [38].\n\n4.8. Neuronal Regeneration\nNeuronal denervation is a key factor that contributes to skeletal muscle loss, and it is related to a plethora of pathological conditions [3,149]. Experimental induction of oxidative stress and inflammation results in skeletal muscle atrophy through induction of denervation e.g., of sciatic nerve [150]. Injuries of peripheral nerves (e.g., sciatic nerve) interrupt mechanical transmission and microvasculation of the nerve and induce reperfusion. Reperfusion involves pooling of oxygen and nutrients promoting high emission of free radicals, which attack protein and lipid contents surrounding the injury site resulting in excessive tissue loss [113]. Likewise, alterations in gut microbiome in aged rats are associated with alterations in serum level of vitamin B12 and fat metabolism as well as reductions in the gastrocnemius muscle mass and sciatic response amplitude [151]. Furthermore, dysregulation of insulin-mediated GLUT4 activity in certain areas of the central nervous system impairs neuronal metabolism and plasticity [69]. Meanwhile, activation of PGC-1α, a core regulator of mitochondrial content and oxidative metabolism, increases muscle fiber resistance to denervation and atrophy through downregulation of two ubiquitin-ligases involved in the ubiquitin-proteasome pathway: MuRF1 and Atrogin-1 [1,152].\nPropolis treatment for four weeks restored gastrocnemius muscle weight and improved functional performance (e.g., walking) in rats with crush injury of the sciatic nerve. Effects of propolis were associated with increased nerve healing and regeneration as depicted by faster healing of the myelin sheath and ultra-structurally normal unmyelinated axons and Schwann cells. Investigations of motor conduction from the sciatic nerve to the gastrocnemius muscle indicated that nerve recovery induced by propolis treatment promoted optimal physical functioning by allowing motor conduction to reach the gastrocnemius muscle [113]. Neuroprotective effects of propolis in motor neurons are documented in the literature. Both kaempferide and kaempferol protected motor neurons against atrophy induced by the toxic copper-zinc superoxide dismutase in amyotrophic lateral sclerosis—a serious neurodegenerative disease that involves selective and progressive loss of motor neurons [65]. In addition, orally administered chrysin (a flavonoid that is copious in propolis) to rats intoxicated by 6-hydroxidopamine showed neuroprotective effects by mitigating neuroinflammation, enhancing levels of neurotrophins and neuronal recovery factors (e.g., brain derived neurotrophic factor and glial cell line-derived neurotrophic factor), and maintaining integrity of dopaminergic neurons resulting in better motor performance [72].\nThe release of acetylcholine (a neurotransmitter that regulates cognition) at the synaptic cleft of the neuromuscular junction is essential for motor neurotransmission, which controls excitation-contraction coupling and cell size. However, free radicals, cytokines, and AGEs impair neurotransmission by altering the production of acetylcholine [6,21,149,153]. On the other hand, upregulation of acetylcholine receptors improves neurotransmission [154]. Treatment with royal jelly may correct acetylcholine neurotransmission given its high content of acetylcholine (4–8 mM) [60]. In addition, royal jelly, propolis, and bee pollen are rich in antioxidant elements that have a potential to scavenge ROS and mitigate other pathologies that contribute to acetylcholine deficiency (e.g., neuroinflammation) [73,101,102,103]. In this respect, treatment of experimental models of carrageenan-induced hind paw edema with hydroalcoholic extract of red propolis and its biomarker, formononetin, is reported to inhibit leukocyte migration and ameliorate inflammatory neurogenic pain induced by injections of formalin and glutamate [115]. However, investigations of the action of bee products on neurotransmission are very scarce.\n\n4.9. Improving Muscular Blood Supply\nAging is associated with higher onset of atherosclerosis and restenosis, which involve vascular and microvascular damages that result from hyperproliferation of vascular smooth muscle cells (VSMCs) [155]. Muscle unloading (e.g., in sedentary lifestyle) involves chronic neuromuscular inactivity, which results in reductions in capillary number, luminal diameter, and capillary volume as well as heightened production of anti-angiogenic factors, such as p53 and TSP-1 in skeletal muscle [110]. Microvascular alterations and impaired nitric oxide (NO) production are key causes of decreased blood flow to the skeletal muscle. Poor muscular blood supply induces muscle wasting via a mechanism that entails impaired glucose metabolism and suboptimal protein anabolism [156,157]. In addition, ischemic injury in skeletal muscle is associated with high ROS release from polymorphonuclear leukocytes, which infiltrate muscle tissues. Free radicals alter cellular structure and function by attacking lipid and protein biomolecules that exist in the structure of biological membranes, enzymes, and transport proteins [102]. Therefore, improving vascularization and blood supply to skeletal muscle is a possible mechanism for the prevention of muscle wasting.\nMitchell and colleagues examined changes in microvascular blood volume, microvascular flow velocity, and microvascular blood flow in the quadriceps muscle following treatment with 15 g of amino acids in young and old subjects (20–70 years old). They detected improvements in all the 3 parameters only in young groups, and those effects were associated with proper insulin activity. Thus, the authors suggested that refeeding effects on muscular blood supply may be hindered by dysfunctions in postprandial circulation and glucose dysregulation [157]. Bee products such as bee pollen and propolis have a potential to boost microcirculation and correct pathologies that contribute to vascular dysfunction such as hyperglycemia and dyslipidemia [36,155]. In this context, CAPE, one of the basic constituents of propolis, was reported to combat vascular damages by counteracting the proliferative activity of platelet-derived growth factor. The molecular mechanism involved inducing cell-cycle arrest in VSMCs via activation of p38mitogen-activated protein kinase (MAPK), which was associated with accumulation of hypoxia-inducible factor (HIF)-1α—mainly due to inhibition of HIF prolylhydroxylase, a key contributor to proteasomal degradation of HIF-1α—and subsequent induction of HO-1 [155]. In the same regard, supplementing rats undergoing capillary regression (resulting from two weeks of hind limb unloading) in the soleus muscle with two daily intragastric doses of propolis for two weeks restored capillary number, capillary structure, capillary volume, and capillary to muscle fiber ratio through a mechanism that involves inhibition of anti-angiogenic factors and activation of pro-angiogenic factors (e.g., VEGF). The relative muscle-to-body weight in treated animals was higher than in the unloaded control animals, and the number of TUNEL-positive apoptotic endothelial cells in the soleus muscle was similar to that in the normal control animals [110]. Likewise, bee pollen (both neat and processed) increased blood vessels in the gastrocnemius muscle of rats undergoing muscle injury because of vigorous exercise [90]. Treating C2C12 myoblasts with propolis ethanolic extract increased VEGF production [108]. VEGF is a pro-angiogenic factor that contributes to angiogenesis by recruiting endothelial cells and promoting their differentiation to form new vascular networks. VEGF protects skeletal muscle undergoing unloading against the progression of capillary regression [110]. Its expression in skeletal muscle and associated angiogenic response increase following exercise due to change in the activity of HIF-1α and AMPK. It promotes the generation of ATP following mitochondrial biogenesis in order to meet oxygen demand [158]. Altogether, these reports signify that bee products and endurance exercise share common mechanisms to produce their vitality effects in skeletal muscle.\n\n4.10. Improving the Composition of Gut Microbiome\nBee products such as royal jelly and propolis display potent antifungal, bactericidal, microbicidal, anti-inflammatory, antioxidant, and healing effects [2,66]. Most bee products investigated in this review were administered orally. Therefore, it is likely that their therapeutic effects may start locally within the GI tract, which frequently undergoes propagation of harmful endobacteria, inflammation, aberrations, and permeability in advanced age [10,24,152]. In this respect, Roquetto and colleagues [116] supplemented C57BL/6 mice on HFD with crude propolis (0.2%) for two and five weeks. HFD increased the proportion of the phylum Firmicutes as well as levels of circulating lipopolysaccharide (LPS) and inflammatory biomarkers. DNA sequencing for the 16S rRNA of the gut microbiota revealed that five weeks of propolis treatment rendered the microbiota profile almost normal. Compared with untreated mice, propolis-supplemented animals demonstrated lower levels of serum triacylglycerols, glucose, and circulating LPS, along with reduced expression of TLR4 and inflammatory cytokines in skeletal muscle [116].\nLactic acid bacteria profusely exist in bee saliva and all bee products [36,83,84]. Various species of lactic acid bacteria have been experimentally used to correct GI dysbiosis and related muscle wasting [159,160]. Moreover, oligosaccharides have been chemically isolated from bee products [32,161]. These api-materials are classified as prebiotics, fermented non-digestible compounds that promote the proliferative activity of health-promoting bacteria [24,161]. Supplementing frail old adults with fructooligosaccharides expressed positive effects on skeletal muscle strength (handgrip) and endurance (exhaustion) [162]. On the other side, microbiome of the gut can affect the biological activity of bee products. The literature shows that certain endobacteria transform dietary polyphenols into phenolic acids, which can easily access the circulation and then cross the blood brain barrier to produce therapeutic effects [163]. Hence, it is important that future investigations of bee products among sarcopenic subjects examine the effect of these products on the composition of GI microbial population and its association with muscle-related outcomes."}

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,{"id":"A59","pred":"hp_id","subj":"T59","obj":"http://purl.obolibrary.org/obo/HP_0007354"},{"id":"A60","pred":"hp_id","subj":"T60","obj":"http://purl.obolibrary.org/obo/HP_0002180"},{"id":"A61","pred":"hp_id","subj":"T61","obj":"http://purl.obolibrary.org/obo/HP_0000969"},{"id":"A62","pred":"hp_id","subj":"T62","obj":"http://purl.obolibrary.org/obo/HP_0012531"},{"id":"A63","pred":"hp_id","subj":"T63","obj":"http://purl.obolibrary.org/obo/HP_0002621"},{"id":"A64","pred":"hp_id","subj":"T64","obj":"http://purl.obolibrary.org/obo/HP_0003202"},{"id":"A65","pred":"hp_id","subj":"T65","obj":"http://purl.obolibrary.org/obo/HP_0003202"},{"id":"A66","pred":"hp_id","subj":"T66","obj":"http://purl.obolibrary.org/obo/HP_0003074"},{"id":"A67","pred":"hp_id","subj":"T67","obj":"http://purl.obolibrary.org/obo/HP_0003119"},{"id":"A68","pred":"hp_id","subj":"T68","obj":"http://purl.obolibrary.org/obo/HP_0012418"},{"id":"A69","pred":"hp_id","subj":"T69","obj":"http://purl.obolibrary.org/obo/HP_0003202"}],"text":"4. Mechanisms of Action of Royal Jelly, Bee Pollen, and Propolis in Sarcopenia\nRelatively few studies have explored the mechanism through which royal jelly, bee pollen, and propolis may be beneficial for sarcopenia. In vivo and in vitro studies included in this review uncovered a number of inter-related cellular and molecular events that underlie the effect of these bee products on skeletal muscle including suppression of catabolic genes, counteracting metabolic abnormalities, inflammation, and oxidative damages as well as enhancement of motor neuronal regeneration, promotion of stem cell function, and correction of the structure of gut microbiome (Figure 1, Panel D). These mechanisms are exclusively described in the coming paragraphs.\n\n4.1. Modulating Inflammatory Responses in Skeletal Muscle\nThe role that inflammation plays in skeletal muscle is not quite clear as it looks. Inflammatory mediators behave in a dual fashion in muscle cells. During injury, cytokines and chemokines stimulate muscle repair and regeneration via activation of myoblasts, a core event in muscle remodeling [108]. Similarly, serum and muscle levels of IL-6 temporarily increase following physical exercise, and IL-6 blocks the activity of catabolic cytokines such as TNF-α. On the other hand, chronic inflammation in muscle cells, which correlates with persistent mitochondrial dysfunction and metabolic dysregulation, pathologically activates muscle fiber transformation and atrophy, eventually resulting in the development of sarcopenia [23,114]. It seems that bee products also act dually in skeletal muscle: they support the activity of cytokines that promote muscle remodeling [108] and suppress muscle-consuming cytokines [38,101,108]. In this regard, treating undifferentiated C2C12 myoblasts with ethanolic extracts of Brazilian propolis (100 μg/mL for 8 h) triggered the migration of RAW264 macrophage and increased their production of angiogenic factors (e.g., vascular endothelial growth factor A (VEGF-A) and metalloproteinase-12 (MMP-12)), chemokines (e.g., CCL-2 and CCL-5), and cytokines (e.g., IL-6, which increased by 40-folds). Propolis inhibited the expression of IL-1β and TNF-α at 4, 8, and 12 h of incubation. These effects were nuclear factor kappa B (NF-κB)-dependent given that propolis simultaneously increased nuclear translocation of p65 and p50 NF-κB proteins 3 h after treatment. Meanwhile, inhibiting IκB kinase (IKK) by BMS-345541 profoundly hindered the effect of propolis on the expression of CCL-2, CCL-5, and IL-6 by 66%, 81%, and 69%, respectively. Propolis also enhanced the expression of MAIL/IκBζ. This molecule modulates chromatin and selectively induces the production of IL-6, leukemia inhibitory factor (LIF), and CCL-2 [108].\nChronic muscle tissue infiltration by inflammatory cells (e.g., leukocytes, neutrophils, and monocytes) activates oxidative and inflammatory signaling cascades that degrade cellular structures and promote necrosis such as inducible nitric oxide synthase (iNOS) and NF-kB [90,101,115]. CAPE and high levels (200 and 300 mg/kg) of crude and processed bee pollen reduced inflammatory cell infiltration into the gastrocnemius muscle of rats with muscle injury induced by eccentric exercise and ischemia reperfusion [90,101,102]. This effect was revealed by lower activity of myeloperoxidase, an indicator of neutrophil sequestration [101,102]. As such, CAPE and bee pollen not only suppressed lipid peroxidation (lower levels of malondialdehyde, MDA) but also inhibited the activity of myostatin and the production of muscle depleting cytokines and chemokines such as IL-1β, α2-macroglobulin, and monocyte chemotactic protein 1 (MCP-1) [36,38,90,101]. The underlying mechanism entailed downregulation of nuclear p65NF-κB and blockage of its consensus binding sites in skeletal muscle [101]. As a result, bee products increased muscle mass both in sarcopenic obese rat and malnourished old rats [36] and restored the structure of myofibers (despite the persistence of necrosis) compared with untreated eccentric exercising animals, which demonstrated necrotic and fragmented myofibers [90].\nRoyal jelly downregulated the activity of tumor necrosis factor receptor 1 (TNFR1) in the adipose tissue of aged obese rats receiving HFD [100]. TNFR1 interacts with TNFR2 to negatively regulate toll-like receptors (TLR) and Nod-like receptor signaling and stimulate excessive release of cytokines via activation of key inflammatory pathways such as NF-κB [107]. Mitigation of TNFR1 was associated with a significant increase of the weight of hind limb muscle and reductions in insulin levels, homeostatic model assessment of insulin resistance (HOMA-IR), serum lipids, muscle triglyceride levels, body weight gain, and abdominal fat weight. Therefore, royal jelly may protect against muscle loss in conditions involving impairment of the adipokine profile mainly through suppression of inflammatory responses associated with high fat mass, which is followed by correction of metabolic irregularities [100].