PMC:7601109 / 69420-83763 JSONTXT

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Discussion\nAge-related deteriorations in skeletal muscle are multifactorial in nature, which contributes to the high failure rates of drugs designed to target sarcopenia. Thus, there is a strong need for new therapeutic agents that express multidimensional effects in order to provide physically frail elders a chance to restore their health and QoL [21]. Given the scarcity of human trials using bee products among physically frail and sarcopenic subjects, cell culture and animal studies may provide useful information about the effect of bee products on skeletal muscle and help identifying their probable mechanism of action. Both in vivo and in vitro studies indicate that substances produced by honey bees such as royal jelly, bee pollen, and propolis can positively modulate basic cellular functions of myoblasts as well as mature myocytes. These products seem to be promising anti-sarcopenic agents because they can promote muscle protein synthesis [36,104], decrease mitochondrial oxidative stress [36,90,106], mitigate inflammation [38,90,101,108,115], improve muscular blood supply [102,110], enhance peripheral motor conduction [113], accelerate the removal of AGEs [38], counteract catabolism, and decrease markers of skeletal muscle atrophy [97,101,102,103].\nOne of the major pathologies underlying age-related skeletal muscle failure is insulin resistance, which alters glucose metabolism [3,4,21,118,130,164]. Numerous studies signify that bee products may protect against muscle wasting by correcting metabolic dysregulations in skeletal muscle via activation of some of the key nutrient sensing molecules [69,96,100,106,109,111]. In this respect, bee pollen permitted mTORC1 to mitigate anabolic resistance through the regulation of muscle protein and muscle growth in malnourished sarcopenic old rats [36]. Royal jelly and CAPE restored muscle mass and metabolism through activation of AKT, a substrate of mTOR [96,111]. Polyphenols in propolis [70], CAPE [111], and 10-HDA [106] activated AMPK resulting in enhanced skeletal muscle glucose uptake. In the meantime, royal jelly improved mitochondrial biogenesis in skeletal muscle via activation of AMPK [106]. AMPK and mTOR are master regulators of metabolism and autophagy [2,165]; they keep muscle integrity by stimulating protein synthesis [21,22]. Accordingly, all these findings denote that bee products represent a promising nutritional strategy that can tackle skeletal muscle wasting in old age by correcting its underling metabolic causes. However, the detailed physiological processes involved still need to be deeply unraveled in further investigations.\nThe activity of mTOR depends mainly on the bioavailability of essential amino acids in addition to many other molecules in the cellular microenvironment [136]. Evidence from preclinical and human studies confirms that ingestion of essential amino acids increases their cellular bioavailability, which is associated with upregulation of the activity of the nutrient sensing mTORC1 kinase following its translocation from the cytosol to the surface of lysosomes [135,136]. Research shows that ingestion of small amounts of essential amino acids (6.8 g) by healthy older adults could stimulate muscle protein synthesis by activating mTORC1 signaling even without involvement in resistance exercise training [137]. Other factors affect the capacity of essential amino acids to stimulate muscle protein synthesis. Amino acid bioavailability depends to a great extent on the bacterial strains of resident gut microbiome, which can either promote amino acid loss by degrading them or substantially contribute to their availability by producing some of them e.g., lysine [152]. Furthermore, amino acid supplements in old age do not enhance muscle protein metabolism, combat anabolic resistance, or improve muscle condition under sedentary conditions [25,166].\nAccording to Table 1, different models of skeletal muscle injury (e.g., natural aging [96], sarcopenic obesity [54], AGE-induced muscle wasting [38], malnutrition-related muscle loss [36], exhaustive exercise [90,109], etc.) were used to evaluate the effect of bee products on skeletal muscle. The effects of bee products on muscle mass varied considerably: some studies reported that bee products increased muscle mass [36,54,90,96,100,105,113] and improved physical performance [95,96,97,98,99] while others could not or did not depict any significant change in muscle mass [38,102,103,104,110,117]. However, the latter revealed major beneficial effects related to the biology of skeletal muscle aging such as improved muscle protein deposition [104], enhanced activity of mitochondrial enzymes [106], decreased muscle infiltration by inflammatory cells, decreased muscle proteolysis, lowered lipid peroxidation and protein carbonylation [102,103], increased microvascular blood supply, heightened production of antioxidants [110], and increased clearance of AGEs from skeletal muscle [38]. These findings suggest that bee products may prevent the development of sarcopenia if supplemented earlier before the occurrence of muscle atrophy. In this regard, supplementing young football players with royal jelly for two months resulted in a significant increase in muscle and bone mass compared with control players who did not receive royal jelly [167].\nAs for the effect of bee products on sarcopenia in humans, we could locate only one randomized control trial (RCT), which examined the effect of pRJ (1.2 g/d or 4.8 g/d over 1 year) on muscle strength among institutionalized aged population. This study revealed no significant effect of pRJ on the tested muscular functions: handgrip strength, six-minute walk test, timed up and go test, and standing on one leg with eyes closed [59]. Nonetheless, such outcome indexes may not be sufficient to evaluate the overall effect of royal jelly on muscular performance and quality. In addition, the literature documents gut microbiome alterations-related to muscle loss in institutionalized old adults compared with older adults living in the community, which might affect the efficacy of nutritional therapies in this particular group [164,168,169].\nThe relation between muscle mass or strength and physical function in old people is not as direct or clear as originally presumed. Existing knowledge indicates that muscle strength may be intact in people with muscle loss. Likewise, decreased muscle strength may not necessarily alter physical performance [21,170]. Research notes that selection of interventions that merely increase muscle mass and/or strength entails ignoring valuable therapies that contribute to various biological processes of muscle recovery by interfering with pathologies conducive to muscle loss. More, combining functional measures of muscle performance with different comprehensive biomarkers (e.g., of metabolism, inflammation, oxidative stress, etc.) in skeletal muscle and the whole body may identify therapies that can positively affect muscle qualities independent of mass increase [21]. In support of this argument, treating sarcopenic elderly with oral amino acids (which represent only one ingredient of royal jelly or bee pollen) significantly increased whole-body lean mass 6 and 18 months after treatment as indicated by dual-energy X-ray absorptiometry. This effect was attributed to enhancement of insulin sensitivity and anabolism as portrayed by significant reductions in fasting blood glucose, serum insulin, HOMA-IR, and serum tumor necrosis factor-α (TNF-α) as well as increase of serum level of IGF-1 and IGF-1/TNF-α ratio [171]. Animal studies lend further support to those reports. For instance, royal jelly had no effect on muscle differentiation genes (myogenic differentiation 1 (MyoD), myogenein, myostatin) in sarcopenic mice, indicating that royal jelly may not improve age-related deterioration of muscle strength—once it occurs. On the other hand, royal jelly significantly reduced the progression of muscle atrophy by decreasing the expression of catabolism genes E3 ubiquitin ligases MuRF1 and atrogin-1 in old mice to levels similar to those in young mice [97]. Royal jelly also stimulated the differentiation of satellite stem cells both in vivo and in vitro and improved the regenerative capacity of injured muscle [96,97]. Therefore, royal jelly treatment might reduce the progression of age-related muscular atrophy [59]. Future RCTs that evaluate the effect of bee products on muscle qualities and motor performance in humans should be properly designed to include biological markers of motor functioning along with behavioral measures.\nMultifactorial conditions such as sarcopenia should be addressed by multimodal interventions. Nutrition and physical exercise are key strategies that can preserve muscle mass and function in older adults both in clinical and community settings [21]. Thus, it might be helpful to compare the effect of combining bee products with other conventional treatments such as other dietary elements and exercise given that factors such as physical activity and diet can interfere with or promote the effect of bee products on muscle qualities and disorders that underlie muscle weakness [105,106]. Fat mass increases with age, especially after age-related hormonal decline (e.g., after menopause), and it activates inflammatory processes that disturb body physiology [172]. In this regard, supplementing obese rats with milk naturally enriched with PUFA and polyphenols from propolis increased gastrocnemius muscle mass and tended to increase the mass of the soleus muscle. It decreased the diameter of adipocytes and tended to decrease serum levels of low-density lipoprotein. These findings suggest a role of propolis-enriched milk in the mitigation of sarcopenic obesity, albeit it had no effect on body weight [105]. On the other side, many studies show that exercise has significantly improved muscle mass and strength in sarcopenic seniors [4,42,132,173]. Propolis treatment of undifferentiated L6 myoblast selectively stimulated IL-6 production and inhibited pathological cytokines such as interleukin (IL)-1β and TNF-α [108]. This interesting in vitro investigation indicates that propolis can mimic the mechanism through which exercise induces skeletal muscle remodeling [23,114]. Evidence from preclinical studies shows that concurrent treatment of rats on endurance training with royal jelly enhanced mitochondrial adaptation in muscles that combine both type I and type II fibers such as the soleus muscle whereas neither royal jelly alone nor exercise alone could influence the activity of mitochondrial enzymes in that muscle [106]. Moreover, bee pollen and propolis treatment of rats on exhaustive exercise increased the production of antioxidant enzymes, blocked the production of free radicals, promoted glycogen use in the skeletal muscle and liver, and restored muscle fiber structure [90,109].