4.3. Metabolic Regulation Skeletal 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]. AMPK, 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]. The 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]. Japanese 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]. Several 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]. Similar 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].