\n\n4.2. Counteracting Oxidative Stress in Skeletal Muscle\nHigh production of reactive oxygen species (ROS) in skeletal muscle tissues has serious destructive effects, which alter the integrity of skeletal muscle resulting into fatigue, muscle wasting, and muscle weakness [90,101]. Sources of intramuscular ROS are numerous including mitochondrial dysfunction (e.g., alteration of mitochondrial enzymes in the respiratory chain as well as enzymes responsible for β-oxidation), neutrophil infiltration, and the activity of cytokines and major muscle degrading molecules such as myostatin [21,36,38,101,102,118]. Oxidative and nitrosative damages in skeletal muscle tissues are mediated by the activity of numerous pro-oxidant enzymes that are associated with inflammatory processes such as cyclooxygenase-2 (COX-2) and iNOS [101]. ROS triggers the activity of corrosive molecules such as poly (ADP-ribose) polymerase (PARP), xanthine oxidase, and adenosine deaminase, which contribute to DNA damage, lipid peroxidation (e.g., increased MDA), and protein nitrotyrosylation as well as ATP catabolism in muscle tissues [101,102].\nRoyal jelly enhanced the activity of antioxidant enzymes and suppressed lipid peroxidation in a d-galactose induced model of aging [95]. Two weeks of propolis treatment in rats undergoing hind limb unloading significantly reduced nuclear ROS levels and numbers of apoptotic endothelial cells in the soleus muscle to levels similar to normal rats [110]. Moreover, propolis significantly suppressed MDA activity in skeletal muscle and increased liver levels of SOD as well as gastrocnemius muscle levels of SOD, glutathione peroxidase and catalase in rats on eccentric exercise training (70% VO2max treadmill running exercise for 60 min) compared with rats receiving exercise alone or no treatment [109]. In addition, intraperitoneal pre-administration of CAPE (60 min before induction of ischemia reperfusion) significantly ameliorated the effects associated with high ROS levels, which accompany acute ischemia such as protein peroxidation and ATP catabolism in the gastrocnemius muscle [102].\nBee products probably reduced ROS production via regulation of the activity of mitochondrial enzymes. Royal jelly increased the maximal activity of citrate synthase (CS) and β-hydroxyacyl coenzyme A dehydrogenase (β-HAD) in the soleus muscle of rats on endurance training [106]. Bee pollen restored mitochondrial complex-I, -II, -III, and -IV enzyme activity to normal, increased SOD and glutathione, and reduced MDA, NO, and total protein content in the gastrocnemius muscle of rats on exhaustive exercise [90]. It also increased the activity of CS and complex IV in malnourished old rats via a mechanism that involved activation of mTOR [36]. mTOR is a major signaling pathway that regulates various signaling cascades involved in metabolism and autophagy such nuclear respiratory factor 2 (NRF2) [2]. Therefore, it is possible that the antioxidant activity demonstrated by bee products, particularly that expressed in the mitochondria, is associated with their metabolic and hypoglycemic activities. For instance, 10-HDA increased expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) in skeletal muscle of diabetic mice [112,119]. Similarly, aged mice treated with amino acids similar to those found in royal jelly demonstrated improved size of muscle fiber by increasing PGC-1α mRNA levels. PGC-1α functions as a key regulator of sirtuin 1, which limits ROS production through stimulation of mitochondrial biogenesis and ROS defense system, thus protecting metabolically active tissues against oxidative damage [120]. Mechanistically, when PGC-1α gets activated, it interacts with other bioactive molecules such as muscle-specific transcription factors to stimulate the expression of genes that induce mitochondrial oxidative metabolism in brown fat and fiber-type switching in skeletal muscle [121].\nThe antioxidant activity of royal jelly and CAPE might be related to their strong capacity to activate the master redox-active NRF2 signaling pathway [73,122], which stimulates the production of internal antioxidants such as heme oxygenase-1 (HO-1), which scavenge free radicals [123]. Meanwhile, NRF2 and HO-1 block ROS production indirectly via suppression of inflammatory reactions [122]. In this context, CAPE reduced degenerative myopathy in rats on eccentric exercise via a complex mechanism that involved inhibition of NF-κB and its downstream pro-oxidant COX-2 and iNOS [101]. Correspondingly, CAPE decreased markers of oxidative cellular damages (protein carbonyl, protein nitrosylation, xanthine oxidase, and adenosine deaminase) associated with ischemia reperfusion and eccentric exercise in the gastrocnemius muscle [101,102,103]. In this regard, CAPE operated via a mechanism that involved inhibition of neutrophil and leukocyte infiltration into the gastrocnemius muscle, which was associated with decreased levels of myeloperoxidase. Myeloperoxidase contributes to excessive production of ROS and oxidative organ damage through a mechanism that embroils increased synthesis of hypochlorous acid [101,102]. Furthermore, CAPE accelerated purine salvage for ATP synthesis and inhibited ROS-induced lipid peroxidation via attenuation of the activity of adenosine deaminase [102].\nIn summary, the reported antioxidant effects of bee products were multifaceted involving increased production of antioxidant enzymes [90,95,109,110], and decreased ROS production [90,101,102,103,110] (secondary to reduction of inflammatory cell infiltration into skeletal muscle) [90,101,102,103], and restoration of mitochondrial activity [36,90,106].\n\n4.3. Metabolic Regulation\nSkeletal muscle is the main tissue that utilizes insulin for glucose uptake. Insulin regulates mitochondrial oxidative phosphorylation of proteins in human skeletal muscle and contributes to calcium mobilization from the sarcoplasmic-endoplasmic reticulum to mitochondria to stimulate the translocation of glucose transporter 4 (GLUT4) to the cell surface for glucose uptake. This process improves muscle protein synthesis in healthy people when the delivery of amino acids to skeletal muscle is increased, eventually leading to increased muscular mass [124,125,126]. Insulin resistance and glucose intolerance increase with old age evoking muscle loss. In this respect, hypoglycemic agents such as metformin can improve skeletal muscle metabolism via activation of adenosine monophosphate activated protein kinase (AMPK) [21].\nAMPK, a heterotrimeric complex that consists of a catalytic subunit and two regulatory subunits, is an intracellular energy sensor that regulates glucose and lipid metabolism. It gets activated when cellular energy is depleted through allosteric binding of AMP or phosphorylation by AMPK kinase at Thr172 of the catalytic subunit by AMPK kinase. Upregulated AMPK activates signaling pathways that generate ATP from glucose and fatty acid oxidation, and it simultaneously blocks signaling that contributes to the synthesis of cholesterol, fatty acid, and triacylglycerol [111]. In addition, AMPK masters numerous signaling cascades such as Forkhead Box O transcription factor (FOXO) and AKT/mTOR, which regulate the expression of genes associated with inflammation, oxidative stress, mitochondrial function, autophagy, metabolism, and apoptosis [127,128].\nThe molecular events involved in the effect of bee products on catabolic genes and anabolic resistance in skeletal muscle could be much related to their hypoglycemic effects, which positively affect the quality of skeletal muscle. Evidence signifies a positive effect of royal jelly acid (10-HDA) on inflammation and autophagy via upregulation of AMPK, which subsequently alters NF-κB and NLRP3 inflammasome-IL1β signaling [129]. Positive effects of whole royal jelly on skeletal muscle are associated with improved insulin signaling [96,100]. In one study, royal jelly improved serum IGF-1 levels in aged rats and increased AKT signaling in satellite cells extracted from aged rats in a separate in vitro investigation [96]. In another study, royal jelly decreased fat mass and improved anabolic resistance in the skeletal muscle of old obese rats on HFD via downregulation of inflammatory responses in adipose tissue as indicated by downregulation of TNFR1. This effect was associated with enhanced sensitivity to insulin—portrayed by reduction of serum insulin level and HOMA-IR [100].\nJapanese researchers proved that oral consumption of royal jelly and 10-HDA induced mitochondrial adaptation in the soleus muscle when accompanied with endurance training. These compounds also enhanced glucose uptake in skeletal muscle by inducing the phosphorylation of AMPK [106,112], an effect that was mediated by the upstream kinase Ca²⁺/calmodulin-dependent kinaseβ—independently of changes in AMP:ATP ratio and the liver kinase B1 pathway. Activation of AMPK was followed by translocation of GLUT4 to the plasma membrane of L6 myotubes [106]. It is note-worthy that effects of royal jelly on mitochondrial biogenesis under endurance training were muscle-specific. In this respect, neither endurance training nor royal jelly alone had an effect on the maximal activities of CS and β-HAD—the enzyme that catalyzes the rate-limiting step of β-oxidation of long-chain fatty acids—in the soleus muscle, which comprises type I fiber (around 35–45%) and type IIa (around 35–50%). On the other hand, royal jelly enhanced the activity of these enzymes in the soleus muscle of mice on endurance training. Of interest, endurance training increased the activity of CS and β-HAD in the plantaris and tibialis anterior muscles (which are mainly type II fiber with a total percentage of type IIb and type IIx fiber types of 90%) while royal jelly failed to exert an effect on these muscles in sedentary mice [106]. Nonetheless, the observed effects of royal jelly in the soleus muscle represent a merit. This is mainly because the oxidative type I fibers (e.g., soleus muscle) naturally undergo higher protein turnover (especially degradation), which makes them unable to grow in size or respond properly to insufficient nutrient intake [130].\nSeveral lines of evidence indicate that propolis may affect muscle quality through the regulation of glucose metabolism [69,70,109,111]. This effect was vividly depicted in vivo by increased glycogen level in skeletal muscle and reduced serum levels of glucose and insulin [109]. Same as insulin, ethanolic extracts of propolis and CAPE induced glucose uptake [69,70,111] and potentiated insulin-mediated AKT activation and glucose uptake in differentiated L6 myoblast cells [111]. Likewise, Italian propolis at concentrations of 0.1 and 1 mg/mL as well as 4-geranyloxyferulic acid and auraptene (2 oxyprenylated phenylpropanoids, which are abundant in propolis) remarkably increased GLUT4 translocation to the plasma membrane and accelerated GLUT4-mediated glucose uptake in L6 skeletal myoblasts. The effect of propolis at a concentration of 11 mg/mL was significantly superior to the effect of insulin (0.1 μM), which was used as a positive control [69].\nSimilar to royal jelly, the effects of propolis (1 μg/mL), CAPE (10 μM), artepillin C, coumaric acid, and kaempferide on glucose metabolism occurred via activation of AMPK. These effects were comparable to those of 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), a potent AMPK activator. In the meantime, co-treatment with inhibitors of AMPK (e.g., compound C) and of phosphatidylinositol 3-kinase (PI3K) (e.g., LY-294002) blocked the effects of CAPE [70,111]. Phosphorylation of AMPK results in activation of the insulin receptor (IR) and subsequent phosphorylation of PI3K followed by activation of AKT and protein kinase C (PKC) leading to GLUT4 translocation and subsequent activation of several molecules that modulate insulin-stimulated glucose transport, eventually leading to glucose influx into cells of several tissues such as skeletal muscle and adipose tissue [69,70,111]. It is worth noting that the effects of CAPE on AMPK and AKT were quick (within 1 h and 3 min, respectively), and they vanished quickly (both molecules returned back to their basal levels within 12 h and 30 min, respectively) [111].\n\n4.4. Enhancement of Muscle Protein Synthesis\nImbalance between muscle protein synthesis and degradation is associated with low protein intake and altered efficiency of the GI tract in old age, which triggers skeletal muscle loss and poor physical performance [36,40], given that proteins are the main building blocks of muscle myofibers. Moreover, transmembrane proteins and micro-peptides (e.g., myomixer and myomaker/Tmem8c) contribute to the formation of myofibers by promoting myoblast fusion via a mechanism that involves appropriate localization of Tmem8c at the plasma membrane of myoblasts allowing trafficking related to palmitoylation of C-terminal cysteine residues and C-terminal leucine [17]. Amino acid supplements (e.g., leucine, a master dietary regulator of muscle protein turnover, and its metabolite β-hydroxy β-methylbutyrate) and early refeeding with high protein diet (especially fast digestive proteins) can preserve muscle mass and function, revert sarcopenia, and enhance mobility and quality of life (QoL) by correcting age-related nutritional deficiencies, muscle protein turnover, and immune dysregulation—these effects are even greater when combined with other nutrients like vitamin D or omega 3 fatty acids as well as with physical exercise [6,131,132,133,134,135,136,137,138].\nResearch indicates that age-related skeletal muscle wasting results mainly from insufficient delivery of amino acids to skeletal muscle due to dysregulations in the activity of mTORC1- and activating transcription factor-4 (ATF4)-mediated amino acid sensing pathways. Meanwhile, interventions that ameliorate age-related damages in skeletal muscle operate primarily by reversing alterations in the delivery of amino acids to skeletal muscle via upregulation of mTORC1 and/or ATF4 [139]. mTORC1 is a nutrient sensing protein that acts as a core regulator of protein metabolism. It is sensitive to amino acids, energy status (ATP), stress (e.g., oxidative stress), and growth factors (e.g., insulin), which all can regulate its signaling [2,136]. Nevertheless, bioavailability of amino acids is necessary for growth factors to effectively activate mTORC1. Even more, amino acids on their own can adequately activate mTORC1 [136]. Evidence from preclinical and human studies confirms that ingestion of essential amino acids (similar to those found in royal jelly and bee pollen such as valine) increases cellular bioavailability of amino acids, which is associated with activation of the endothelial nitric oxide synthase (eNOs) pathway. eNOs further upregulates mTORC1 kinase. Translocation of mTORC1 from the cytosol to the surface of lysosomes is associated with improved mitochondrial biogenesis and cellular oxidative capacity in skeletal muscle due to activation of its substrates: P70 ribosomal proteins S6 kinase (S6K) and eukaryotic translation initiation 4E-binding protein 1 (eIF4E, also known as 4eBP1) [120,135,136].\nAs shown in Table 1, royal jelly and 10-HDA significantly increased muscle mass [54,96,100] and improved motor performance in aged rats [95,98,99]. In addition, dietary supplementation with monofloral bee pollen significantly improved the rate of muscle protein synthesis and restored muscle mass in emaciated old rats via upregulation of mTOR and two related downstream controllers of protein translation: p70S6k and 4eBP1, which were suppressed in malnourished old rats [36]. Although propolis improved various muscle-related parameters, its effect on muscle mass in rodents was limited—relative to royal jelly and bee pollen. However, it fostered muscle protein deposition in post-larva Nile tilapia [104]. Moreover, milk naturally enriched with PUFA and polyphenols from propolis remarkably increased the weight of the gastrocnemius muscle of growing obese rats while whole milk and milk enriched with PUFA only could not express any effect on skeletal muscle [105]. Therefore, this finding denotes that propolis could have enhanced the delivery of amino acids available in milk to skeletal muscle leading to its growth. Altogether, it is likely that the observed anabolic effects of royal jelly and bee pollen are associated with their high content of proteins and amino acids [32,36,83,84,85,86].