\nIn most studies, whole royal jelly, bee pollen, and propolis were used. However, these products appeared in different forms e.g., neat vs processed bee pollen [90], water [109] vs ethanolic extracts [110] of propolis, lyophilized [98,99] and crude [97] vs enzyme-treated [59,95,96,97] royal jelly. Both processed bee pollen [36] and pRJ [97,106] had better effects compared with crude bee pollen and royal jelly. In addition, a large group of constituents of royal jelly and propolis were used such as 10-HDA [54,106], CAPE [69,101,102,103], artepillin C, coumaric acid, kaempferide [70], boropinic acid, 4-geranyloxyferulic acid, 7-isopentenyloxycoumarin, and auraptene [69]. 10-HDA was the only element in royal jelly that was tested in skeletal muscle. It enhanced glucose uptake via AMPK phosphorylation [106]. It also restored body weight, restored skeletal muscle mass (only in males), and reduced fat mass (only in females) in aged rats undergoing chronic stress [54]. CAPE is one of the most investigated compounds in propolis: it enhanced skeletal muscle glucose uptake [111], inhibited cytokine and ROS production, prevented protein carbonylation, lipid peroxidation, and muscle proteolysis [101,102,103]. The effects of whole ethanolic extracts of propolis and CAPE on glucose uptake in skeletal muscle were comparable to those of insulin [69,109,111]. More, investigations of the effect of flavonoids and oxyprenylated phenylpropanoids abundant in ethanolic extracts of propolis on glucose uptake in skeletal muscle revealed superior effects of kaempferide [70], 4-geranyloxyferulic acid, and auraptene. Among 5 oxyprenylated phenylpropanoids derived from propolis, auraptene most potently activated GLUT4 translocation and accelerated glucose influx into skeletal muscle cells. Measurement of the incorporated amounts of these compounds into myotubes indicated that auraptene had the highest bioavailability among other effective compounds [69].\nMatters concerning dosage and duration of treatment remain issues of concern should these compounds be used to prevent and treat sarcopenia. In addition, the effect of other active ingredients of bee products on skeletal muscle pathologies is worth investigation. For instance, MRJPs are reported to contribute to most therapeutic properties of royal jelly due to their rich amino acid content (up to 578 amino acids) [47]. In the meantime, the literature documents a potent regulatory effect of amino acids on skeletal muscle protein turnover [6,131,132]. Nonetheless, the effect of MRJPs on skeletal muscle were not studied until now.\nDespite the details illustrated in this review, many questions remain unanswered. The most important question among all is which bee product or bee component can produce the best benefits against skeletal muscle senescence and under which circumstances? Sarcopenia is the result of several interrelated factors such as neuromuscular dysfunction, oxidative stress, metabolic alterations, poor blood supply, hormonal deficiencies (e.g., sex hormones), chronic inflammation, and lifestyle choices (e.g., physical inactivity and unhealthy diet) [21]. The effect of bee products on some of these factors are underaddressed (e.g., neuromuscular dysfunction, muscle blood supply, and gut microbiome) while some other have not been explored yet (e.g., sex steroids and their association with muscular function)."}

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Discussion\nAge-related deteriorations in skeletal muscle are multifactorial in nature, which contributes to the high failure rates of drugs designed to target sarcopenia. Thus, there is a strong need for new therapeutic agents that express multidimensional effects in order to provide physically frail elders a chance to restore their health and QoL [21]. Given the scarcity of human trials using bee products among physically frail and sarcopenic subjects, cell culture and animal studies may provide useful information about the effect of bee products on skeletal muscle and help identifying their probable mechanism of action. Both in vivo and in vitro studies indicate that substances produced by honey bees such as royal jelly, bee pollen, and propolis can positively modulate basic cellular functions of myoblasts as well as mature myocytes. These products seem to be promising anti-sarcopenic agents because they can promote muscle protein synthesis [36,104], decrease mitochondrial oxidative stress [36,90,106], mitigate inflammation [38,90,101,108,115], improve muscular blood supply [102,110], enhance peripheral motor conduction [113], accelerate the removal of AGEs [38], counteract catabolism, and decrease markers of skeletal muscle atrophy [97,101,102,103].\nOne of the major pathologies underlying age-related skeletal muscle failure is insulin resistance, which alters glucose metabolism [3,4,21,118,130,164]. Numerous studies signify that bee products may protect against muscle wasting by correcting metabolic dysregulations in skeletal muscle via activation of some of the key nutrient sensing molecules [69,96,100,106,109,111]. In this respect, bee pollen permitted mTORC1 to mitigate anabolic resistance through the regulation of muscle protein and muscle growth in malnourished sarcopenic old rats [36]. Royal jelly and CAPE restored muscle mass and metabolism through activation of AKT, a substrate of mTOR [96,111]. Polyphenols in propolis [70], CAPE [111], and 10-HDA [106] activated AMPK resulting in enhanced skeletal muscle glucose uptake. In the meantime, royal jelly improved mitochondrial biogenesis in skeletal muscle via activation of AMPK [106]. AMPK and mTOR are master regulators of metabolism and autophagy [2,165]; they keep muscle integrity by stimulating protein synthesis [21,22]. Accordingly, all these findings denote that bee products represent a promising nutritional strategy that can tackle skeletal muscle wasting in old age by correcting its underling metabolic causes. However, the detailed physiological processes involved still need to be deeply unraveled in further investigations.\nThe activity of mTOR depends mainly on the bioavailability of essential amino acids in addition to many other molecules in the cellular microenvironment [136]. Evidence from preclinical and human studies confirms that ingestion of essential amino acids increases their cellular bioavailability, which is associated with upregulation of the activity of the nutrient sensing mTORC1 kinase following its translocation from the cytosol to the surface of lysosomes [135,136]. Research shows that ingestion of small amounts of essential amino acids (6.8 g) by healthy older adults could stimulate muscle protein synthesis by activating mTORC1 signaling even without involvement in resistance exercise training [137]. Other factors affect the capacity of essential amino acids to stimulate muscle protein synthesis. Amino acid bioavailability depends to a great extent on the bacterial strains of resident gut microbiome, which can either promote amino acid loss by degrading them or substantially contribute to their availability by producing some of them e.g., lysine [152]. Furthermore, amino acid supplements in old age do not enhance muscle protein metabolism, combat anabolic resistance, or improve muscle condition under sedentary conditions [25,166].\nAccording to Table 1, different models of skeletal muscle injury (e.g., natural aging [96], sarcopenic obesity [54], AGE-induced muscle wasting [38], malnutrition-related muscle loss [36], exhaustive exercise [90,109], etc.) were used to evaluate the effect of bee products on skeletal muscle. The effects of bee products on muscle mass varied considerably: some studies reported that bee products increased muscle mass [36,54,90,96,100,105,113] and improved physical performance [95,96,97,98,99] while others could not or did not depict any significant change in muscle mass [38,102,103,104,110,117]. However, the latter revealed major beneficial effects related to the biology of skeletal muscle aging such as improved muscle protein deposition [104], enhanced activity of mitochondrial enzymes [106], decreased muscle infiltration by inflammatory cells, decreased muscle proteolysis, lowered lipid peroxidation and protein carbonylation [102,103], increased microvascular blood supply, heightened production of antioxidants [110], and increased clearance of AGEs from skeletal muscle [38]. These findings suggest that bee products may prevent the development of sarcopenia if supplemented earlier before the occurrence of muscle atrophy. In this regard, supplementing young football players with royal jelly for two months resulted in a significant increase in muscle and bone mass compared with control players who did not receive royal jelly [167].\nAs for the effect of bee products on sarcopenia in humans, we could locate only one randomized control trial (RCT), which examined the effect of pRJ (1.2 g/d or 4.8 g/d over 1 year) on muscle strength among institutionalized aged population. This study revealed no significant effect of pRJ on the tested muscular functions: handgrip strength, six-minute walk test, timed up and go test, and standing on one leg with eyes closed [59]. Nonetheless, such outcome indexes may not be sufficient to evaluate the overall effect of royal jelly on muscular performance and quality. In addition, the literature documents gut microbiome alterations-related to muscle loss in institutionalized old adults compared with older adults living in the community, which might affect the efficacy of nutritional therapies in this particular group [164,168,169].