\n\n4.5. Suppression of Catabolic Activity in Skeletal Muscle\nSkeletal muscle tissues represent the largest protein store in the human body (30–45% of total protein). Muscular mass, strength, and functions are greatly governed by the rates of muscle protein synthesis and turnover [124]. Muscle protein metabolism is regulated by the interaction of a wide range of genes. Aging is associated with various stresses, which increase the expression of catabolic genes such as E3 ubiquitin ligases MuRF1 and atrogin-1 (MAFbx). These genes heighten the occurrence of age-related muscular atrophy [97]. Oral consumption of royal jelly by aged HET mice resulted in lower levels of catabolic genes (e.g., MuRF1 and MAFbx), which were similar to those in young mice. In the meantime, the expression of these genes in the control mice was high indicating that royal jelly can delay age-related muscular apoptosis by suppressing the activity of catabolic genes [97]. Two other studies reported that CAPE suppressed catabolism that contributed to degenerative myopathy in the gastrocnemius muscle of rats undergoing eccentric exercising or femoral artery ligation as reflected by decreased serum levels of creatine kinase, a marker of muscular proteolysis [101,102,103]. Apart from skeletal muscle, CAPE was reported to protect heart muscle against age-related deteriorations such as accumulation of lipofuscin, nuclear irregularity, mitochondrial degeneration, and myofilament disorganization and disruption [33].\nThe molecular mechanism underling blockage of muscle proteolysis by bee products in sarcopenic rodents involves an interplay of various signaling pathways. Royal jelly and bee pollen activated mTOR and its substrate AKT, which are suggested to inhibit muscular proteolysis [36,96]. Similar to the effect of royal jelly on catabolic genes in HET mice, treating both L6 myoblasts and rats with propolis, CAPE, and kaempferide resulted in potent activation of AKT in a PI3K-dependent manner [111], in addition to phosphorylation of IR, PI3K, and AMPK [70]. AKT, a key substrate of mTORC2, is a conserved serine/threonine nutrient sensing protein kinase that belongs to the PI3k-related protein kinase family. Upon presence of growth factors, PI3k gets activated by IR substrate resulting in stimulation of a series of signaling cascades that involve activation of AKT, which leads to further activation of mTORC1. mTORC1 activates the phosphorylation of two main regulators of cap-dependent protein synthesis: S6K and eIF4E [2,140]. In addition, mTORC1 contributes to autophagy—a turnover process that involves clearance of dysfunctional organelles and long-lived protein aggregations with provision of energy and macromolecular precursors in return—by binding with AMPK resulting in phosphorylation of autophagy genes such as Unc51-like kinase 1 at different sites [140]. In fact, royal jelly is reported to fine-tune the transcriptional activity of the FOXO through modulating the activity of insulin/IGF-1 signaling [141]. FOXO plays a major role in the activation of AKT pathway, which implicates regulation of multiple stress–response pathways such as ROS detoxification and DNA repair and translation. In addition, the FOXOs family exerts a direct effect on certain muscle atrophy genes such as MUSA1 and a formerly uncharacterized ligase known as Specific of Muscle Atrophy and Regulated by Transcription (SMART) [142].\n\n4.6. Enhancement of Stem Cell Function\nReduction of the number and functional capacity of the muscle satellite cells is considered a core contributor to the development of age-related muscular dysfunction [96]. Induction of myogenesis via in vivo reprogramming of muscle satellite cells is a currently studied strategy that has not been successfully used for sarcopenia treatment yet [143]. On the other hand, treating sarcopenic rats with both royal jelly and pRJ was reported to increase the number of Pax7-positive satellite cells in vivo and in vitro (pRJ only). pRJ induced self-renewal of satellite cells via activation of AKT signaling [96,97]. AKT activity was associated with activation of IGF-1 as indicated by increased serum levels of IGF-1. IGF-1 plays a crucial rule in the activation of various signaling pathways; it is believed to be a major mediator of muscle growth and repair that functions by stimulating the proliferation and differentiation of satellite cells into myotubes, albeit the exact mechanism is not clear yet [96]. Similarly, pRJ activated AKT-signaling pathway in satellite cells culture, which was associated with increased proliferation of myosatellite cells and their differentiation into myotubes—an effect that is contradictory to muscle loss. AKT is thought to contribute to the synthesis of muscular proteins and inhibition of muscle proteolysis [96].\n\n4.7. Counteracting Glycation Stress\nOxidative stress, inflammation, and insensitivity to insulin, which accompany advanced age, contribute to the production of advanced glycation end products (AGEs) via enhancement of the activity of the Receptor for Advanced Glycation End products (RAGE) [144,145]. AGEs destroy the protein and lipid ingredients of muscle tissues by promoting the production of destructive molecules such as free radicals and inflammatory cytokines [101,102,113]. Thanks to their potent antioxidant properties, polyphenolic compounds exert multifaceted anti-glycation functions. On one hand, they scavenge free-radicals and chelate transition metals that are involved in the synthesis of dicarbonyl intermediates subsequently resulting in inhibition of the formation of AGEs. On the other hand, polyphenolic compounds antagonize AGE receptors, mainly RAGE, and facilitate the removal of already formed a,b-dicarbonyl intermediates such as methylglyoxal, promoting the degradation of AGEs [37,38,146]. Royal jelly is reported to downregulate the activity of RAGE, the main receptor for AGEs, in an aged model of cognitive impairment [147]. However, its anti-glycation effect has not been investigated in skeletal muscle yet. Propolis exhibits strong anti-AGE properties, which are superior to those of quercetin or chlorogenic acid, well-known natural AGE inhibitors. Its flavonoid fraction potently impedes the synthesis of AGEs by trapping dicarbonyl intermediates [37]. Table 1 shows that propolis accelerated AGEs clearance in a model of muscle aging induced by administration of a precursor of AGEs (methylglyoxal) via activation of glyoxalase 1, an enzyme that eliminates dicarbonyl compounds (key elements of AGEs) [38]. CAPE inhibited the production of AGEs-related molecules such as protein carbonyl in the gastrocnemius muscle of rats via blockage of the activity of xanthine oxidase and adenosine deaminase [101,102,103]. The latter negatively affects insulin signaling and promotes the development of hyperglycemia, which represents a favorable condition for the production of AGEs [148]. However, propolis could not counteract the wasting effects of AGEs that already occurred in the extensor digitorum longus muscle though it tended to restore soleus muscle mass. This finding denotes that different muscle tissues respond differently to treatment, probably based on their ratio of type I to type II fibers. It also signifies the importance of early use of bee products (e.g., propolis) for the prevention of AGEs formation in skeletal muscle in people with high risk for AGEs formation such as diabetics [38].\n\n4.8. Neuronal Regeneration\nNeuronal denervation is a key factor that contributes to skeletal muscle loss, and it is related to a plethora of pathological conditions [3,149]. Experimental induction of oxidative stress and inflammation results in skeletal muscle atrophy through induction of denervation e.g., of sciatic nerve [150]. Injuries of peripheral nerves (e.g., sciatic nerve) interrupt mechanical transmission and microvasculation of the nerve and induce reperfusion. Reperfusion involves pooling of oxygen and nutrients promoting high emission of free radicals, which attack protein and lipid contents surrounding the injury site resulting in excessive tissue loss [113]. Likewise, alterations in gut microbiome in aged rats are associated with alterations in serum level of vitamin B12 and fat metabolism as well as reductions in the gastrocnemius muscle mass and sciatic response amplitude [151]. Furthermore, dysregulation of insulin-mediated GLUT4 activity in certain areas of the central nervous system impairs neuronal metabolism and plasticity [69]. Meanwhile, activation of PGC-1α, a core regulator of mitochondrial content and oxidative metabolism, increases muscle fiber resistance to denervation and atrophy through downregulation of two ubiquitin-ligases involved in the ubiquitin-proteasome pathway: MuRF1 and Atrogin-1 [1,152].\nPropolis treatment for four weeks restored gastrocnemius muscle weight and improved functional performance (e.g., walking) in rats with crush injury of the sciatic nerve. Effects of propolis were associated with increased nerve healing and regeneration as depicted by faster healing of the myelin sheath and ultra-structurally normal unmyelinated axons and Schwann cells. Investigations of motor conduction from the sciatic nerve to the gastrocnemius muscle indicated that nerve recovery induced by propolis treatment promoted optimal physical functioning by allowing motor conduction to reach the gastrocnemius muscle [113]. Neuroprotective effects of propolis in motor neurons are documented in the literature. Both kaempferide and kaempferol protected motor neurons against atrophy induced by the toxic copper-zinc superoxide dismutase in amyotrophic lateral sclerosis—a serious neurodegenerative disease that involves selective and progressive loss of motor neurons [65]. In addition, orally administered chrysin (a flavonoid that is copious in propolis) to rats intoxicated by 6-hydroxidopamine showed neuroprotective effects by mitigating neuroinflammation, enhancing levels of neurotrophins and neuronal recovery factors (e.g., brain derived neurotrophic factor and glial cell line-derived neurotrophic factor), and maintaining integrity of dopaminergic neurons resulting in better motor performance [72].\nThe release of acetylcholine (a neurotransmitter that regulates cognition) at the synaptic cleft of the neuromuscular junction is essential for motor neurotransmission, which controls excitation-contraction coupling and cell size. However, free radicals, cytokines, and AGEs impair neurotransmission by altering the production of acetylcholine [6,21,149,153]. On the other hand, upregulation of acetylcholine receptors improves neurotransmission [154]. Treatment with royal jelly may correct acetylcholine neurotransmission given its high content of acetylcholine (4–8 mM) [60]. In addition, royal jelly, propolis, and bee pollen are rich in antioxidant elements that have a potential to scavenge ROS and mitigate other pathologies that contribute to acetylcholine deficiency (e.g., neuroinflammation) [73,101,102,103]. In this respect, treatment of experimental models of carrageenan-induced hind paw edema with hydroalcoholic extract of red propolis and its biomarker, formononetin, is reported to inhibit leukocyte migration and ameliorate inflammatory neurogenic pain induced by injections of formalin and glutamate [115]. However, investigations of the action of bee products on neurotransmission are very scarce.\n\n4.9. Improving Muscular Blood Supply\nAging is associated with higher onset of atherosclerosis and restenosis, which involve vascular and microvascular damages that result from hyperproliferation of vascular smooth muscle cells (VSMCs) [155]. Muscle unloading (e.g., in sedentary lifestyle) involves chronic neuromuscular inactivity, which results in reductions in capillary number, luminal diameter, and capillary volume as well as heightened production of anti-angiogenic factors, such as p53 and TSP-1 in skeletal muscle [110]. Microvascular alterations and impaired nitric oxide (NO) production are key causes of decreased blood flow to the skeletal muscle. Poor muscular blood supply induces muscle wasting via a mechanism that entails impaired glucose metabolism and suboptimal protein anabolism [156,157]. In addition, ischemic injury in skeletal muscle is associated with high ROS release from polymorphonuclear leukocytes, which infiltrate muscle tissues. Free radicals alter cellular structure and function by attacking lipid and protein biomolecules that exist in the structure of biological membranes, enzymes, and transport proteins [102]. Therefore, improving vascularization and blood supply to skeletal muscle is a possible mechanism for the prevention of muscle wasting.\nMitchell and colleagues examined changes in microvascular blood volume, microvascular flow velocity, and microvascular blood flow in the quadriceps muscle following treatment with 15 g of amino acids in young and old subjects (20–70 years old). They detected improvements in all the 3 parameters only in young groups, and those effects were associated with proper insulin activity. Thus, the authors suggested that refeeding effects on muscular blood supply may be hindered by dysfunctions in postprandial circulation and glucose dysregulation [157]. Bee products such as bee pollen and propolis have a potential to boost microcirculation and correct pathologies that contribute to vascular dysfunction such as hyperglycemia and dyslipidemia [36,155]. In this context, CAPE, one of the basic constituents of propolis, was reported to combat vascular damages by counteracting the proliferative activity of platelet-derived growth factor. The molecular mechanism involved inducing cell-cycle arrest in VSMCs via activation of p38mitogen-activated protein kinase (MAPK), which was associated with accumulation of hypoxia-inducible factor (HIF)-1α—mainly due to inhibition of HIF prolylhydroxylase, a key contributor to proteasomal degradation of HIF-1α—and subsequent induction of HO-1 [155]. In the same regard, supplementing rats undergoing capillary regression (resulting from two weeks of hind limb unloading) in the soleus muscle with two daily intragastric doses of propolis for two weeks restored capillary number, capillary structure, capillary volume, and capillary to muscle fiber ratio through a mechanism that involves inhibition of anti-angiogenic factors and activation of pro-angiogenic factors (e.g., VEGF). The relative muscle-to-body weight in treated animals was higher than in the unloaded control animals, and the number of TUNEL-positive apoptotic endothelial cells in the soleus muscle was similar to that in the normal control animals [110]. Likewise, bee pollen (both neat and processed) increased blood vessels in the gastrocnemius muscle of rats undergoing muscle injury because of vigorous exercise [90]. Treating C2C12 myoblasts with propolis ethanolic extract increased VEGF production [108]. VEGF is a pro-angiogenic factor that contributes to angiogenesis by recruiting endothelial cells and promoting their differentiation to form new vascular networks. VEGF protects skeletal muscle undergoing unloading against the progression of capillary regression [110]. Its expression in skeletal muscle and associated angiogenic response increase following exercise due to change in the activity of HIF-1α and AMPK. It promotes the generation of ATP following mitochondrial biogenesis in order to meet oxygen demand [158]. Altogether, these reports signify that bee products and endurance exercise share common mechanisms to produce their vitality effects in skeletal muscle.\n\n4.10. Improving the Composition of Gut Microbiome\nBee products such as royal jelly and propolis display potent antifungal, bactericidal, microbicidal, anti-inflammatory, antioxidant, and healing effects [2,66]. Most bee products investigated in this review were administered orally. Therefore, it is likely that their therapeutic effects may start locally within the GI tract, which frequently undergoes propagation of harmful endobacteria, inflammation, aberrations, and permeability in advanced age [10,24,152]. In this respect, Roquetto and colleagues [116] supplemented C57BL/6 mice on HFD with crude propolis (0.2%) for two and five weeks. HFD increased the proportion of the phylum Firmicutes as well as levels of circulating lipopolysaccharide (LPS) and inflammatory biomarkers. DNA sequencing for the 16S rRNA of the gut microbiota revealed that five weeks of propolis treatment rendered the microbiota profile almost normal. Compared with untreated mice, propolis-supplemented animals demonstrated lower levels of serum triacylglycerols, glucose, and circulating LPS, along with reduced expression of TLR4 and inflammatory cytokines in skeletal muscle [116].\nLactic acid bacteria profusely exist in bee saliva and all bee products [36,83,84]. Various species of lactic acid bacteria have been experimentally used to correct GI dysbiosis and related muscle wasting [159,160]. Moreover, oligosaccharides have been chemically isolated from bee products [32,161]. These api-materials are classified as prebiotics, fermented non-digestible compounds that promote the proliferative activity of health-promoting bacteria [24,161]. Supplementing frail old adults with fructooligosaccharides expressed positive effects on skeletal muscle strength (handgrip) and endurance (exhaustion) [162]. On the other side, microbiome of the gut can affect the biological activity of bee products. The literature shows that certain endobacteria transform dietary polyphenols into phenolic acids, which can easily access the circulation and then cross the blood brain barrier to produce therapeutic effects [163]. Hence, it is important that future investigations of bee products among sarcopenic subjects examine the effect of these products on the composition of GI microbial population and its association with muscle-related outcomes."}