\nThe relation between muscle mass or strength and physical function in old people is not as direct or clear as originally presumed. Existing knowledge indicates that muscle strength may be intact in people with muscle loss. Likewise, decreased muscle strength may not necessarily alter physical performance [21,170]. Research notes that selection of interventions that merely increase muscle mass and/or strength entails ignoring valuable therapies that contribute to various biological processes of muscle recovery by interfering with pathologies conducive to muscle loss. More, combining functional measures of muscle performance with different comprehensive biomarkers (e.g., of metabolism, inflammation, oxidative stress, etc.) in skeletal muscle and the whole body may identify therapies that can positively affect muscle qualities independent of mass increase [21]. In support of this argument, treating sarcopenic elderly with oral amino acids (which represent only one ingredient of royal jelly or bee pollen) significantly increased whole-body lean mass 6 and 18 months after treatment as indicated by dual-energy X-ray absorptiometry. This effect was attributed to enhancement of insulin sensitivity and anabolism as portrayed by significant reductions in fasting blood glucose, serum insulin, HOMA-IR, and serum tumor necrosis factor-α (TNF-α) as well as increase of serum level of IGF-1 and IGF-1/TNF-α ratio [171]. Animal studies lend further support to those reports. For instance, royal jelly had no effect on muscle differentiation genes (myogenic differentiation 1 (MyoD), myogenein, myostatin) in sarcopenic mice, indicating that royal jelly may not improve age-related deterioration of muscle strength—once it occurs. On the other hand, royal jelly significantly reduced the progression of muscle atrophy by decreasing the expression of catabolism genes E3 ubiquitin ligases MuRF1 and atrogin-1 in old mice to levels similar to those in young mice [97]. Royal jelly also stimulated the differentiation of satellite stem cells both in vivo and in vitro and improved the regenerative capacity of injured muscle [96,97]. Therefore, royal jelly treatment might reduce the progression of age-related muscular atrophy [59]. Future RCTs that evaluate the effect of bee products on muscle qualities and motor performance in humans should be properly designed to include biological markers of motor functioning along with behavioral measures.\nMultifactorial conditions such as sarcopenia should be addressed by multimodal interventions. Nutrition and physical exercise are key strategies that can preserve muscle mass and function in older adults both in clinical and community settings [21]. Thus, it might be helpful to compare the effect of combining bee products with other conventional treatments such as other dietary elements and exercise given that factors such as physical activity and diet can interfere with or promote the effect of bee products on muscle qualities and disorders that underlie muscle weakness [105,106]. Fat mass increases with age, especially after age-related hormonal decline (e.g., after menopause), and it activates inflammatory processes that disturb body physiology [172]. In this regard, supplementing obese rats with milk naturally enriched with PUFA and polyphenols from propolis increased gastrocnemius muscle mass and tended to increase the mass of the soleus muscle. It decreased the diameter of adipocytes and tended to decrease serum levels of low-density lipoprotein. These findings suggest a role of propolis-enriched milk in the mitigation of sarcopenic obesity, albeit it had no effect on body weight [105]. On the other side, many studies show that exercise has significantly improved muscle mass and strength in sarcopenic seniors [4,42,132,173]. Propolis treatment of undifferentiated L6 myoblast selectively stimulated IL-6 production and inhibited pathological cytokines such as interleukin (IL)-1β and TNF-α [108]. This interesting in vitro investigation indicates that propolis can mimic the mechanism through which exercise induces skeletal muscle remodeling [23,114]. Evidence from preclinical studies shows that concurrent treatment of rats on endurance training with royal jelly enhanced mitochondrial adaptation in muscles that combine both type I and type II fibers such as the soleus muscle whereas neither royal jelly alone nor exercise alone could influence the activity of mitochondrial enzymes in that muscle [106]. Moreover, bee pollen and propolis treatment of rats on exhaustive exercise increased the production of antioxidant enzymes, blocked the production of free radicals, promoted glycogen use in the skeletal muscle and liver, and restored muscle fiber structure [90,109].\nIn most studies, whole royal jelly, bee pollen, and propolis were used. However, these products appeared in different forms e.g., neat vs processed bee pollen [90], water [109] vs ethanolic extracts [110] of propolis, lyophilized [98,99] and crude [97] vs enzyme-treated [59,95,96,97] royal jelly. Both processed bee pollen [36] and pRJ [97,106] had better effects compared with crude bee pollen and royal jelly. In addition, a large group of constituents of royal jelly and propolis were used such as 10-HDA [54,106], CAPE [69,101,102,103], artepillin C, coumaric acid, kaempferide [70], boropinic acid, 4-geranyloxyferulic acid, 7-isopentenyloxycoumarin, and auraptene [69]. 10-HDA was the only element in royal jelly that was tested in skeletal muscle. It enhanced glucose uptake via AMPK phosphorylation [106]. It also restored body weight, restored skeletal muscle mass (only in males), and reduced fat mass (only in females) in aged rats undergoing chronic stress [54]. CAPE is one of the most investigated compounds in propolis: it enhanced skeletal muscle glucose uptake [111], inhibited cytokine and ROS production, prevented protein carbonylation, lipid peroxidation, and muscle proteolysis [101,102,103]. The effects of whole ethanolic extracts of propolis and CAPE on glucose uptake in skeletal muscle were comparable to those of insulin [69,109,111]. More, investigations of the effect of flavonoids and oxyprenylated phenylpropanoids abundant in ethanolic extracts of propolis on glucose uptake in skeletal muscle revealed superior effects of kaempferide [70], 4-geranyloxyferulic acid, and auraptene. Among 5 oxyprenylated phenylpropanoids derived from propolis, auraptene most potently activated GLUT4 translocation and accelerated glucose influx into skeletal muscle cells. Measurement of the incorporated amounts of these compounds into myotubes indicated that auraptene had the highest bioavailability among other effective compounds [69].\nMatters concerning dosage and duration of treatment remain issues of concern should these compounds be used to prevent and treat sarcopenia. In addition, the effect of other active ingredients of bee products on skeletal muscle pathologies is worth investigation. For instance, MRJPs are reported to contribute to most therapeutic properties of royal jelly due to their rich amino acid content (up to 578 amino acids) [47]. In the meantime, the literature documents a potent regulatory effect of amino acids on skeletal muscle protein turnover [6,131,132]. Nonetheless, the effect of MRJPs on skeletal muscle were not studied until now.\nDespite the details illustrated in this review, many questions remain unanswered. The most important question among all is which bee product or bee component can produce the best benefits against skeletal muscle senescence and under which circumstances? Sarcopenia is the result of several interrelated factors such as neuromuscular dysfunction, oxidative stress, metabolic alterations, poor blood supply, hormonal deficiencies (e.g., sex hormones), chronic inflammation, and lifestyle choices (e.g., physical inactivity and unhealthy diet) [21]. The effect of bee products on some of these factors are underaddressed (e.g., neuromuscular dysfunction, muscle blood supply, and gut microbiome) while some other have not been explored yet (e.g., sex steroids and their association with muscular function)."}

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Discussion\nAge-related deteriorations in skeletal muscle are multifactorial in nature, which contributes to the high failure rates of drugs designed to target sarcopenia. Thus, there is a strong need for new therapeutic agents that express multidimensional effects in order to provide physically frail elders a chance to restore their health and QoL [21]. Given the scarcity of human trials using bee products among physically frail and sarcopenic subjects, cell culture and animal studies may provide useful information about the effect of bee products on skeletal muscle and help identifying their probable mechanism of action. Both in vivo and in vitro studies indicate that substances produced by honey bees such as royal jelly, bee pollen, and propolis can positively modulate basic cellular functions of myoblasts as well as mature myocytes. These products seem to be promising anti-sarcopenic agents because they can promote muscle protein synthesis [36,104], decrease mitochondrial oxidative stress [36,90,106], mitigate inflammation [38,90,101,108,115], improve muscular blood supply [102,110], enhance peripheral motor conduction [113], accelerate the removal of AGEs [38], counteract catabolism, and decrease markers of skeletal muscle atrophy [97,101,102,103].\nOne of the major pathologies underlying age-related skeletal muscle failure is insulin resistance, which alters glucose metabolism [3,4,21,118,130,164]. Numerous studies signify that bee products may protect against muscle wasting by correcting metabolic dysregulations in skeletal muscle via activation of some of the key nutrient sensing molecules [69,96,100,106,109,111]. In this respect, bee pollen permitted mTORC1 to mitigate anabolic resistance through the regulation of muscle protein and muscle growth in malnourished sarcopenic old rats [36]. Royal jelly and CAPE restored muscle mass and metabolism through activation of AKT, a substrate of mTOR [96,111]. Polyphenols in propolis [70], CAPE [111], and 10-HDA [106] activated AMPK resulting in enhanced skeletal muscle glucose uptake. In the meantime, royal jelly improved mitochondrial biogenesis in skeletal muscle via activation of AMPK [106]. AMPK and mTOR are master regulators of metabolism and autophagy [2,165]; they keep muscle integrity by stimulating protein synthesis [21,22]. Accordingly, all these findings denote that bee products represent a promising nutritional strategy that can tackle skeletal muscle wasting in old age by correcting its underling metabolic causes. However, the detailed physiological processes involved still need to be deeply unraveled in further investigations.