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Mechanisms of Action of Royal Jelly, Bee Pollen, and Propolis in Sarcopenia\nRelatively few studies have explored the mechanism through which royal jelly, bee pollen, and propolis may be beneficial for sarcopenia. In vivo and in vitro studies included in this review uncovered a number of inter-related cellular and molecular events that underlie the effect of these bee products on skeletal muscle including suppression of catabolic genes, counteracting metabolic abnormalities, inflammation, and oxidative damages as well as enhancement of motor neuronal regeneration, promotion of stem cell function, and correction of the structure of gut microbiome (Figure 1, Panel D). These mechanisms are exclusively described in the coming paragraphs.\n\n4.1. Modulating Inflammatory Responses in Skeletal Muscle\nThe role that inflammation plays in skeletal muscle is not quite clear as it looks. Inflammatory mediators behave in a dual fashion in muscle cells. During injury, cytokines and chemokines stimulate muscle repair and regeneration via activation of myoblasts, a core event in muscle remodeling [108]. Similarly, serum and muscle levels of IL-6 temporarily increase following physical exercise, and IL-6 blocks the activity of catabolic cytokines such as TNF-α. On the other hand, chronic inflammation in muscle cells, which correlates with persistent mitochondrial dysfunction and metabolic dysregulation, pathologically activates muscle fiber transformation and atrophy, eventually resulting in the development of sarcopenia [23,114]. It seems that bee products also act dually in skeletal muscle: they support the activity of cytokines that promote muscle remodeling [108] and suppress muscle-consuming cytokines [38,101,108]. In this regard, treating undifferentiated C2C12 myoblasts with ethanolic extracts of Brazilian propolis (100 μg/mL for 8 h) triggered the migration of RAW264 macrophage and increased their production of angiogenic factors (e.g., vascular endothelial growth factor A (VEGF-A) and metalloproteinase-12 (MMP-12)), chemokines (e.g., CCL-2 and CCL-5), and cytokines (e.g., IL-6, which increased by 40-folds). Propolis inhibited the expression of IL-1β and TNF-α at 4, 8, and 12 h of incubation. These effects were nuclear factor kappa B (NF-κB)-dependent given that propolis simultaneously increased nuclear translocation of p65 and p50 NF-κB proteins 3 h after treatment. Meanwhile, inhibiting IκB kinase (IKK) by BMS-345541 profoundly hindered the effect of propolis on the expression of CCL-2, CCL-5, and IL-6 by 66%, 81%, and 69%, respectively. Propolis also enhanced the expression of MAIL/IκBζ. This molecule modulates chromatin and selectively induces the production of IL-6, leukemia inhibitory factor (LIF), and CCL-2 [108].\nChronic muscle tissue infiltration by inflammatory cells (e.g., leukocytes, neutrophils, and monocytes) activates oxidative and inflammatory signaling cascades that degrade cellular structures and promote necrosis such as inducible nitric oxide synthase (iNOS) and NF-kB [90,101,115]. CAPE and high levels (200 and 300 mg/kg) of crude and processed bee pollen reduced inflammatory cell infiltration into the gastrocnemius muscle of rats with muscle injury induced by eccentric exercise and ischemia reperfusion [90,101,102]. This effect was revealed by lower activity of myeloperoxidase, an indicator of neutrophil sequestration [101,102]. As such, CAPE and bee pollen not only suppressed lipid peroxidation (lower levels of malondialdehyde, MDA) but also inhibited the activity of myostatin and the production of muscle depleting cytokines and chemokines such as IL-1β, α2-macroglobulin, and monocyte chemotactic protein 1 (MCP-1) [36,38,90,101]. The underlying mechanism entailed downregulation of nuclear p65NF-κB and blockage of its consensus binding sites in skeletal muscle [101]. As a result, bee products increased muscle mass both in sarcopenic obese rat and malnourished old rats [36] and restored the structure of myofibers (despite the persistence of necrosis) compared with untreated eccentric exercising animals, which demonstrated necrotic and fragmented myofibers [90].\nRoyal jelly downregulated the activity of tumor necrosis factor receptor 1 (TNFR1) in the adipose tissue of aged obese rats receiving HFD [100]. TNFR1 interacts with TNFR2 to negatively regulate toll-like receptors (TLR) and Nod-like receptor signaling and stimulate excessive release of cytokines via activation of key inflammatory pathways such as NF-κB [107]. Mitigation of TNFR1 was associated with a significant increase of the weight of hind limb muscle and reductions in insulin levels, homeostatic model assessment of insulin resistance (HOMA-IR), serum lipids, muscle triglyceride levels, body weight gain, and abdominal fat weight. Therefore, royal jelly may protect against muscle loss in conditions involving impairment of the adipokine profile mainly through suppression of inflammatory responses associated with high fat mass, which is followed by correction of metabolic irregularities [100].\n\n4.2. Counteracting Oxidative Stress in Skeletal Muscle\nHigh production of reactive oxygen species (ROS) in skeletal muscle tissues has serious destructive effects, which alter the integrity of skeletal muscle resulting into fatigue, muscle wasting, and muscle weakness [90,101]. Sources of intramuscular ROS are numerous including mitochondrial dysfunction (e.g., alteration of mitochondrial enzymes in the respiratory chain as well as enzymes responsible for β-oxidation), neutrophil infiltration, and the activity of cytokines and major muscle degrading molecules such as myostatin [21,36,38,101,102,118]. Oxidative and nitrosative damages in skeletal muscle tissues are mediated by the activity of numerous pro-oxidant enzymes that are associated with inflammatory processes such as cyclooxygenase-2 (COX-2) and iNOS [101]. ROS triggers the activity of corrosive molecules such as poly (ADP-ribose) polymerase (PARP), xanthine oxidase, and adenosine deaminase, which contribute to DNA damage, lipid peroxidation (e.g., increased MDA), and protein nitrotyrosylation as well as ATP catabolism in muscle tissues [101,102].\nRoyal jelly enhanced the activity of antioxidant enzymes and suppressed lipid peroxidation in a d-galactose induced model of aging [95]. Two weeks of propolis treatment in rats undergoing hind limb unloading significantly reduced nuclear ROS levels and numbers of apoptotic endothelial cells in the soleus muscle to levels similar to normal rats [110]. Moreover, propolis significantly suppressed MDA activity in skeletal muscle and increased liver levels of SOD as well as gastrocnemius muscle levels of SOD, glutathione peroxidase and catalase in rats on eccentric exercise training (70% VO2max treadmill running exercise for 60 min) compared with rats receiving exercise alone or no treatment [109]. In addition, intraperitoneal pre-administration of CAPE (60 min before induction of ischemia reperfusion) significantly ameliorated the effects associated with high ROS levels, which accompany acute ischemia such as protein peroxidation and ATP catabolism in the gastrocnemius muscle [102].\nBee products probably reduced ROS production via regulation of the activity of mitochondrial enzymes. Royal jelly increased the maximal activity of citrate synthase (CS) and β-hydroxyacyl coenzyme A dehydrogenase (β-HAD) in the soleus muscle of rats on endurance training [106]. Bee pollen restored mitochondrial complex-I, -II, -III, and -IV enzyme activity to normal, increased SOD and glutathione, and reduced MDA, NO, and total protein content in the gastrocnemius muscle of rats on exhaustive exercise [90]. It also increased the activity of CS and complex IV in malnourished old rats via a mechanism that involved activation of mTOR [36]. mTOR is a major signaling pathway that regulates various signaling cascades involved in metabolism and autophagy such nuclear respiratory factor 2 (NRF2) [2]. Therefore, it is possible that the antioxidant activity demonstrated by bee products, particularly that expressed in the mitochondria, is associated with their metabolic and hypoglycemic activities. For instance, 10-HDA increased expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) in skeletal muscle of diabetic mice [112,119]. Similarly, aged mice treated with amino acids similar to those found in royal jelly demonstrated improved size of muscle fiber by increasing PGC-1α mRNA levels. PGC-1α functions as a key regulator of sirtuin 1, which limits ROS production through stimulation of mitochondrial biogenesis and ROS defense system, thus protecting metabolically active tissues against oxidative damage [120]. Mechanistically, when PGC-1α gets activated, it interacts with other bioactive molecules such as muscle-specific transcription factors to stimulate the expression of genes that induce mitochondrial oxidative metabolism in brown fat and fiber-type switching in skeletal muscle [121].\nThe antioxidant activity of royal jelly and CAPE might be related to their strong capacity to activate the master redox-active NRF2 signaling pathway [73,122], which stimulates the production of internal antioxidants such as heme oxygenase-1 (HO-1), which scavenge free radicals [123]. Meanwhile, NRF2 and HO-1 block ROS production indirectly via suppression of inflammatory reactions [122]. In this context, CAPE reduced degenerative myopathy in rats on eccentric exercise via a complex mechanism that involved inhibition of NF-κB and its downstream pro-oxidant COX-2 and iNOS [101]. Correspondingly, CAPE decreased markers of oxidative cellular damages (protein carbonyl, protein nitrosylation, xanthine oxidase, and adenosine deaminase) associated with ischemia reperfusion and eccentric exercise in the gastrocnemius muscle [101,102,103]. In this regard, CAPE operated via a mechanism that involved inhibition of neutrophil and leukocyte infiltration into the gastrocnemius muscle, which was associated with decreased levels of myeloperoxidase. Myeloperoxidase contributes to excessive production of ROS and oxidative organ damage through a mechanism that embroils increased synthesis of hypochlorous acid [101,102]. Furthermore, CAPE accelerated purine salvage for ATP synthesis and inhibited ROS-induced lipid peroxidation via attenuation of the activity of adenosine deaminase [102].\nIn summary, the reported antioxidant effects of bee products were multifaceted involving increased production of antioxidant enzymes [90,95,109,110], and decreased ROS production [90,101,102,103,110] (secondary to reduction of inflammatory cell infiltration into skeletal muscle) [90,101,102,103], and restoration of mitochondrial activity [36,90,106].\n\n4.3. Metabolic Regulation\nSkeletal muscle is the main tissue that utilizes insulin for glucose uptake. Insulin regulates mitochondrial oxidative phosphorylation of proteins in human skeletal muscle and contributes to calcium mobilization from the sarcoplasmic-endoplasmic reticulum to mitochondria to stimulate the translocation of glucose transporter 4 (GLUT4) to the cell surface for glucose uptake. This process improves muscle protein synthesis in healthy people when the delivery of amino acids to skeletal muscle is increased, eventually leading to increased muscular mass [124,125,126]. Insulin resistance and glucose intolerance increase with old age evoking muscle loss. In this respect, hypoglycemic agents such as metformin can improve skeletal muscle metabolism via activation of adenosine monophosphate activated protein kinase (AMPK) [21].\nAMPK, a heterotrimeric complex that consists of a catalytic subunit and two regulatory subunits, is an intracellular energy sensor that regulates glucose and lipid metabolism. It gets activated when cellular energy is depleted through allosteric binding of AMP or phosphorylation by AMPK kinase at Thr172 of the catalytic subunit by AMPK kinase. Upregulated AMPK activates signaling pathways that generate ATP from glucose and fatty acid oxidation, and it simultaneously blocks signaling that contributes to the synthesis of cholesterol, fatty acid, and triacylglycerol [111]. In addition, AMPK masters numerous signaling cascades such as Forkhead Box O transcription factor (FOXO) and AKT/mTOR, which regulate the expression of genes associated with inflammation, oxidative stress, mitochondrial function, autophagy, metabolism, and apoptosis [127,128].\nThe molecular events involved in the effect of bee products on catabolic genes and anabolic resistance in skeletal muscle could be much related to their hypoglycemic effects, which positively affect the quality of skeletal muscle. Evidence signifies a positive effect of royal jelly acid (10-HDA) on inflammation and autophagy via upregulation of AMPK, which subsequently alters NF-κB and NLRP3 inflammasome-IL1β signaling [129]. Positive effects of whole royal jelly on skeletal muscle are associated with improved insulin signaling [96,100]. In one study, royal jelly improved serum IGF-1 levels in aged rats and increased AKT signaling in satellite cells extracted from aged rats in a separate in vitro investigation [96]. In another study, royal jelly decreased fat mass and improved anabolic resistance in the skeletal muscle of old obese rats on HFD via downregulation of inflammatory responses in adipose tissue as indicated by downregulation of TNFR1. This effect was associated with enhanced sensitivity to insulin—portrayed by reduction of serum insulin level and HOMA-IR [100].