\nThe activity of mTOR depends mainly on the bioavailability of essential amino acids in addition to many other molecules in the cellular microenvironment [136]. Evidence from preclinical and human studies confirms that ingestion of essential amino acids increases their cellular bioavailability, which is associated with upregulation of the activity of the nutrient sensing mTORC1 kinase following its translocation from the cytosol to the surface of lysosomes [135,136]. Research shows that ingestion of small amounts of essential amino acids (6.8 g) by healthy older adults could stimulate muscle protein synthesis by activating mTORC1 signaling even without involvement in resistance exercise training [137]. Other factors affect the capacity of essential amino acids to stimulate muscle protein synthesis. Amino acid bioavailability depends to a great extent on the bacterial strains of resident gut microbiome, which can either promote amino acid loss by degrading them or substantially contribute to their availability by producing some of them e.g., lysine [152]. Furthermore, amino acid supplements in old age do not enhance muscle protein metabolism, combat anabolic resistance, or improve muscle condition under sedentary conditions [25,166].\nAccording to Table 1, different models of skeletal muscle injury (e.g., natural aging [96], sarcopenic obesity [54], AGE-induced muscle wasting [38], malnutrition-related muscle loss [36], exhaustive exercise [90,109], etc.) were used to evaluate the effect of bee products on skeletal muscle. The effects of bee products on muscle mass varied considerably: some studies reported that bee products increased muscle mass [36,54,90,96,100,105,113] and improved physical performance [95,96,97,98,99] while others could not or did not depict any significant change in muscle mass [38,102,103,104,110,117]. However, the latter revealed major beneficial effects related to the biology of skeletal muscle aging such as improved muscle protein deposition [104], enhanced activity of mitochondrial enzymes [106], decreased muscle infiltration by inflammatory cells, decreased muscle proteolysis, lowered lipid peroxidation and protein carbonylation [102,103], increased microvascular blood supply, heightened production of antioxidants [110], and increased clearance of AGEs from skeletal muscle [38]. These findings suggest that bee products may prevent the development of sarcopenia if supplemented earlier before the occurrence of muscle atrophy. In this regard, supplementing young football players with royal jelly for two months resulted in a significant increase in muscle and bone mass compared with control players who did not receive royal jelly [167].\nAs for the effect of bee products on sarcopenia in humans, we could locate only one randomized control trial (RCT), which examined the effect of pRJ (1.2 g/d or 4.8 g/d over 1 year) on muscle strength among institutionalized aged population. This study revealed no significant effect of pRJ on the tested muscular functions: handgrip strength, six-minute walk test, timed up and go test, and standing on one leg with eyes closed [59]. Nonetheless, such outcome indexes may not be sufficient to evaluate the overall effect of royal jelly on muscular performance and quality. In addition, the literature documents gut microbiome alterations-related to muscle loss in institutionalized old adults compared with older adults living in the community, which might affect the efficacy of nutritional therapies in this particular group [164,168,169].\nThe relation between muscle mass or strength and physical function in old people is not as direct or clear as originally presumed. Existing knowledge indicates that muscle strength may be intact in people with muscle loss. Likewise, decreased muscle strength may not necessarily alter physical performance [21,170]. Research notes that selection of interventions that merely increase muscle mass and/or strength entails ignoring valuable therapies that contribute to various biological processes of muscle recovery by interfering with pathologies conducive to muscle loss. More, combining functional measures of muscle performance with different comprehensive biomarkers (e.g., of metabolism, inflammation, oxidative stress, etc.) in skeletal muscle and the whole body may identify therapies that can positively affect muscle qualities independent of mass increase [21]. In support of this argument, treating sarcopenic elderly with oral amino acids (which represent only one ingredient of royal jelly or bee pollen) significantly increased whole-body lean mass 6 and 18 months after treatment as indicated by dual-energy X-ray absorptiometry. This effect was attributed to enhancement of insulin sensitivity and anabolism as portrayed by significant reductions in fasting blood glucose, serum insulin, HOMA-IR, and serum tumor necrosis factor-α (TNF-α) as well as increase of serum level of IGF-1 and IGF-1/TNF-α ratio [171]. Animal studies lend further support to those reports. For instance, royal jelly had no effect on muscle differentiation genes (myogenic differentiation 1 (MyoD), myogenein, myostatin) in sarcopenic mice, indicating that royal jelly may not improve age-related deterioration of muscle strength—once it occurs. On the other hand, royal jelly significantly reduced the progression of muscle atrophy by decreasing the expression of catabolism genes E3 ubiquitin ligases MuRF1 and atrogin-1 in old mice to levels similar to those in young mice [97]. Royal jelly also stimulated the differentiation of satellite stem cells both in vivo and in vitro and improved the regenerative capacity of injured muscle [96,97]. Therefore, royal jelly treatment might reduce the progression of age-related muscular atrophy [59]. Future RCTs that evaluate the effect of bee products on muscle qualities and motor performance in humans should be properly designed to include biological markers of motor functioning along with behavioral measures.\nMultifactorial conditions such as sarcopenia should be addressed by multimodal interventions. Nutrition and physical exercise are key strategies that can preserve muscle mass and function in older adults both in clinical and community settings [21]. Thus, it might be helpful to compare the effect of combining bee products with other conventional treatments such as other dietary elements and exercise given that factors such as physical activity and diet can interfere with or promote the effect of bee products on muscle qualities and disorders that underlie muscle weakness [105,106]. Fat mass increases with age, especially after age-related hormonal decline (e.g., after menopause), and it activates inflammatory processes that disturb body physiology [172]. In this regard, supplementing obese rats with milk naturally enriched with PUFA and polyphenols from propolis increased gastrocnemius muscle mass and tended to increase the mass of the soleus muscle. It decreased the diameter of adipocytes and tended to decrease serum levels of low-density lipoprotein. These findings suggest a role of propolis-enriched milk in the mitigation of sarcopenic obesity, albeit it had no effect on body weight [105]. On the other side, many studies show that exercise has significantly improved muscle mass and strength in sarcopenic seniors [4,42,132,173]. Propolis treatment of undifferentiated L6 myoblast selectively stimulated IL-6 production and inhibited pathological cytokines such as interleukin (IL)-1β and TNF-α [108]. This interesting in vitro investigation indicates that propolis can mimic the mechanism through which exercise induces skeletal muscle remodeling [23,114]. Evidence from preclinical studies shows that concurrent treatment of rats on endurance training with royal jelly enhanced mitochondrial adaptation in muscles that combine both type I and type II fibers such as the soleus muscle whereas neither royal jelly alone nor exercise alone could influence the activity of mitochondrial enzymes in that muscle [106]. Moreover, bee pollen and propolis treatment of rats on exhaustive exercise increased the production of antioxidant enzymes, blocked the production of free radicals, promoted glycogen use in the skeletal muscle and liver, and restored muscle fiber structure [90,109].\nIn most studies, whole royal jelly, bee pollen, and propolis were used. However, these products appeared in different forms e.g., neat vs processed bee pollen [90], water [109] vs ethanolic extracts [110] of propolis, lyophilized [98,99] and crude [97] vs enzyme-treated [59,95,96,97] royal jelly. Both processed bee pollen [36] and pRJ [97,106] had better effects compared with crude bee pollen and royal jelly. In addition, a large group of constituents of royal jelly and propolis were used such as 10-HDA [54,106], CAPE [69,101,102,103], artepillin C, coumaric acid, kaempferide [70], boropinic acid, 4-geranyloxyferulic acid, 7-isopentenyloxycoumarin, and auraptene [69]. 