\nJapanese researchers proved that oral consumption of royal jelly and 10-HDA induced mitochondrial adaptation in the soleus muscle when accompanied with endurance training. These compounds also enhanced glucose uptake in skeletal muscle by inducing the phosphorylation of AMPK [106,112], an effect that was mediated by the upstream kinase Ca²⁺/calmodulin-dependent kinaseβ—independently of changes in AMP:ATP ratio and the liver kinase B1 pathway. Activation of AMPK was followed by translocation of GLUT4 to the plasma membrane of L6 myotubes [106]. It is note-worthy that effects of royal jelly on mitochondrial biogenesis under endurance training were muscle-specific. In this respect, neither endurance training nor royal jelly alone had an effect on the maximal activities of CS and β-HAD—the enzyme that catalyzes the rate-limiting step of β-oxidation of long-chain fatty acids—in the soleus muscle, which comprises type I fiber (around 35–45%) and type IIa (around 35–50%). On the other hand, royal jelly enhanced the activity of these enzymes in the soleus muscle of mice on endurance training. Of interest, endurance training increased the activity of CS and β-HAD in the plantaris and tibialis anterior muscles (which are mainly type II fiber with a total percentage of type IIb and type IIx fiber types of 90%) while royal jelly failed to exert an effect on these muscles in sedentary mice [106]. Nonetheless, the observed effects of royal jelly in the soleus muscle represent a merit. This is mainly because the oxidative type I fibers (e.g., soleus muscle) naturally undergo higher protein turnover (especially degradation), which makes them unable to grow in size or respond properly to insufficient nutrient intake [130].\nSeveral lines of evidence indicate that propolis may affect muscle quality through the regulation of glucose metabolism [69,70,109,111]. This effect was vividly depicted in vivo by increased glycogen level in skeletal muscle and reduced serum levels of glucose and insulin [109]. Same as insulin, ethanolic extracts of propolis and CAPE induced glucose uptake [69,70,111] and potentiated insulin-mediated AKT activation and glucose uptake in differentiated L6 myoblast cells [111]. Likewise, Italian propolis at concentrations of 0.1 and 1 mg/mL as well as 4-geranyloxyferulic acid and auraptene (2 oxyprenylated phenylpropanoids, which are abundant in propolis) remarkably increased GLUT4 translocation to the plasma membrane and accelerated GLUT4-mediated glucose uptake in L6 skeletal myoblasts. The effect of propolis at a concentration of 11 mg/mL was significantly superior to the effect of insulin (0.1 μM), which was used as a positive control [69].\nSimilar to royal jelly, the effects of propolis (1 μg/mL), CAPE (10 μM), artepillin C, coumaric acid, and kaempferide on glucose metabolism occurred via activation of AMPK. These effects were comparable to those of 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), a potent AMPK activator. In the meantime, co-treatment with inhibitors of AMPK (e.g., compound C) and of phosphatidylinositol 3-kinase (PI3K) (e.g., LY-294002) blocked the effects of CAPE [70,111]. Phosphorylation of AMPK results in activation of the insulin receptor (IR) and subsequent phosphorylation of PI3K followed by activation of AKT and protein kinase C (PKC) leading to GLUT4 translocation and subsequent activation of several molecules that modulate insulin-stimulated glucose transport, eventually leading to glucose influx into cells of several tissues such as skeletal muscle and adipose tissue [69,70,111]. It is worth noting that the effects of CAPE on AMPK and AKT were quick (within 1 h and 3 min, respectively), and they vanished quickly (both molecules returned back to their basal levels within 12 h and 30 min, respectively) [111].\n\n4.4. Enhancement of Muscle Protein Synthesis\nImbalance between muscle protein synthesis and degradation is associated with low protein intake and altered efficiency of the GI tract in old age, which triggers skeletal muscle loss and poor physical performance [36,40], given that proteins are the main building blocks of muscle myofibers. Moreover, transmembrane proteins and micro-peptides (e.g., myomixer and myomaker/Tmem8c) contribute to the formation of myofibers by promoting myoblast fusion via a mechanism that involves appropriate localization of Tmem8c at the plasma membrane of myoblasts allowing trafficking related to palmitoylation of C-terminal cysteine residues and C-terminal leucine [17]. Amino acid supplements (e.g., leucine, a master dietary regulator of muscle protein turnover, and its metabolite β-hydroxy β-methylbutyrate) and early refeeding with high protein diet (especially fast digestive proteins) can preserve muscle mass and function, revert sarcopenia, and enhance mobility and quality of life (QoL) by correcting age-related nutritional deficiencies, muscle protein turnover, and immune dysregulation—these effects are even greater when combined with other nutrients like vitamin D or omega 3 fatty acids as well as with physical exercise [6,131,132,133,134,135,136,137,138].\nResearch indicates that age-related skeletal muscle wasting results mainly from insufficient delivery of amino acids to skeletal muscle due to dysregulations in the activity of mTORC1- and activating transcription factor-4 (ATF4)-mediated amino acid sensing pathways. Meanwhile, interventions that ameliorate age-related damages in skeletal muscle operate primarily by reversing alterations in the delivery of amino acids to skeletal muscle via upregulation of mTORC1 and/or ATF4 [139]. mTORC1 is a nutrient sensing protein that acts as a core regulator of protein metabolism. It is sensitive to amino acids, energy status (ATP), stress (e.g., oxidative stress), and growth factors (e.g., insulin), which all can regulate its signaling [2,136]. Nevertheless, bioavailability of amino acids is necessary for growth factors to effectively activate mTORC1. Even more, amino acids on their own can adequately activate mTORC1 [136]. Evidence from preclinical and human studies confirms that ingestion of essential amino acids (similar to those found in royal jelly and bee pollen such as valine) increases cellular bioavailability of amino acids, which is associated with activation of the endothelial nitric oxide synthase (eNOs) pathway. eNOs further upregulates mTORC1 kinase. Translocation of mTORC1 from the cytosol to the surface of lysosomes is associated with improved mitochondrial biogenesis and cellular oxidative capacity in skeletal muscle due to activation of its substrates: P70 ribosomal proteins S6 kinase (S6K) and eukaryotic translation initiation 4E-binding protein 1 (eIF4E, also known as 4eBP1) [120,135,136].\nAs shown in Table 1, royal jelly and 10-HDA significantly increased muscle mass [54,96,100] and improved motor performance in aged rats [95,98,99]. In addition, dietary supplementation with monofloral bee pollen significantly improved the rate of muscle protein synthesis and restored muscle mass in emaciated old rats via upregulation of mTOR and two related downstream controllers of protein translation: p70S6k and 4eBP1, which were suppressed in malnourished old rats [36]. Although propolis improved various muscle-related parameters, its effect on muscle mass in rodents was limited—relative to royal jelly and bee pollen. However, it fostered muscle protein deposition in post-larva Nile tilapia [104]. Moreover, milk naturally enriched with PUFA and polyphenols from propolis remarkably increased the weight of the gastrocnemius muscle of growing obese rats while whole milk and milk enriched with PUFA only could not express any effect on skeletal muscle [105]. Therefore, this finding denotes that propolis could have enhanced the delivery of amino acids available in milk to skeletal muscle leading to its growth. Altogether, it is likely that the observed anabolic effects of royal jelly and bee pollen are associated with their high content of proteins and amino acids [32,36,83,84,85,86].\n\n4.5. Suppression of Catabolic Activity in Skeletal Muscle\nSkeletal muscle tissues represent the largest protein store in the human body (30–45% of total protein). Muscular mass, strength, and functions are greatly governed by the rates of muscle protein synthesis and turnover [124]. Muscle protein metabolism is regulated by the interaction of a wide range of genes. Aging is associated with various stresses, which increase the expression of catabolic genes such as E3 ubiquitin ligases MuRF1 and atrogin-1 (MAFbx). These genes heighten the occurrence of age-related muscular atrophy [97]. Oral consumption of royal jelly by aged HET mice resulted in lower levels of catabolic genes (e.g., MuRF1 and MAFbx), which were similar to those in young mice. In the meantime, the expression of these genes in the control mice was high indicating that royal jelly can delay age-related muscular apoptosis by suppressing the activity of catabolic genes [97]. Two other studies reported that CAPE suppressed catabolism that contributed to degenerative myopathy in the gastrocnemius muscle of rats undergoing eccentric exercising or femoral artery ligation as reflected by decreased serum levels of creatine kinase, a marker of muscular proteolysis [101,102,103]. Apart from skeletal muscle, CAPE was reported to protect heart muscle against age-related deteriorations such as accumulation of lipofuscin, nuclear irregularity, mitochondrial degeneration, and myofilament disorganization and disruption [33].\nThe molecular mechanism underling blockage of muscle proteolysis by bee products in sarcopenic rodents involves an interplay of various signaling pathways. Royal jelly and bee pollen activated mTOR and its substrate AKT, which are suggested to inhibit muscular proteolysis [36,96]. Similar to the effect of royal jelly on catabolic genes in HET mice, treating both L6 myoblasts and rats with propolis, CAPE, and kaempferide resulted in potent activation of AKT in a PI3K-dependent manner [111], in addition to phosphorylation of IR, PI3K, and AMPK [70]. AKT, a key substrate of mTORC2, is a conserved serine/threonine nutrient sensing protein kinase that belongs to the PI3k-related protein kinase family. Upon presence of growth factors, PI3k gets activated by IR substrate resulting in stimulation of a series of signaling cascades that involve activation of AKT, which leads to further activation of mTORC1. mTORC1 activates the phosphorylation of two main regulators of cap-dependent protein synthesis: S6K and eIF4E [2,140]. In addition, mTORC1 contributes to autophagy—a turnover process that involves clearance of dysfunctional organelles and long-lived protein aggregations with provision of energy and macromolecular precursors in return—by binding with AMPK resulting in phosphorylation of autophagy genes such as Unc51-like kinase 1 at different sites [140]. In fact, royal jelly is reported to fine-tune the transcriptional activity of the FOXO through modulating the activity of insulin/IGF-1 signaling [141]. FOXO plays a major role in the activation of AKT pathway, which implicates regulation of multiple stress–response pathways such as ROS detoxification and DNA repair and translation. In addition, the FOXOs family exerts a direct effect on certain muscle atrophy genes such as MUSA1 and a formerly uncharacterized ligase known as Specific of Muscle Atrophy and Regulated by Transcription (SMART) [142].\n\n4.6. Enhancement of Stem Cell Function\nReduction of the number and functional capacity of the muscle satellite cells is considered a core contributor to the development of age-related muscular dysfunction [96]. Induction of myogenesis via in vivo reprogramming of muscle satellite cells is a currently studied strategy that has not been successfully used for sarcopenia treatment yet [143]. On the other hand, treating sarcopenic rats with both royal jelly and pRJ was reported to increase the number of Pax7-positive satellite cells in vivo and in vitro (pRJ only). pRJ induced self-renewal of satellite cells via activation of AKT signaling [96,97]. AKT activity was associated with activation of IGF-1 as indicated by increased serum levels of IGF-1. IGF-1 plays a crucial rule in the activation of various signaling pathways; it is believed to be a major mediator of muscle growth and repair that functions by stimulating the proliferation and differentiation of satellite cells into myotubes, albeit the exact mechanism is not clear yet [96]. Similarly, pRJ activated AKT-signaling pathway in satellite cells culture, which was associated with increased proliferation of myosatellite cells and their differentiation into myotubes—an effect that is contradictory to muscle loss. AKT is thought to contribute to the synthesis of muscular proteins and inhibition of muscle proteolysis [96].\n\n4.7. Counteracting Glycation Stress\nOxidative stress, inflammation, and insensitivity to insulin, which accompany advanced age, contribute to the production of advanced glycation end products (AGEs) via enhancement of the activity of the Receptor for Advanced Glycation End products (RAGE) [144,145]. AGEs destroy the protein and lipid ingredients of muscle tissues by promoting the production of destructive molecules such as free radicals and inflammatory cytokines [101,102,113]. Thanks to their potent antioxidant properties, polyphenolic compounds exert multifaceted anti-glycation functions. On one hand, they scavenge free-radicals and chelate transition metals that are involved in the synthesis of dicarbonyl intermediates subsequently resulting in inhibition of the formation of AGEs. On the other hand, polyphenolic compounds antagonize AGE receptors, mainly RAGE, and facilitate the removal of already formed a,b-dicarbonyl intermediates such as methylglyoxal, promoting the degradation of AGEs [37,38,146]. Royal jelly is reported to downregulate the activity of RAGE, the main receptor for AGEs, in an aged model of cognitive impairment [147]. However, its anti-glycation effect has not been investigated in skeletal muscle yet. Propolis exhibits strong anti-AGE properties, which are superior to those of quercetin or chlorogenic acid, well-known natural AGE inhibitors. Its flavonoid fraction potently impedes the synthesis of AGEs by trapping dicarbonyl intermediates [37]. Table 1 shows that propolis accelerated AGEs clearance in a model of muscle aging induced by administration of a precursor of AGEs (methylglyoxal) via activation of glyoxalase 1, an enzyme that eliminates dicarbonyl compounds (key elements of AGEs) [38]. CAPE inhibited the production of AGEs-related molecules such as protein carbonyl in the gastrocnemius muscle of rats via blockage of the activity of xanthine oxidase and adenosine deaminase [101,102,103]. The latter negatively affects insulin signaling and promotes the development of hyperglycemia, which represents a favorable condition for the production of AGEs [148]. However, propolis could not counteract the wasting effects of AGEs that already occurred in the extensor digitorum longus muscle though it tended to restore soleus muscle mass. This finding denotes that different muscle tissues respond differently to treatment, probably based on their ratio of type I to type II fibers. It also signifies the importance of early use of bee products (e.g., propolis) for the prevention of AGEs formation in skeletal muscle in people with high risk for AGEs formation such as diabetics [38].\n\n4.8. Neuronal Regeneration\nNeuronal denervation is a key factor that contributes to skeletal muscle loss, and it is related to a plethora of pathological conditions [3,149]. Experimental induction of oxidative stress and inflammation results in skeletal muscle atrophy through induction of denervation e.g., of sciatic nerve [150]. Injuries of peripheral nerves (e.g., sciatic nerve) interrupt mechanical transmission and microvasculation of the nerve and induce reperfusion. Reperfusion involves pooling of oxygen and nutrients promoting high emission of free radicals, which attack protein and lipid contents surrounding the injury site resulting in excessive tissue loss [113]. Likewise, alterations in gut microbiome in aged rats are associated with alterations in serum level of vitamin B12 and fat metabolism as well as reductions in the gastrocnemius muscle mass and sciatic response amplitude [151]. Furthermore, dysregulation of insulin-mediated GLUT4 activity in certain areas of the central nervous system impairs neuronal metabolism and plasticity [69]. Meanwhile, activation of PGC-1α, a core regulator of mitochondrial content and oxidative metabolism, increases muscle fiber resistance to denervation and atrophy through downregulation of two ubiquitin-ligases involved in the ubiquitin-proteasome pathway: MuRF1 and Atrogin-1 [1,152].