10-HDA was the only element in royal jelly that was tested in skeletal muscle. It enhanced glucose uptake via AMPK phosphorylation [106]. It also restored body weight, restored skeletal muscle mass (only in males), and reduced fat mass (only in females) in aged rats undergoing chronic stress [54]. CAPE is one of the most investigated compounds in propolis: it enhanced skeletal muscle glucose uptake [111], inhibited cytokine and ROS production, prevented protein carbonylation, lipid peroxidation, and muscle proteolysis [101,102,103]. The effects of whole ethanolic extracts of propolis and CAPE on glucose uptake in skeletal muscle were comparable to those of insulin [69,109,111]. More, investigations of the effect of flavonoids and oxyprenylated phenylpropanoids abundant in ethanolic extracts of propolis on glucose uptake in skeletal muscle revealed superior effects of kaempferide [70], 4-geranyloxyferulic acid, and auraptene. Among 5 oxyprenylated phenylpropanoids derived from propolis, auraptene most potently activated GLUT4 translocation and accelerated glucose influx into skeletal muscle cells. Measurement of the incorporated amounts of these compounds into myotubes indicated that auraptene had the highest bioavailability among other effective compounds [69].\nMatters concerning dosage and duration of treatment remain issues of concern should these compounds be used to prevent and treat sarcopenia. In addition, the effect of other active ingredients of bee products on skeletal muscle pathologies is worth investigation. For instance, MRJPs are reported to contribute to most therapeutic properties of royal jelly due to their rich amino acid content (up to 578 amino acids) [47]. In the meantime, the literature documents a potent regulatory effect of amino acids on skeletal muscle protein turnover [6,131,132]. Nonetheless, the effect of MRJPs on skeletal muscle were not studied until now.\nDespite the details illustrated in this review, many questions remain unanswered. The most important question among all is which bee product or bee component can produce the best benefits against skeletal muscle senescence and under which circumstances? Sarcopenia is the result of several interrelated factors such as neuromuscular dysfunction, oxidative stress, metabolic alterations, poor blood supply, hormonal deficiencies (e.g., sex hormones), chronic inflammation, and lifestyle choices (e.g., physical inactivity and unhealthy diet) [21]. The effect of bee products on some of these factors are underaddressed (e.g., neuromuscular dysfunction, muscle blood supply, and gut microbiome) while some other have not been explored yet (e.g., sex steroids and their association with muscular function)."}

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Discussion\nAge-related deteriorations in skeletal muscle are multifactorial in nature, which contributes to the high failure rates of drugs designed to target sarcopenia. Thus, there is a strong need for new therapeutic agents that express multidimensional effects in order to provide physically frail elders a chance to restore their health and QoL [21]. Given the scarcity of human trials using bee products among physically frail and sarcopenic subjects, cell culture and animal studies may provide useful information about the effect of bee products on skeletal muscle and help identifying their probable mechanism of action. Both in vivo and in vitro studies indicate that substances produced by honey bees such as royal jelly, bee pollen, and propolis can positively modulate basic cellular functions of myoblasts as well as mature myocytes. These products seem to be promising anti-sarcopenic agents because they can promote muscle protein synthesis [36,104], decrease mitochondrial oxidative stress [36,90,106], mitigate inflammation [38,90,101,108,115], improve muscular blood supply [102,110], enhance peripheral motor conduction [113], accelerate the removal of AGEs [38], counteract catabolism, and decrease markers of skeletal muscle atrophy [97,101,102,103].\nOne of the major pathologies underlying age-related skeletal muscle failure is insulin resistance, which alters glucose metabolism [3,4,21,118,130,164]. Numerous studies signify that bee products may protect against muscle wasting by correcting metabolic dysregulations in skeletal muscle via activation of some of the key nutrient sensing molecules [69,96,100,106,109,111]. In this respect, bee pollen permitted mTORC1 to mitigate anabolic resistance through the regulation of muscle protein and muscle growth in malnourished sarcopenic old rats [36]. Royal jelly and CAPE restored muscle mass and metabolism through activation of AKT, a substrate of mTOR [96,111]. Polyphenols in propolis [70], CAPE [111], and 10-HDA [106] activated AMPK resulting in enhanced skeletal muscle glucose uptake. In the meantime, royal jelly improved mitochondrial biogenesis in skeletal muscle via activation of AMPK [106]. AMPK and mTOR are master regulators of metabolism and autophagy [2,165]; they keep muscle integrity by stimulating protein synthesis [21,22]. Accordingly, all these findings denote that bee products represent a promising nutritional strategy that can tackle skeletal muscle wasting in old age by correcting its underling metabolic causes. However, the detailed physiological processes involved still need to be deeply unraveled in further investigations.\nThe activity of mTOR depends mainly on the bioavailability of essential amino acids in addition to many other molecules in the cellular microenvironment [136]. Evidence from preclinical and human studies confirms that ingestion of essential amino acids increases their cellular bioavailability, which is associated with upregulation of the activity of the nutrient sensing mTORC1 kinase following its translocation from the cytosol to the surface of lysosomes [135,136]. Research shows that ingestion of small amounts of essential amino acids (6.8 g) by healthy older adults could stimulate muscle protein synthesis by activating mTORC1 signaling even without involvement in resistance exercise training [137]. Other factors affect the capacity of essential amino acids to stimulate muscle protein synthesis. Amino acid bioavailability depends to a great extent on the bacterial strains of resident gut microbiome, which can either promote amino acid loss by degrading them or substantially contribute to their availability by producing some of them e.g., lysine [152]. Furthermore, amino acid supplements in old age do not enhance muscle protein metabolism, combat anabolic resistance, or improve muscle condition under sedentary conditions [25,166].\nAccording to Table 1, different models of skeletal muscle injury (e.g., natural aging [96], sarcopenic obesity [54], AGE-induced muscle wasting [38], malnutrition-related muscle loss [36], exhaustive exercise [90,109], etc.) were used to evaluate the effect of bee products on skeletal muscle. The effects of bee products on muscle mass varied considerably: some studies reported that bee products increased muscle mass [36,54,90,96,100,105,113] and improved physical performance [95,96,97,98,99] while others could not or did not depict any significant change in muscle mass [38,102,103,104,110,117]. However, the latter revealed major beneficial effects related to the biology of skeletal muscle aging such as improved muscle protein deposition [104], enhanced activity of mitochondrial enzymes [106], decreased muscle infiltration by inflammatory cells, decreased muscle proteolysis, lowered lipid peroxidation and protein carbonylation [102,103], increased microvascular blood supply, heightened production of antioxidants [110], and increased clearance of AGEs from skeletal muscle [38]. These findings suggest that bee products may prevent the development of sarcopenia if supplemented earlier before the occurrence of muscle atrophy. In this regard, supplementing young football players with royal jelly for two months resulted in a significant increase in muscle and bone mass compared with control players who did not receive royal jelly [167].\nAs for the effect of bee products on sarcopenia in humans, we could locate only one randomized control trial (RCT), which examined the effect of pRJ (1.2 g/d or 4.8 g/d over 1 year) on muscle strength among institutionalized aged population. This study revealed no significant effect of pRJ on the tested muscular functions: handgrip strength, six-minute walk test, timed up and go test, and standing on one leg with eyes closed [59]. Nonetheless, such outcome indexes may not be sufficient to evaluate the overall effect of royal jelly on muscular performance and quality. In addition, the literature documents gut microbiome alterations-related to muscle loss in institutionalized old adults compared with older adults living in the community, which might affect the efficacy of nutritional therapies in this particular group [164,168,169].\nThe relation between muscle mass or strength and physical function in old people is not as direct or clear as originally presumed. Existing knowledge indicates that muscle strength may be intact in people with muscle loss. Likewise, decreased muscle strength may not necessarily alter physical performance [21,170]. Research notes that selection of interventions that merely increase muscle mass and/or strength entails ignoring valuable therapies that contribute to various biological processes of muscle recovery by interfering with pathologies conducive to muscle loss. More, combining functional measures of muscle performance with different comprehensive biomarkers (e.g., of metabolism, inflammation, oxidative stress, etc.) in skeletal muscle and the whole body may identify therapies that can positively affect muscle qualities independent of mass increase [21]. In support of this argument, treating sarcopenic elderly with oral amino acids (which represent only one ingredient of royal jelly or bee pollen) significantly increased whole-body lean mass 6 and 18 months after treatment as indicated by dual-energy X-ray absorptiometry. This effect was attributed to enhancement of insulin sensitivity and anabolism as portrayed by significant reductions in fasting blood glucose, serum insulin, HOMA-IR, and serum tumor necrosis factor-α (TNF-α) as well as increase of serum level of IGF-1 and IGF-1/TNF-α ratio [171]. Animal studies lend further support to those reports. For instance, royal jelly had no effect on muscle differentiation genes (myogenic differentiation 1 (MyoD), myogenein, myostatin) in sarcopenic mice, indicating that royal jelly may not improve age-related deterioration of muscle strength—once it occurs. On the other hand, royal jelly significantly reduced the progression of muscle atrophy by decreasing the expression of catabolism genes E3 ubiquitin ligases MuRF1 and atrogin-1 in old mice to levels similar to those in young mice [97]. Royal jelly also stimulated the differentiation of satellite stem cells both in vivo and in vitro and improved the regenerative capacity of injured muscle [96,97]. Therefore, royal jelly treatment might reduce the progression of age-related muscular atrophy [59]. Future RCTs that evaluate the effect of bee products on muscle qualities and motor performance in humans should be properly designed to include biological markers of motor functioning along with behavioral measures.