\nPropolis treatment for four weeks restored gastrocnemius muscle weight and improved functional performance (e.g., walking) in rats with crush injury of the sciatic nerve. Effects of propolis were associated with increased nerve healing and regeneration as depicted by faster healing of the myelin sheath and ultra-structurally normal unmyelinated axons and Schwann cells. Investigations of motor conduction from the sciatic nerve to the gastrocnemius muscle indicated that nerve recovery induced by propolis treatment promoted optimal physical functioning by allowing motor conduction to reach the gastrocnemius muscle [113]. Neuroprotective effects of propolis in motor neurons are documented in the literature. Both kaempferide and kaempferol protected motor neurons against atrophy induced by the toxic copper-zinc superoxide dismutase in amyotrophic lateral sclerosis—a serious neurodegenerative disease that involves selective and progressive loss of motor neurons [65]. In addition, orally administered chrysin (a flavonoid that is copious in propolis) to rats intoxicated by 6-hydroxidopamine showed neuroprotective effects by mitigating neuroinflammation, enhancing levels of neurotrophins and neuronal recovery factors (e.g., brain derived neurotrophic factor and glial cell line-derived neurotrophic factor), and maintaining integrity of dopaminergic neurons resulting in better motor performance [72].\nThe release of acetylcholine (a neurotransmitter that regulates cognition) at the synaptic cleft of the neuromuscular junction is essential for motor neurotransmission, which controls excitation-contraction coupling and cell size. However, free radicals, cytokines, and AGEs impair neurotransmission by altering the production of acetylcholine [6,21,149,153]. On the other hand, upregulation of acetylcholine receptors improves neurotransmission [154]. Treatment with royal jelly may correct acetylcholine neurotransmission given its high content of acetylcholine (4–8 mM) [60]. In addition, royal jelly, propolis, and bee pollen are rich in antioxidant elements that have a potential to scavenge ROS and mitigate other pathologies that contribute to acetylcholine deficiency (e.g., neuroinflammation) [73,101,102,103]. In this respect, treatment of experimental models of carrageenan-induced hind paw edema with hydroalcoholic extract of red propolis and its biomarker, formononetin, is reported to inhibit leukocyte migration and ameliorate inflammatory neurogenic pain induced by injections of formalin and glutamate [115]. However, investigations of the action of bee products on neurotransmission are very scarce.\n\n4.9. Improving Muscular Blood Supply\nAging is associated with higher onset of atherosclerosis and restenosis, which involve vascular and microvascular damages that result from hyperproliferation of vascular smooth muscle cells (VSMCs) [155]. Muscle unloading (e.g., in sedentary lifestyle) involves chronic neuromuscular inactivity, which results in reductions in capillary number, luminal diameter, and capillary volume as well as heightened production of anti-angiogenic factors, such as p53 and TSP-1 in skeletal muscle [110]. Microvascular alterations and impaired nitric oxide (NO) production are key causes of decreased blood flow to the skeletal muscle. Poor muscular blood supply induces muscle wasting via a mechanism that entails impaired glucose metabolism and suboptimal protein anabolism [156,157]. In addition, ischemic injury in skeletal muscle is associated with high ROS release from polymorphonuclear leukocytes, which infiltrate muscle tissues. Free radicals alter cellular structure and function by attacking lipid and protein biomolecules that exist in the structure of biological membranes, enzymes, and transport proteins [102]. Therefore, improving vascularization and blood supply to skeletal muscle is a possible mechanism for the prevention of muscle wasting.\nMitchell and colleagues examined changes in microvascular blood volume, microvascular flow velocity, and microvascular blood flow in the quadriceps muscle following treatment with 15 g of amino acids in young and old subjects (20–70 years old). They detected improvements in all the 3 parameters only in young groups, and those effects were associated with proper insulin activity. Thus, the authors suggested that refeeding effects on muscular blood supply may be hindered by dysfunctions in postprandial circulation and glucose dysregulation [157]. Bee products such as bee pollen and propolis have a potential to boost microcirculation and correct pathologies that contribute to vascular dysfunction such as hyperglycemia and dyslipidemia [36,155]. In this context, CAPE, one of the basic constituents of propolis, was reported to combat vascular damages by counteracting the proliferative activity of platelet-derived growth factor. The molecular mechanism involved inducing cell-cycle arrest in VSMCs via activation of p38mitogen-activated protein kinase (MAPK), which was associated with accumulation of hypoxia-inducible factor (HIF)-1α—mainly due to inhibition of HIF prolylhydroxylase, a key contributor to proteasomal degradation of HIF-1α—and subsequent induction of HO-1 [155]. In the same regard, supplementing rats undergoing capillary regression (resulting from two weeks of hind limb unloading) in the soleus muscle with two daily intragastric doses of propolis for two weeks restored capillary number, capillary structure, capillary volume, and capillary to muscle fiber ratio through a mechanism that involves inhibition of anti-angiogenic factors and activation of pro-angiogenic factors (e.g., VEGF). The relative muscle-to-body weight in treated animals was higher than in the unloaded control animals, and the number of TUNEL-positive apoptotic endothelial cells in the soleus muscle was similar to that in the normal control animals [110]. Likewise, bee pollen (both neat and processed) increased blood vessels in the gastrocnemius muscle of rats undergoing muscle injury because of vigorous exercise [90]. Treating C2C12 myoblasts with propolis ethanolic extract increased VEGF production [108]. VEGF is a pro-angiogenic factor that contributes to angiogenesis by recruiting endothelial cells and promoting their differentiation to form new vascular networks. VEGF protects skeletal muscle undergoing unloading against the progression of capillary regression [110]. Its expression in skeletal muscle and associated angiogenic response increase following exercise due to change in the activity of HIF-1α and AMPK. It promotes the generation of ATP following mitochondrial biogenesis in order to meet oxygen demand [158]. Altogether, these reports signify that bee products and endurance exercise share common mechanisms to produce their vitality effects in skeletal muscle.\n\n4.10. Improving the Composition of Gut Microbiome\nBee products such as royal jelly and propolis display potent antifungal, bactericidal, microbicidal, anti-inflammatory, antioxidant, and healing effects [2,66]. Most bee products investigated in this review were administered orally. Therefore, it is likely that their therapeutic effects may start locally within the GI tract, which frequently undergoes propagation of harmful endobacteria, inflammation, aberrations, and permeability in advanced age [10,24,152]. In this respect, Roquetto and colleagues [116] supplemented C57BL/6 mice on HFD with crude propolis (0.2%) for two and five weeks. HFD increased the proportion of the phylum Firmicutes as well as levels of circulating lipopolysaccharide (LPS) and inflammatory biomarkers. DNA sequencing for the 16S rRNA of the gut microbiota revealed that five weeks of propolis treatment rendered the microbiota profile almost normal. Compared with untreated mice, propolis-supplemented animals demonstrated lower levels of serum triacylglycerols, glucose, and circulating LPS, along with reduced expression of TLR4 and inflammatory cytokines in skeletal muscle [116].\nLactic acid bacteria profusely exist in bee saliva and all bee products [36,83,84]. Various species of lactic acid bacteria have been experimentally used to correct GI dysbiosis and related muscle wasting [159,160]. Moreover, oligosaccharides have been chemically isolated from bee products [32,161]. These api-materials are classified as prebiotics, fermented non-digestible compounds that promote the proliferative activity of health-promoting bacteria [24,161]. Supplementing frail old adults with fructooligosaccharides expressed positive effects on skeletal muscle strength (handgrip) and endurance (exhaustion) [162]. On the other side, microbiome of the gut can affect the biological activity of bee products. The literature shows that certain endobacteria transform dietary polyphenols into phenolic acids, which can easily access the circulation and then cross the blood brain barrier to produce therapeutic effects [163]. Hence, it is important that future investigations of bee products among sarcopenic subjects examine the effect of these products on the composition of GI microbial population and its association with muscle-related outcomes."}

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Mechanisms of Action of Royal Jelly, Bee Pollen, and Propolis in Sarcopenia\nRelatively few studies have explored the mechanism through which royal jelly, bee pollen, and propolis may be beneficial for sarcopenia. In vivo and in vitro studies included in this review uncovered a number of inter-related cellular and molecular events that underlie the effect of these bee products on skeletal muscle including suppression of catabolic genes, counteracting metabolic abnormalities, inflammation, and oxidative damages as well as enhancement of motor neuronal regeneration, promotion of stem cell function, and correction of the structure of gut microbiome (Figure 1, Panel D). These mechanisms are exclusively described in the coming paragraphs.\n\n4.1. Modulating Inflammatory Responses in Skeletal Muscle\nThe role that inflammation plays in skeletal muscle is not quite clear as it looks. Inflammatory mediators behave in a dual fashion in muscle cells. During injury, cytokines and chemokines stimulate muscle repair and regeneration via activation of myoblasts, a core event in muscle remodeling [108]. Similarly, serum and muscle levels of IL-6 temporarily increase following physical exercise, and IL-6 blocks the activity of catabolic cytokines such as TNF-α. On the other hand, chronic inflammation in muscle cells, which correlates with persistent mitochondrial dysfunction and metabolic dysregulation, pathologically activates muscle fiber transformation and atrophy, eventually resulting in the development of sarcopenia [23,114]. It seems that bee products also act dually in skeletal muscle: they support the activity of cytokines that promote muscle remodeling [108] and suppress muscle-consuming cytokines [38,101,108]. In this regard, treating undifferentiated C2C12 myoblasts with ethanolic extracts of Brazilian propolis (100 μg/mL for 8 h) triggered the migration of RAW264 macrophage and increased their production of angiogenic factors (e.g., vascular endothelial growth factor A (VEGF-A) and metalloproteinase-12 (MMP-12)), chemokines (e.g., CCL-2 and CCL-5), and cytokines (e.g., IL-6, which increased by 40-folds). Propolis inhibited the expression of IL-1β and TNF-α at 4, 8, and 12 h of incubation. These effects were nuclear factor kappa B (NF-κB)-dependent given that propolis simultaneously increased nuclear translocation of p65 and p50 NF-κB proteins 3 h after treatment. Meanwhile, inhibiting IκB kinase (IKK) by BMS-345541 profoundly hindered the effect of propolis on the expression of CCL-2, CCL-5, and IL-6 by 66%, 81%, and 69%, respectively. Propolis also enhanced the expression of MAIL/IκBζ. This molecule modulates chromatin and selectively induces the production of IL-6, leukemia inhibitory factor (LIF), and CCL-2 [108].\nChronic muscle tissue infiltration by inflammatory cells (e.g., leukocytes, neutrophils, and monocytes) activates oxidative and inflammatory signaling cascades that degrade cellular structures and promote necrosis such as inducible nitric oxide synthase (iNOS) and NF-kB [90,101,115]. CAPE and high levels (200 and 300 mg/kg) of crude and processed bee pollen reduced inflammatory cell infiltration into the gastrocnemius muscle of rats with muscle injury induced by eccentric exercise and ischemia reperfusion [90,101,102]. This effect was revealed by lower activity of myeloperoxidase, an indicator of neutrophil sequestration [101,102]. As such, CAPE and bee pollen not only suppressed lipid peroxidation (lower levels of malondialdehyde, MDA) but also inhibited the activity of myostatin and the production of muscle depleting cytokines and chemokines such as IL-1β, α2-macroglobulin, and monocyte chemotactic protein 1 (MCP-1) [36,38,90,101]. The underlying mechanism entailed downregulation of nuclear p65NF-κB and blockage of its consensus binding sites in skeletal muscle [101]. As a result, bee products increased muscle mass both in sarcopenic obese rat and malnourished old rats [36] and restored the structure of myofibers (despite the persistence of necrosis) compared with untreated eccentric exercising animals, which demonstrated necrotic and fragmented myofibers [90].\nRoyal jelly downregulated the activity of tumor necrosis factor receptor 1 (TNFR1) in the adipose tissue of aged obese rats receiving HFD [100]. TNFR1 interacts with TNFR2 to negatively regulate toll-like receptors (TLR) and Nod-like receptor signaling and stimulate excessive release of cytokines via activation of key inflammatory pathways such as NF-κB [107]. Mitigation of TNFR1 was associated with a significant increase of the weight of hind limb muscle and reductions in insulin levels, homeostatic model assessment of insulin resistance (HOMA-IR), serum lipids, muscle triglyceride levels, body weight gain, and abdominal fat weight. Therefore, royal jelly may protect against muscle loss in conditions involving impairment of the adipokine profile mainly through suppression of inflammatory responses associated with high fat mass, which is followed by correction of metabolic irregularities [100].\n\n4.2. Counteracting Oxidative Stress in Skeletal Muscle\nHigh production of reactive oxygen species (ROS) in skeletal muscle tissues has serious destructive effects, which alter the integrity of skeletal muscle resulting into fatigue, muscle wasting, and muscle weakness [90,101]. Sources of intramuscular ROS are numerous including mitochondrial dysfunction (e.g., alteration of mitochondrial enzymes in the respiratory chain as well as enzymes responsible for β-oxidation), neutrophil infiltration, and the activity of cytokines and major muscle degrading molecules such as myostatin [21,36,38,101,102,118]. Oxidative and nitrosative damages in skeletal muscle tissues are mediated by the activity of numerous pro-oxidant enzymes that are associated with inflammatory processes such as cyclooxygenase-2 (COX-2) and iNOS [101]. ROS triggers the activity of corrosive molecules such as poly (ADP-ribose) polymerase (PARP), xanthine oxidase, and adenosine deaminase, which contribute to DNA damage, lipid peroxidation (e.g., increased MDA), and protein nitrotyrosylation as well as ATP catabolism in muscle tissues [101,102].\nRoyal jelly enhanced the activity of antioxidant enzymes and suppressed lipid peroxidation in a d-galactose induced model of aging [95]. Two weeks of propolis treatment in rats undergoing hind limb unloading significantly reduced nuclear ROS levels and numbers of apoptotic endothelial cells in the soleus muscle to levels similar to normal rats [110]. Moreover, propolis significantly suppressed MDA activity in skeletal muscle and increased liver levels of SOD as well as gastrocnemius muscle levels of SOD, glutathione peroxidase and catalase in rats on eccentric exercise training (70% VO2max treadmill running exercise for 60 min) compared with rats receiving exercise alone or no treatment [109]. In addition, intraperitoneal pre-administration of CAPE (60 min before induction of ischemia reperfusion) significantly ameliorated the effects associated with high ROS levels, which accompany acute ischemia such as protein peroxidation and ATP catabolism in the gastrocnemius muscle [102].