\nMultifactorial conditions such as sarcopenia should be addressed by multimodal interventions. Nutrition and physical exercise are key strategies that can preserve muscle mass and function in older adults both in clinical and community settings [21]. Thus, it might be helpful to compare the effect of combining bee products with other conventional treatments such as other dietary elements and exercise given that factors such as physical activity and diet can interfere with or promote the effect of bee products on muscle qualities and disorders that underlie muscle weakness [105,106]. Fat mass increases with age, especially after age-related hormonal decline (e.g., after menopause), and it activates inflammatory processes that disturb body physiology [172]. In this regard, supplementing obese rats with milk naturally enriched with PUFA and polyphenols from propolis increased gastrocnemius muscle mass and tended to increase the mass of the soleus muscle. It decreased the diameter of adipocytes and tended to decrease serum levels of low-density lipoprotein. These findings suggest a role of propolis-enriched milk in the mitigation of sarcopenic obesity, albeit it had no effect on body weight [105]. On the other side, many studies show that exercise has significantly improved muscle mass and strength in sarcopenic seniors [4,42,132,173]. Propolis treatment of undifferentiated L6 myoblast selectively stimulated IL-6 production and inhibited pathological cytokines such as interleukin (IL)-1β and TNF-α [108]. This interesting in vitro investigation indicates that propolis can mimic the mechanism through which exercise induces skeletal muscle remodeling [23,114]. Evidence from preclinical studies shows that concurrent treatment of rats on endurance training with royal jelly enhanced mitochondrial adaptation in muscles that combine both type I and type II fibers such as the soleus muscle whereas neither royal jelly alone nor exercise alone could influence the activity of mitochondrial enzymes in that muscle [106]. Moreover, bee pollen and propolis treatment of rats on exhaustive exercise increased the production of antioxidant enzymes, blocked the production of free radicals, promoted glycogen use in the skeletal muscle and liver, and restored muscle fiber structure [90,109].\nIn most studies, whole royal jelly, bee pollen, and propolis were used. However, these products appeared in different forms e.g., neat vs processed bee pollen [90], water [109] vs ethanolic extracts [110] of propolis, lyophilized [98,99] and crude [97] vs enzyme-treated [59,95,96,97] royal jelly. Both processed bee pollen [36] and pRJ [97,106] had better effects compared with crude bee pollen and royal jelly. In addition, a large group of constituents of royal jelly and propolis were used such as 10-HDA [54,106], CAPE [69,101,102,103], artepillin C, coumaric acid, kaempferide [70], boropinic acid, 4-geranyloxyferulic acid, 7-isopentenyloxycoumarin, and auraptene [69]. 10-HDA was the only element in royal jelly that was tested in skeletal muscle. It enhanced glucose uptake via AMPK phosphorylation [106]. It also restored body weight, restored skeletal muscle mass (only in males), and reduced fat mass (only in females) in aged rats undergoing chronic stress [54]. CAPE is one of the most investigated compounds in propolis: it enhanced skeletal muscle glucose uptake [111], inhibited cytokine and ROS production, prevented protein carbonylation, lipid peroxidation, and muscle proteolysis [101,102,103]. The effects of whole ethanolic extracts of propolis and CAPE on glucose uptake in skeletal muscle were comparable to those of insulin [69,109,111]. More, investigations of the effect of flavonoids and oxyprenylated phenylpropanoids abundant in ethanolic extracts of propolis on glucose uptake in skeletal muscle revealed superior effects of kaempferide [70], 4-geranyloxyferulic acid, and auraptene. Among 5 oxyprenylated phenylpropanoids derived from propolis, auraptene most potently activated GLUT4 translocation and accelerated glucose influx into skeletal muscle cells. Measurement of the incorporated amounts of these compounds into myotubes indicated that auraptene had the highest bioavailability among other effective compounds [69].\nMatters concerning dosage and duration of treatment remain issues of concern should these compounds be used to prevent and treat sarcopenia. In addition, the effect of other active ingredients of bee products on skeletal muscle pathologies is worth investigation. For instance, MRJPs are reported to contribute to most therapeutic properties of royal jelly due to their rich amino acid content (up to 578 amino acids) [47]. In the meantime, the literature documents a potent regulatory effect of amino acids on skeletal muscle protein turnover [6,131,132]. Nonetheless, the effect of MRJPs on skeletal muscle were not studied until now.\nDespite the details illustrated in this review, many questions remain unanswered. The most important question among all is which bee product or bee component can produce the best benefits against skeletal muscle senescence and under which circumstances? Sarcopenia is the result of several interrelated factors such as neuromuscular dysfunction, oxidative stress, metabolic alterations, poor blood supply, hormonal deficiencies (e.g., sex hormones), chronic inflammation, and lifestyle choices (e.g., physical inactivity and unhealthy diet) [21]. The effect of bee products on some of these factors are underaddressed (e.g., neuromuscular dysfunction, muscle blood supply, and gut microbiome) while some other have not been explored yet (e.g., sex steroids and their association with muscular function)."}

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Discussion\nAge-related deteriorations in skeletal muscle are multifactorial in nature, which contributes to the high failure rates of drugs designed to target sarcopenia. Thus, there is a strong need for new therapeutic agents that express multidimensional effects in order to provide physically frail elders a chance to restore their health and QoL [21]. Given the scarcity of human trials using bee products among physically frail and sarcopenic subjects, cell culture and animal studies may provide useful information about the effect of bee products on skeletal muscle and help identifying their probable mechanism of action. Both in vivo and in vitro studies indicate that substances produced by honey bees such as royal jelly, bee pollen, and propolis can positively modulate basic cellular functions of myoblasts as well as mature myocytes. These products seem to be promising anti-sarcopenic agents because they can promote muscle protein synthesis [36,104], decrease mitochondrial oxidative stress [36,90,106], mitigate inflammation [38,90,101,108,115], improve muscular blood supply [102,110], enhance peripheral motor conduction [113], accelerate the removal of AGEs [38], counteract catabolism, and decrease markers of skeletal muscle atrophy [97,101,102,103].\nOne of the major pathologies underlying age-related skeletal muscle failure is insulin resistance, which alters glucose metabolism [3,4,21,118,130,164]. Numerous studies signify that bee products may protect against muscle wasting by correcting metabolic dysregulations in skeletal muscle via activation of some of the key nutrient sensing molecules [69,96,100,106,109,111]. In this respect, bee pollen permitted mTORC1 to mitigate anabolic resistance through the regulation of muscle protein and muscle growth in malnourished sarcopenic old rats [36]. Royal jelly and CAPE restored muscle mass and metabolism through activation of AKT, a substrate of mTOR [96,111]. Polyphenols in propolis [70], CAPE [111], and 10-HDA [106] activated AMPK resulting in enhanced skeletal muscle glucose uptake. In the meantime, royal jelly improved mitochondrial biogenesis in skeletal muscle via activation of AMPK [106]. AMPK and mTOR are master regulators of metabolism and autophagy [2,165]; they keep muscle integrity by stimulating protein synthesis [21,22]. Accordingly, all these findings denote that bee products represent a promising nutritional strategy that can tackle skeletal muscle wasting in old age by correcting its underling metabolic causes. However, the detailed physiological processes involved still need to be deeply unraveled in further investigations.\nThe activity of mTOR depends mainly on the bioavailability of essential amino acids in addition to many other molecules in the cellular microenvironment [136]. Evidence from preclinical and human studies confirms that ingestion of essential amino acids increases their cellular bioavailability, which is associated with upregulation of the activity of the nutrient sensing mTORC1 kinase following its translocation from the cytosol to the surface of lysosomes [135,136]. Research shows that ingestion of small amounts of essential amino acids (6.8 g) by healthy older adults could stimulate muscle protein synthesis by activating mTORC1 signaling even without involvement in resistance exercise training [137]. Other factors affect the capacity of essential amino acids to stimulate muscle protein synthesis. Amino acid bioavailability depends to a great extent on the bacterial strains of resident gut microbiome, which can either promote amino acid loss by degrading them or substantially contribute to their availability by producing some of them e.g., lysine [152]. Furthermore, amino acid supplements in old age do not enhance muscle protein metabolism, combat anabolic resistance, or improve muscle condition under sedentary conditions [25,166].