\nBee products probably reduced ROS production via regulation of the activity of mitochondrial enzymes. Royal jelly increased the maximal activity of citrate synthase (CS) and β-hydroxyacyl coenzyme A dehydrogenase (β-HAD) in the soleus muscle of rats on endurance training [106]. Bee pollen restored mitochondrial complex-I, -II, -III, and -IV enzyme activity to normal, increased SOD and glutathione, and reduced MDA, NO, and total protein content in the gastrocnemius muscle of rats on exhaustive exercise [90]. It also increased the activity of CS and complex IV in malnourished old rats via a mechanism that involved activation of mTOR [36]. mTOR is a major signaling pathway that regulates various signaling cascades involved in metabolism and autophagy such nuclear respiratory factor 2 (NRF2) [2]. Therefore, it is possible that the antioxidant activity demonstrated by bee products, particularly that expressed in the mitochondria, is associated with their metabolic and hypoglycemic activities. For instance, 10-HDA increased expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) in skeletal muscle of diabetic mice [112,119]. Similarly, aged mice treated with amino acids similar to those found in royal jelly demonstrated improved size of muscle fiber by increasing PGC-1α mRNA levels. PGC-1α functions as a key regulator of sirtuin 1, which limits ROS production through stimulation of mitochondrial biogenesis and ROS defense system, thus protecting metabolically active tissues against oxidative damage [120]. Mechanistically, when PGC-1α gets activated, it interacts with other bioactive molecules such as muscle-specific transcription factors to stimulate the expression of genes that induce mitochondrial oxidative metabolism in brown fat and fiber-type switching in skeletal muscle [121].\nThe antioxidant activity of royal jelly and CAPE might be related to their strong capacity to activate the master redox-active NRF2 signaling pathway [73,122], which stimulates the production of internal antioxidants such as heme oxygenase-1 (HO-1), which scavenge free radicals [123]. Meanwhile, NRF2 and HO-1 block ROS production indirectly via suppression of inflammatory reactions [122]. In this context, CAPE reduced degenerative myopathy in rats on eccentric exercise via a complex mechanism that involved inhibition of NF-κB and its downstream pro-oxidant COX-2 and iNOS [101]. Correspondingly, CAPE decreased markers of oxidative cellular damages (protein carbonyl, protein nitrosylation, xanthine oxidase, and adenosine deaminase) associated with ischemia reperfusion and eccentric exercise in the gastrocnemius muscle [101,102,103]. In this regard, CAPE operated via a mechanism that involved inhibition of neutrophil and leukocyte infiltration into the gastrocnemius muscle, which was associated with decreased levels of myeloperoxidase. Myeloperoxidase contributes to excessive production of ROS and oxidative organ damage through a mechanism that embroils increased synthesis of hypochlorous acid [101,102]. Furthermore, CAPE accelerated purine salvage for ATP synthesis and inhibited ROS-induced lipid peroxidation via attenuation of the activity of adenosine deaminase [102].\nIn summary, the reported antioxidant effects of bee products were multifaceted involving increased production of antioxidant enzymes [90,95,109,110], and decreased ROS production [90,101,102,103,110] (secondary to reduction of inflammatory cell infiltration into skeletal muscle) [90,101,102,103], and restoration of mitochondrial activity [36,90,106].\n\n4.3. Metabolic Regulation\nSkeletal muscle is the main tissue that utilizes insulin for glucose uptake. Insulin regulates mitochondrial oxidative phosphorylation of proteins in human skeletal muscle and contributes to calcium mobilization from the sarcoplasmic-endoplasmic reticulum to mitochondria to stimulate the translocation of glucose transporter 4 (GLUT4) to the cell surface for glucose uptake. This process improves muscle protein synthesis in healthy people when the delivery of amino acids to skeletal muscle is increased, eventually leading to increased muscular mass [124,125,126]. Insulin resistance and glucose intolerance increase with old age evoking muscle loss. In this respect, hypoglycemic agents such as metformin can improve skeletal muscle metabolism via activation of adenosine monophosphate activated protein kinase (AMPK) [21].\nAMPK, a heterotrimeric complex that consists of a catalytic subunit and two regulatory subunits, is an intracellular energy sensor that regulates glucose and lipid metabolism. It gets activated when cellular energy is depleted through allosteric binding of AMP or phosphorylation by AMPK kinase at Thr172 of the catalytic subunit by AMPK kinase. Upregulated AMPK activates signaling pathways that generate ATP from glucose and fatty acid oxidation, and it simultaneously blocks signaling that contributes to the synthesis of cholesterol, fatty acid, and triacylglycerol [111]. In addition, AMPK masters numerous signaling cascades such as Forkhead Box O transcription factor (FOXO) and AKT/mTOR, which regulate the expression of genes associated with inflammation, oxidative stress, mitochondrial function, autophagy, metabolism, and apoptosis [127,128].\nThe molecular events involved in the effect of bee products on catabolic genes and anabolic resistance in skeletal muscle could be much related to their hypoglycemic effects, which positively affect the quality of skeletal muscle. Evidence signifies a positive effect of royal jelly acid (10-HDA) on inflammation and autophagy via upregulation of AMPK, which subsequently alters NF-κB and NLRP3 inflammasome-IL1β signaling [129]. Positive effects of whole royal jelly on skeletal muscle are associated with improved insulin signaling [96,100]. In one study, royal jelly improved serum IGF-1 levels in aged rats and increased AKT signaling in satellite cells extracted from aged rats in a separate in vitro investigation [96]. In another study, royal jelly decreased fat mass and improved anabolic resistance in the skeletal muscle of old obese rats on HFD via downregulation of inflammatory responses in adipose tissue as indicated by downregulation of TNFR1. This effect was associated with enhanced sensitivity to insulin—portrayed by reduction of serum insulin level and HOMA-IR [100].\nJapanese researchers proved that oral consumption of royal jelly and 10-HDA induced mitochondrial adaptation in the soleus muscle when accompanied with endurance training. These compounds also enhanced glucose uptake in skeletal muscle by inducing the phosphorylation of AMPK [106,112], an effect that was mediated by the upstream kinase Ca²⁺/calmodulin-dependent kinaseβ—independently of changes in AMP:ATP ratio and the liver kinase B1 pathway. Activation of AMPK was followed by translocation of GLUT4 to the plasma membrane of L6 myotubes [106]. It is note-worthy that effects of royal jelly on mitochondrial biogenesis under endurance training were muscle-specific. In this respect, neither endurance training nor royal jelly alone had an effect on the maximal activities of CS and β-HAD—the enzyme that catalyzes the rate-limiting step of β-oxidation of long-chain fatty acids—in the soleus muscle, which comprises type I fiber (around 35–45%) and type IIa (around 35–50%). On the other hand, royal jelly enhanced the activity of these enzymes in the soleus muscle of mice on endurance training. Of interest, endurance training increased the activity of CS and β-HAD in the plantaris and tibialis anterior muscles (which are mainly type II fiber with a total percentage of type IIb and type IIx fiber types of 90%) while royal jelly failed to exert an effect on these muscles in sedentary mice [106]. Nonetheless, the observed effects of royal jelly in the soleus muscle represent a merit. This is mainly because the oxidative type I fibers (e.g., soleus muscle) naturally undergo higher protein turnover (especially degradation), which makes them unable to grow in size or respond properly to insufficient nutrient intake [130].\nSeveral lines of evidence indicate that propolis may affect muscle quality through the regulation of glucose metabolism [69,70,109,111]. This effect was vividly depicted in vivo by increased glycogen level in skeletal muscle and reduced serum levels of glucose and insulin [109]. Same as insulin, ethanolic extracts of propolis and CAPE induced glucose uptake [69,70,111] and potentiated insulin-mediated AKT activation and glucose uptake in differentiated L6 myoblast cells [111]. Likewise, Italian propolis at concentrations of 0.1 and 1 mg/mL as well as 4-geranyloxyferulic acid and auraptene (2 oxyprenylated phenylpropanoids, which are abundant in propolis) remarkably increased GLUT4 translocation to the plasma membrane and accelerated GLUT4-mediated glucose uptake in L6 skeletal myoblasts. The effect of propolis at a concentration of 11 mg/mL was significantly superior to the effect of insulin (0.1 μM), which was used as a positive control [69].\nSimilar to royal jelly, the effects of propolis (1 μg/mL), CAPE (10 μM), artepillin C, coumaric acid, and kaempferide on glucose metabolism occurred via activation of AMPK. These effects were comparable to those of 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), a potent AMPK activator. In the meantime, co-treatment with inhibitors of AMPK (e.g., compound C) and of phosphatidylinositol 3-kinase (PI3K) (e.g., LY-294002) blocked the effects of CAPE [70,111]. Phosphorylation of AMPK results in activation of the insulin receptor (IR) and subsequent phosphorylation of PI3K followed by activation of AKT and protein kinase C (PKC) leading to GLUT4 translocation and subsequent activation of several molecules that modulate insulin-stimulated glucose transport, eventually leading to glucose influx into cells of several tissues such as skeletal muscle and adipose tissue [69,70,111]. It is worth noting that the effects of CAPE on AMPK and AKT were quick (within 1 h and 3 min, respectively), and they vanished quickly (both molecules returned back to their basal levels within 12 h and 30 min, respectively) [111].\n\n4.4. Enhancement of Muscle Protein Synthesis\nImbalance between muscle protein synthesis and degradation is associated with low protein intake and altered efficiency of the GI tract in old age, which triggers skeletal muscle loss and poor physical performance [36,40], given that proteins are the main building blocks of muscle myofibers. Moreover, transmembrane proteins and micro-peptides (e.g., myomixer and myomaker/Tmem8c) contribute to the formation of myofibers by promoting myoblast fusion via a mechanism that involves appropriate localization of Tmem8c at the plasma membrane of myoblasts allowing trafficking related to palmitoylation of C-terminal cysteine residues and C-terminal leucine [17]. Amino acid supplements (e.g., leucine, a master dietary regulator of muscle protein turnover, and its metabolite β-hydroxy β-methylbutyrate) and early refeeding with high protein diet (especially fast digestive proteins) can preserve muscle mass and function, revert sarcopenia, and enhance mobility and quality of life (QoL) by correcting age-related nutritional deficiencies, muscle protein turnover, and immune dysregulation—these effects are even greater when combined with other nutrients like vitamin D or omega 3 fatty acids as well as with physical exercise [6,131,132,133,134,135,136,137,138].\nResearch indicates that age-related skeletal muscle wasting results mainly from insufficient delivery of amino acids to skeletal muscle due to dysregulations in the activity of mTORC1- and activating transcription factor-4 (ATF4)-mediated amino acid sensing pathways. Meanwhile, interventions that ameliorate age-related damages in skeletal muscle operate primarily by reversing alterations in the delivery of amino acids to skeletal muscle via upregulation of mTORC1 and/or ATF4 [139]. mTORC1 is a nutrient sensing protein that acts as a core regulator of protein metabolism. It is sensitive to amino acids, energy status (ATP), stress (e.g., oxidative stress), and growth factors (e.g., insulin), which all can regulate its signaling [2,136]. Nevertheless, bioavailability of amino acids is necessary for growth factors to effectively activate mTORC1. Even more, amino acids on their own can adequately activate mTORC1 [136]. Evidence from preclinical and human studies confirms that ingestion of essential amino acids (similar to those found in royal jelly and bee pollen such as valine) increases cellular bioavailability of amino acids, which is associated with activation of the endothelial nitric oxide synthase (eNOs) pathway. eNOs further upregulates mTORC1 kinase. Translocation of mTORC1 from the cytosol to the surface of lysosomes is associated with improved mitochondrial biogenesis and cellular oxidative capacity in skeletal muscle due to activation of its substrates: P70 ribosomal proteins S6 kinase (S6K) and eukaryotic translation initiation 4E-binding protein 1 (eIF4E, also known as 4eBP1) [120,135,136].\nAs shown in Table 1, royal jelly and 10-HDA significantly increased muscle mass [54,96,100] and improved motor performance in aged rats [95,98,99]. In addition, dietary supplementation with monofloral bee pollen significantly improved the rate of muscle protein synthesis and restored muscle mass in emaciated old rats via upregulation of mTOR and two related downstream controllers of protein translation: p70S6k and 4eBP1, which were suppressed in malnourished old rats [36]. Although propolis improved various muscle-related parameters, its effect on muscle mass in rodents was limited—relative to royal jelly and bee pollen. However, it fostered muscle protein deposition in post-larva Nile tilapia [104]. Moreover, milk naturally enriched with PUFA and polyphenols from propolis remarkably increased the weight of the gastrocnemius muscle of growing obese rats while whole milk and milk enriched with PUFA only could not express any effect on skeletal muscle [105]. Therefore, this finding denotes that propolis could have enhanced the delivery of amino acids available in milk to skeletal muscle leading to its growth. Altogether, it is likely that the observed anabolic effects of royal jelly and bee pollen are associated with their high content of proteins and amino acids [32,36,83,84,85,86].\n\n4.5. Suppression of Catabolic Activity in Skeletal Muscle\nSkeletal muscle tissues represent the largest protein store in the human body (30–45% of total protein). Muscular mass, strength, and functions are greatly governed by the rates of muscle protein synthesis and turnover [124]. Muscle protein metabolism is regulated by the interaction of a wide range of genes. Aging is associated with various stresses, which increase the expression of catabolic genes such as E3 ubiquitin ligases MuRF1 and atrogin-1 (MAFbx). These genes heighten the occurrence of age-related muscular atrophy [97]. Oral consumption of royal jelly by aged HET mice resulted in lower levels of catabolic genes (e.g., MuRF1 and MAFbx), which were similar to those in young mice. In the meantime, the expression of these genes in the control mice was high indicating that royal jelly can delay age-related muscular apoptosis by suppressing the activity of catabolic genes [97]. Two other studies reported that CAPE suppressed catabolism that contributed to degenerative myopathy in the gastrocnemius muscle of rats undergoing eccentric exercising or femoral artery ligation as reflected by decreased serum levels of creatine kinase, a marker of muscular proteolysis [101,102,103]. Apart from skeletal muscle, CAPE was reported to protect heart muscle against age-related deteriorations such as accumulation of lipofuscin, nuclear irregularity, mitochondrial degeneration, and myofilament disorganization and disruption [33].