\nAccording to Table 1, different models of skeletal muscle injury (e.g., natural aging [96], sarcopenic obesity [54], AGE-induced muscle wasting [38], malnutrition-related muscle loss [36], exhaustive exercise [90,109], etc.) were used to evaluate the effect of bee products on skeletal muscle. The effects of bee products on muscle mass varied considerably: some studies reported that bee products increased muscle mass [36,54,90,96,100,105,113] and improved physical performance [95,96,97,98,99] while others could not or did not depict any significant change in muscle mass [38,102,103,104,110,117]. However, the latter revealed major beneficial effects related to the biology of skeletal muscle aging such as improved muscle protein deposition [104], enhanced activity of mitochondrial enzymes [106], decreased muscle infiltration by inflammatory cells, decreased muscle proteolysis, lowered lipid peroxidation and protein carbonylation [102,103], increased microvascular blood supply, heightened production of antioxidants [110], and increased clearance of AGEs from skeletal muscle [38]. These findings suggest that bee products may prevent the development of sarcopenia if supplemented earlier before the occurrence of muscle atrophy. In this regard, supplementing young football players with royal jelly for two months resulted in a significant increase in muscle and bone mass compared with control players who did not receive royal jelly [167].\nAs for the effect of bee products on sarcopenia in humans, we could locate only one randomized control trial (RCT), which examined the effect of pRJ (1.2 g/d or 4.8 g/d over 1 year) on muscle strength among institutionalized aged population. This study revealed no significant effect of pRJ on the tested muscular functions: handgrip strength, six-minute walk test, timed up and go test, and standing on one leg with eyes closed [59]. Nonetheless, such outcome indexes may not be sufficient to evaluate the overall effect of royal jelly on muscular performance and quality. In addition, the literature documents gut microbiome alterations-related to muscle loss in institutionalized old adults compared with older adults living in the community, which might affect the efficacy of nutritional therapies in this particular group [164,168,169].\nThe relation between muscle mass or strength and physical function in old people is not as direct or clear as originally presumed. Existing knowledge indicates that muscle strength may be intact in people with muscle loss. Likewise, decreased muscle strength may not necessarily alter physical performance [21,170]. Research notes that selection of interventions that merely increase muscle mass and/or strength entails ignoring valuable therapies that contribute to various biological processes of muscle recovery by interfering with pathologies conducive to muscle loss. More, combining functional measures of muscle performance with different comprehensive biomarkers (e.g., of metabolism, inflammation, oxidative stress, etc.) in skeletal muscle and the whole body may identify therapies that can positively affect muscle qualities independent of mass increase [21]. In support of this argument, treating sarcopenic elderly with oral amino acids (which represent only one ingredient of royal jelly or bee pollen) significantly increased whole-body lean mass 6 and 18 months after treatment as indicated by dual-energy X-ray absorptiometry. This effect was attributed to enhancement of insulin sensitivity and anabolism as portrayed by significant reductions in fasting blood glucose, serum insulin, HOMA-IR, and serum tumor necrosis factor-α (TNF-α) as well as increase of serum level of IGF-1 and IGF-1/TNF-α ratio [171]. Animal studies lend further support to those reports. For instance, royal jelly had no effect on muscle differentiation genes (myogenic differentiation 1 (MyoD), myogenein, myostatin) in sarcopenic mice, indicating that royal jelly may not improve age-related deterioration of muscle strength—once it occurs. On the other hand, royal jelly significantly reduced the progression of muscle atrophy by decreasing the expression of catabolism genes E3 ubiquitin ligases MuRF1 and atrogin-1 in old mice to levels similar to those in young mice [97]. Royal jelly also stimulated the differentiation of satellite stem cells both in vivo and in vitro and improved the regenerative capacity of injured muscle [96,97]. Therefore, royal jelly treatment might reduce the progression of age-related muscular atrophy [59]. Future RCTs that evaluate the effect of bee products on muscle qualities and motor performance in humans should be properly designed to include biological markers of motor functioning along with behavioral measures.\nMultifactorial conditions such as sarcopenia should be addressed by multimodal interventions. Nutrition and physical exercise are key strategies that can preserve muscle mass and function in older adults both in clinical and community settings [21]. Thus, it might be helpful to compare the effect of combining bee products with other conventional treatments such as other dietary elements and exercise given that factors such as physical activity and diet can interfere with or promote the effect of bee products on muscle qualities and disorders that underlie muscle weakness [105,106]. Fat mass increases with age, especially after age-related hormonal decline (e.g., after menopause), and it activates inflammatory processes that disturb body physiology [172]. In this regard, supplementing obese rats with milk naturally enriched with PUFA and polyphenols from propolis increased gastrocnemius muscle mass and tended to increase the mass of the soleus muscle. It decreased the diameter of adipocytes and tended to decrease serum levels of low-density lipoprotein. These findings suggest a role of propolis-enriched milk in the mitigation of sarcopenic obesity, albeit it had no effect on body weight [105]. On the other side, many studies show that exercise has significantly improved muscle mass and strength in sarcopenic seniors [4,42,132,173]. Propolis treatment of undifferentiated L6 myoblast selectively stimulated IL-6 production and inhibited pathological cytokines such as interleukin (IL)-1β and TNF-α [108]. This interesting in vitro investigation indicates that propolis can mimic the mechanism through which exercise induces skeletal muscle remodeling [23,114]. Evidence from preclinical studies shows that concurrent treatment of rats on endurance training with royal jelly enhanced mitochondrial adaptation in muscles that combine both type I and type II fibers such as the soleus muscle whereas neither royal jelly alone nor exercise alone could influence the activity of mitochondrial enzymes in that muscle [106]. Moreover, bee pollen and propolis treatment of rats on exhaustive exercise increased the production of antioxidant enzymes, blocked the production of free radicals, promoted glycogen use in the skeletal muscle and liver, and restored muscle fiber structure [90,109].\nIn most studies, whole royal jelly, bee pollen, and propolis were used. However, these products appeared in different forms e.g., neat vs processed bee pollen [90], water [109] vs ethanolic extracts [110] of propolis, lyophilized [98,99] and crude [97] vs enzyme-treated [59,95,96,97] royal jelly. Both processed bee pollen [36] and pRJ [97,106] had better effects compared with crude bee pollen and royal jelly. In addition, a large group of constituents of royal jelly and propolis were used such as 10-HDA [54,106], CAPE [69,101,102,103], artepillin C, coumaric acid, kaempferide [70], boropinic acid, 4-geranyloxyferulic acid, 7-isopentenyloxycoumarin, and auraptene [69]. 10-HDA was the only element in royal jelly that was tested in skeletal muscle. It enhanced glucose uptake via AMPK phosphorylation [106]. It also restored body weight, restored skeletal muscle mass (only in males), and reduced fat mass (only in females) in aged rats undergoing chronic stress [54]. CAPE is one of the most investigated compounds in propolis: it enhanced skeletal muscle glucose uptake [111], inhibited cytokine and ROS production, prevented protein carbonylation, lipid peroxidation, and muscle proteolysis [101,102,103]. The effects of whole ethanolic extracts of propolis and CAPE on glucose uptake in skeletal muscle were comparable to those of insulin [69,109,111]. More, investigations of the effect of flavonoids and oxyprenylated phenylpropanoids abundant in ethanolic extracts of propolis on glucose uptake in skeletal muscle revealed superior effects of kaempferide [70], 4-geranyloxyferulic acid, and auraptene. Among 5 oxyprenylated phenylpropanoids derived from propolis, auraptene most potently activated GLUT4 translocation and accelerated glucose influx into skeletal muscle cells. Measurement of the incorporated amounts of these compounds into myotubes indicated that auraptene had the highest bioavailability among other effective compounds [69].\nMatters concerning dosage and duration of treatment remain issues of concern should these compounds be used to prevent and treat sarcopenia. In addition, the effect of other active ingredients of bee products on skeletal muscle pathologies is worth investigation. For instance, MRJPs are reported to contribute to most therapeutic properties of royal jelly due to their rich amino acid content (up to 578 amino acids) [47]. In the meantime, the literature documents a potent regulatory effect of amino acids on skeletal muscle protein turnover [6,131,132]. Nonetheless, the effect of MRJPs on skeletal muscle were not studied until now.\nDespite the details illustrated in this review, many questions remain unanswered. The most important question among all is which bee product or bee component can produce the best benefits against skeletal muscle senescence and under which circumstances? Sarcopenia is the result of several interrelated factors such as neuromuscular dysfunction, oxidative stress, metabolic alterations, poor blood supply, hormonal deficiencies (e.g., sex hormones), chronic inflammation, and lifestyle choices (e.g., physical inactivity and unhealthy diet) [21]. The effect of bee products on some of these factors are underaddressed (e.g., neuromuscular dysfunction, muscle blood supply, and gut microbiome) while some other have not been explored yet (e.g., sex steroids and their association with muscular function)."}