\nThe molecular mechanism underling blockage of muscle proteolysis by bee products in sarcopenic rodents involves an interplay of various signaling pathways. Royal jelly and bee pollen activated mTOR and its substrate AKT, which are suggested to inhibit muscular proteolysis [36,96]. Similar to the effect of royal jelly on catabolic genes in HET mice, treating both L6 myoblasts and rats with propolis, CAPE, and kaempferide resulted in potent activation of AKT in a PI3K-dependent manner [111], in addition to phosphorylation of IR, PI3K, and AMPK [70]. AKT, a key substrate of mTORC2, is a conserved serine/threonine nutrient sensing protein kinase that belongs to the PI3k-related protein kinase family. Upon presence of growth factors, PI3k gets activated by IR substrate resulting in stimulation of a series of signaling cascades that involve activation of AKT, which leads to further activation of mTORC1. mTORC1 activates the phosphorylation of two main regulators of cap-dependent protein synthesis: S6K and eIF4E [2,140]. In addition, mTORC1 contributes to autophagy—a turnover process that involves clearance of dysfunctional organelles and long-lived protein aggregations with provision of energy and macromolecular precursors in return—by binding with AMPK resulting in phosphorylation of autophagy genes such as Unc51-like kinase 1 at different sites [140]. In fact, royal jelly is reported to fine-tune the transcriptional activity of the FOXO through modulating the activity of insulin/IGF-1 signaling [141]. FOXO plays a major role in the activation of AKT pathway, which implicates regulation of multiple stress–response pathways such as ROS detoxification and DNA repair and translation. In addition, the FOXOs family exerts a direct effect on certain muscle atrophy genes such as MUSA1 and a formerly uncharacterized ligase known as Specific of Muscle Atrophy and Regulated by Transcription (SMART) [142].\n\n4.6. Enhancement of Stem Cell Function\nReduction of the number and functional capacity of the muscle satellite cells is considered a core contributor to the development of age-related muscular dysfunction [96]. Induction of myogenesis via in vivo reprogramming of muscle satellite cells is a currently studied strategy that has not been successfully used for sarcopenia treatment yet [143]. On the other hand, treating sarcopenic rats with both royal jelly and pRJ was reported to increase the number of Pax7-positive satellite cells in vivo and in vitro (pRJ only). pRJ induced self-renewal of satellite cells via activation of AKT signaling [96,97]. AKT activity was associated with activation of IGF-1 as indicated by increased serum levels of IGF-1. IGF-1 plays a crucial rule in the activation of various signaling pathways; it is believed to be a major mediator of muscle growth and repair that functions by stimulating the proliferation and differentiation of satellite cells into myotubes, albeit the exact mechanism is not clear yet [96]. Similarly, pRJ activated AKT-signaling pathway in satellite cells culture, which was associated with increased proliferation of myosatellite cells and their differentiation into myotubes—an effect that is contradictory to muscle loss. AKT is thought to contribute to the synthesis of muscular proteins and inhibition of muscle proteolysis [96].\n\n4.7. Counteracting Glycation Stress\nOxidative stress, inflammation, and insensitivity to insulin, which accompany advanced age, contribute to the production of advanced glycation end products (AGEs) via enhancement of the activity of the Receptor for Advanced Glycation End products (RAGE) [144,145]. AGEs destroy the protein and lipid ingredients of muscle tissues by promoting the production of destructive molecules such as free radicals and inflammatory cytokines [101,102,113]. Thanks to their potent antioxidant properties, polyphenolic compounds exert multifaceted anti-glycation functions. On one hand, they scavenge free-radicals and chelate transition metals that are involved in the synthesis of dicarbonyl intermediates subsequently resulting in inhibition of the formation of AGEs. On the other hand, polyphenolic compounds antagonize AGE receptors, mainly RAGE, and facilitate the removal of already formed a,b-dicarbonyl intermediates such as methylglyoxal, promoting the degradation of AGEs [37,38,146]. Royal jelly is reported to downregulate the activity of RAGE, the main receptor for AGEs, in an aged model of cognitive impairment [147]. However, its anti-glycation effect has not been investigated in skeletal muscle yet. Propolis exhibits strong anti-AGE properties, which are superior to those of quercetin or chlorogenic acid, well-known natural AGE inhibitors. Its flavonoid fraction potently impedes the synthesis of AGEs by trapping dicarbonyl intermediates [37]. Table 1 shows that propolis accelerated AGEs clearance in a model of muscle aging induced by administration of a precursor of AGEs (methylglyoxal) via activation of glyoxalase 1, an enzyme that eliminates dicarbonyl compounds (key elements of AGEs) [38]. CAPE inhibited the production of AGEs-related molecules such as protein carbonyl in the gastrocnemius muscle of rats via blockage of the activity of xanthine oxidase and adenosine deaminase [101,102,103]. The latter negatively affects insulin signaling and promotes the development of hyperglycemia, which represents a favorable condition for the production of AGEs [148]. However, propolis could not counteract the wasting effects of AGEs that already occurred in the extensor digitorum longus muscle though it tended to restore soleus muscle mass. This finding denotes that different muscle tissues respond differently to treatment, probably based on their ratio of type I to type II fibers. It also signifies the importance of early use of bee products (e.g., propolis) for the prevention of AGEs formation in skeletal muscle in people with high risk for AGEs formation such as diabetics [38].\n\n4.8. Neuronal Regeneration\nNeuronal denervation is a key factor that contributes to skeletal muscle loss, and it is related to a plethora of pathological conditions [3,149]. Experimental induction of oxidative stress and inflammation results in skeletal muscle atrophy through induction of denervation e.g., of sciatic nerve [150]. Injuries of peripheral nerves (e.g., sciatic nerve) interrupt mechanical transmission and microvasculation of the nerve and induce reperfusion. Reperfusion involves pooling of oxygen and nutrients promoting high emission of free radicals, which attack protein and lipid contents surrounding the injury site resulting in excessive tissue loss [113]. Likewise, alterations in gut microbiome in aged rats are associated with alterations in serum level of vitamin B12 and fat metabolism as well as reductions in the gastrocnemius muscle mass and sciatic response amplitude [151]. Furthermore, dysregulation of insulin-mediated GLUT4 activity in certain areas of the central nervous system impairs neuronal metabolism and plasticity [69]. Meanwhile, activation of PGC-1α, a core regulator of mitochondrial content and oxidative metabolism, increases muscle fiber resistance to denervation and atrophy through downregulation of two ubiquitin-ligases involved in the ubiquitin-proteasome pathway: MuRF1 and Atrogin-1 [1,152].\nPropolis treatment for four weeks restored gastrocnemius muscle weight and improved functional performance (e.g., walking) in rats with crush injury of the sciatic nerve. Effects of propolis were associated with increased nerve healing and regeneration as depicted by faster healing of the myelin sheath and ultra-structurally normal unmyelinated axons and Schwann cells. Investigations of motor conduction from the sciatic nerve to the gastrocnemius muscle indicated that nerve recovery induced by propolis treatment promoted optimal physical functioning by allowing motor conduction to reach the gastrocnemius muscle [113]. Neuroprotective effects of propolis in motor neurons are documented in the literature. Both kaempferide and kaempferol protected motor neurons against atrophy induced by the toxic copper-zinc superoxide dismutase in amyotrophic lateral sclerosis—a serious neurodegenerative disease that involves selective and progressive loss of motor neurons [65]. In addition, orally administered chrysin (a flavonoid that is copious in propolis) to rats intoxicated by 6-hydroxidopamine showed neuroprotective effects by mitigating neuroinflammation, enhancing levels of neurotrophins and neuronal recovery factors (e.g., brain derived neurotrophic factor and glial cell line-derived neurotrophic factor), and maintaining integrity of dopaminergic neurons resulting in better motor performance [72].\nThe release of acetylcholine (a neurotransmitter that regulates cognition) at the synaptic cleft of the neuromuscular junction is essential for motor neurotransmission, which controls excitation-contraction coupling and cell size. However, free radicals, cytokines, and AGEs impair neurotransmission by altering the production of acetylcholine [6,21,149,153]. On the other hand, upregulation of acetylcholine receptors improves neurotransmission [154]. Treatment with royal jelly may correct acetylcholine neurotransmission given its high content of acetylcholine (4–8 mM) [60]. In addition, royal jelly, propolis, and bee pollen are rich in antioxidant elements that have a potential to scavenge ROS and mitigate other pathologies that contribute to acetylcholine deficiency (e.g., neuroinflammation) [73,101,102,103]. In this respect, treatment of experimental models of carrageenan-induced hind paw edema with hydroalcoholic extract of red propolis and its biomarker, formononetin, is reported to inhibit leukocyte migration and ameliorate inflammatory neurogenic pain induced by injections of formalin and glutamate [115]. However, investigations of the action of bee products on neurotransmission are very scarce.\n\n4.9. Improving Muscular Blood Supply\nAging is associated with higher onset of atherosclerosis and restenosis, which involve vascular and microvascular damages that result from hyperproliferation of vascular smooth muscle cells (VSMCs) [155]. Muscle unloading (e.g., in sedentary lifestyle) involves chronic neuromuscular inactivity, which results in reductions in capillary number, luminal diameter, and capillary volume as well as heightened production of anti-angiogenic factors, such as p53 and TSP-1 in skeletal muscle [110]. Microvascular alterations and impaired nitric oxide (NO) production are key causes of decreased blood flow to the skeletal muscle. Poor muscular blood supply induces muscle wasting via a mechanism that entails impaired glucose metabolism and suboptimal protein anabolism [156,157]. In addition, ischemic injury in skeletal muscle is associated with high ROS release from polymorphonuclear leukocytes, which infiltrate muscle tissues. Free radicals alter cellular structure and function by attacking lipid and protein biomolecules that exist in the structure of biological membranes, enzymes, and transport proteins [102]. Therefore, improving vascularization and blood supply to skeletal muscle is a possible mechanism for the prevention of muscle wasting.\nMitchell and colleagues examined changes in microvascular blood volume, microvascular flow velocity, and microvascular blood flow in the quadriceps muscle following treatment with 15 g of amino acids in young and old subjects (20–70 years old). They detected improvements in all the 3 parameters only in young groups, and those effects were associated with proper insulin activity. Thus, the authors suggested that refeeding effects on muscular blood supply may be hindered by dysfunctions in postprandial circulation and glucose dysregulation [157]. Bee products such as bee pollen and propolis have a potential to boost microcirculation and correct pathologies that contribute to vascular dysfunction such as hyperglycemia and dyslipidemia [36,155]. In this context, CAPE, one of the basic constituents of propolis, was reported to combat vascular damages by counteracting the proliferative activity of platelet-derived growth factor. The molecular mechanism involved inducing cell-cycle arrest in VSMCs via activation of p38mitogen-activated protein kinase (MAPK), which was associated with accumulation of hypoxia-inducible factor (HIF)-1α—mainly due to inhibition of HIF prolylhydroxylase, a key contributor to proteasomal degradation of HIF-1α—and subsequent induction of HO-1 [155]. In the same regard, supplementing rats undergoing capillary regression (resulting from two weeks of hind limb unloading) in the soleus muscle with two daily intragastric doses of propolis for two weeks restored capillary number, capillary structure, capillary volume, and capillary to muscle fiber ratio through a mechanism that involves inhibition of anti-angiogenic factors and activation of pro-angiogenic factors (e.g., VEGF). The relative muscle-to-body weight in treated animals was higher than in the unloaded control animals, and the number of TUNEL-positive apoptotic endothelial cells in the soleus muscle was similar to that in the normal control animals [110]. Likewise, bee pollen (both neat and processed) increased blood vessels in the gastrocnemius muscle of rats undergoing muscle injury because of vigorous exercise [90]. Treating C2C12 myoblasts with propolis ethanolic extract increased VEGF production [108]. VEGF is a pro-angiogenic factor that contributes to angiogenesis by recruiting endothelial cells and promoting their differentiation to form new vascular networks. VEGF protects skeletal muscle undergoing unloading against the progression of capillary regression [110]. Its expression in skeletal muscle and associated angiogenic response increase following exercise due to change in the activity of HIF-1α and AMPK. It promotes the generation of ATP following mitochondrial biogenesis in order to meet oxygen demand [158]. Altogether, these reports signify that bee products and endurance exercise share common mechanisms to produce their vitality effects in skeletal muscle.\n\n4.10. Improving the Composition of Gut Microbiome\nBee products such as royal jelly and propolis display potent antifungal, bactericidal, microbicidal, anti-inflammatory, antioxidant, and healing effects [2,66]. Most bee products investigated in this review were administered orally. Therefore, it is likely that their therapeutic effects may start locally within the GI tract, which frequently undergoes propagation of harmful endobacteria, inflammation, aberrations, and permeability in advanced age [10,24,152]. In this respect, Roquetto and colleagues [116] supplemented C57BL/6 mice on HFD with crude propolis (0.2%) for two and five weeks. HFD increased the proportion of the phylum Firmicutes as well as levels of circulating lipopolysaccharide (LPS) and inflammatory biomarkers. DNA sequencing for the 16S rRNA of the gut microbiota revealed that five weeks of propolis treatment rendered the microbiota profile almost normal. Compared with untreated mice, propolis-supplemented animals demonstrated lower levels of serum triacylglycerols, glucose, and circulating LPS, along with reduced expression of TLR4 and inflammatory cytokines in skeletal muscle [116].\nLactic acid bacteria profusely exist in bee saliva and all bee products [36,83,84]. Various species of lactic acid bacteria have been experimentally used to correct GI dysbiosis and related muscle wasting [159,160]. Moreover, oligosaccharides have been chemically isolated from bee products [32,161]. These api-materials are classified as prebiotics, fermented non-digestible compounds that promote the proliferative activity of health-promoting bacteria [24,161]. Supplementing frail old adults with fructooligosaccharides expressed positive effects on skeletal muscle strength (handgrip) and endurance (exhaustion) [162]. On the other side, microbiome of the gut can affect the biological activity of bee products. The literature shows that certain endobacteria transform dietary polyphenols into phenolic acids, which can easily access the circulation and then cross the blood brain barrier to produce therapeutic effects [163]. Hence, it is important that future investigations of bee products among sarcopenic subjects examine the effect of these products on the composition of GI microbial population and its association with muscle-related outcomes."}