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","span":{"begin":9316,"end":9325},"obj":"http://purl.obolibrary.org/obo/GO_0042697"},{"id":"T375","span":{"begin":10066,"end":10081},"obj":"http://purl.obolibrary.org/obo/GO_0032635"},{"id":"T376","span":{"begin":11712,"end":11726},"obj":"http://purl.obolibrary.org/obo/GO_0046323"},{"id":"T377","span":{"begin":11720,"end":11726},"obj":"http://purl.obolibrary.org/obo/GO_0098739"},{"id":"T378","span":{"begin":11720,"end":11726},"obj":"http://purl.obolibrary.org/obo/GO_0098657"},{"id":"T379","span":{"begin":11731,"end":11735},"obj":"http://purl.obolibrary.org/obo/GO_0050405"},{"id":"T380","span":{"begin":11731,"end":11735},"obj":"http://purl.obolibrary.org/obo/GO_0047322"},{"id":"T381","span":{"begin":11731,"end":11735},"obj":"http://purl.obolibrary.org/obo/GO_0004691"},{"id":"T382","span":{"begin":11736,"end":11751},"obj":"http://purl.obolibrary.org/obo/GO_0016310"},{"id":"T383","span":{"begin":12008,"end":12022},"obj":"http://purl.obolibrary.org/obo/GO_0046323"},{"id":"T384","span":{"begin":12016,"end":12022},"obj":"http://purl.obolibrary.org/obo/GO_0098739"},{"id":"T385","span":{"begin":12016,"end":12022},"obj":"http://purl.obolibrary.org/obo/GO_0098657"},{"id":"T386","span":{"begin":12133,"end":12144},"obj":"http://purl.obolibrary.org/obo/GO_0006508"},{"id":"T387","span":{"begin":12224,"end":12238},"obj":"http://purl.obolibrary.org/obo/GO_0046323"},{"id":"T388","span":{"begin":12232,"end":12238},"obj":"http://purl.obolibrary.org/obo/GO_0098739"},{"id":"T389","span":{"begin":12232,"end":12238},"obj":"http://purl.obolibrary.org/obo/GO_0098657"},{"id":"T390","span":{"begin":12438,"end":12452},"obj":"http://purl.obolibrary.org/obo/GO_0046323"},{"id":"T391","span":{"begin":12446,"end":12452},"obj":"http://purl.obolibrary.org/obo/GO_0098739"},{"id":"T392","span":{"begin":12446,"end":12452},"obj":"http://purl.obolibrary.org/obo/GO_0098657"},{"id":"T393","span":{"begin":13998,"end":14010},"obj":"http://purl.obolibrary.org/obo/GO_0006954"}],"text":"5. Discussion\nAge-related deteriorations in skeletal muscle are multifactorial in nature, which contributes to the high failure rates of drugs designed to target sarcopenia. Thus, there is a strong need for new therapeutic agents that express multidimensional effects in order to provide physically frail elders a chance to restore their health and QoL [21]. Given the scarcity of human trials using bee products among physically frail and sarcopenic subjects, cell culture and animal studies may provide useful information about the effect of bee products on skeletal muscle and help identifying their probable mechanism of action. Both in vivo and in vitro studies indicate that substances produced by honey bees such as royal jelly, bee pollen, and propolis can positively modulate basic cellular functions of myoblasts as well as mature myocytes. These products seem to be promising anti-sarcopenic agents because they can promote muscle protein synthesis [36,104], decrease mitochondrial oxidative stress [36,90,106], mitigate inflammation [38,90,101,108,115], improve muscular blood supply [102,110], enhance peripheral motor conduction [113], accelerate the removal of AGEs [38], counteract catabolism, and decrease markers of skeletal muscle atrophy [97,101,102,103].\nOne of the major pathologies underlying age-related skeletal muscle failure is insulin resistance, which alters glucose metabolism [3,4,21,118,130,164]. Numerous studies signify that bee products may protect against muscle wasting by correcting metabolic dysregulations in skeletal muscle via activation of some of the key nutrient sensing molecules [69,96,100,106,109,111]. In this respect, bee pollen permitted mTORC1 to mitigate anabolic resistance through the regulation of muscle protein and muscle growth in malnourished sarcopenic old rats [36]. Royal jelly and CAPE restored muscle mass and metabolism through activation of AKT, a substrate of mTOR [96,111]. Polyphenols in propolis [70], CAPE [111], and 10-HDA [106] activated AMPK resulting in enhanced skeletal muscle glucose uptake. In the meantime, royal jelly improved mitochondrial biogenesis in skeletal muscle via activation of AMPK [106]. AMPK and mTOR are master regulators of metabolism and autophagy [2,165]; they keep muscle integrity by stimulating protein synthesis [21,22]. Accordingly, all these findings denote that bee products represent a promising nutritional strategy that can tackle skeletal muscle wasting in old age by correcting its underling metabolic causes. However, the detailed physiological processes involved still need to be deeply unraveled in further investigations.\nThe activity of mTOR depends mainly on the bioavailability of essential amino acids in addition to many other molecules in the cellular microenvironment [136]. Evidence from preclinical and human studies confirms that ingestion of essential amino acids increases their cellular bioavailability, which is associated with upregulation of the activity of the nutrient sensing mTORC1 kinase following its translocation from the cytosol to the surface of lysosomes [135,136]. Research shows that ingestion of small amounts of essential amino acids (6.8 g) by healthy older adults could stimulate muscle protein synthesis by activating mTORC1 signaling even without involvement in resistance exercise training [137]. Other factors affect the capacity of essential amino acids to stimulate muscle protein synthesis. Amino acid bioavailability depends to a great extent on the bacterial strains of resident gut microbiome, which can either promote amino acid loss by degrading them or substantially contribute to their availability by producing some of them e.g., lysine [152]. Furthermore, amino acid supplements in old age do not enhance muscle protein metabolism, combat anabolic resistance, or improve muscle condition under sedentary conditions [25,166].\nAccording to Table 1, different models of skeletal muscle injury (e.g., natural aging [96], sarcopenic obesity [54], AGE-induced muscle wasting [38], malnutrition-related muscle loss [36], exhaustive exercise [90,109], etc.) were used to evaluate the effect of bee products on skeletal muscle. The effects of bee products on muscle mass varied considerably: some studies reported that bee products increased muscle mass [36,54,90,96,100,105,113] and improved physical performance [95,96,97,98,99] while others could not or did not depict any significant change in muscle mass [38,102,103,104,110,117]. However, the latter revealed major beneficial effects related to the biology of skeletal muscle aging such as improved muscle protein deposition [104], enhanced activity of mitochondrial enzymes [106], decreased muscle infiltration by inflammatory cells, decreased muscle proteolysis, lowered lipid peroxidation and protein carbonylation [102,103], increased microvascular blood supply, heightened production of antioxidants [110], and increased clearance of AGEs from skeletal muscle [38]. These findings suggest that bee products may prevent the development of sarcopenia if supplemented earlier before the occurrence of muscle atrophy. In this regard, supplementing young football players with royal jelly for two months resulted in a significant increase in muscle and bone mass compared with control players who did not receive royal jelly [167].\nAs for the effect of bee products on sarcopenia in humans, we could locate only one randomized control trial (RCT), which examined the effect of pRJ (1.2 g/d or 4.8 g/d over 1 year) on muscle strength among institutionalized aged population. This study revealed no significant effect of pRJ on the tested muscular functions: handgrip strength, six-minute walk test, timed up and go test, and standing on one leg with eyes closed [59]. Nonetheless, such outcome indexes may not be sufficient to evaluate the overall effect of royal jelly on muscular performance and quality. In addition, the literature documents gut microbiome alterations-related to muscle loss in institutionalized old adults compared with older adults living in the community, which might affect the efficacy of nutritional therapies in this particular group [164,168,169].\nThe relation between muscle mass or strength and physical function in old people is not as direct or clear as originally presumed. Existing knowledge indicates that muscle strength may be intact in people with muscle loss. Likewise, decreased muscle strength may not necessarily alter physical performance [21,170]. Research notes that selection of interventions that merely increase muscle mass and/or strength entails ignoring valuable therapies that contribute to various biological processes of muscle recovery by interfering with pathologies conducive to muscle loss. More, combining functional measures of muscle performance with different comprehensive biomarkers (e.g., of metabolism, inflammation, oxidative stress, etc.) in skeletal muscle and the whole body may identify therapies that can positively affect muscle qualities independent of mass increase [21]. In support of this argument, treating sarcopenic elderly with oral amino acids (which represent only one ingredient of royal jelly or bee pollen) significantly increased whole-body lean mass 6 and 18 months after treatment as indicated by dual-energy X-ray absorptiometry. This effect was attributed to enhancement of insulin sensitivity and anabolism as portrayed by significant reductions in fasting blood glucose, serum insulin, HOMA-IR, and serum tumor necrosis factor-α (TNF-α) as well as increase of serum level of IGF-1 and IGF-1/TNF-α ratio [171]. Animal studies lend further support to those reports. For instance, royal jelly had no effect on muscle differentiation genes (myogenic differentiation 1 (MyoD), myogenein, myostatin) in sarcopenic mice, indicating that royal jelly may not improve age-related deterioration of muscle strength—once it occurs. On the other hand, royal jelly significantly reduced the progression of muscle atrophy by decreasing the expression of catabolism genes E3 ubiquitin ligases MuRF1 and atrogin-1 in old mice to levels similar to those in young mice [97]. Royal jelly also stimulated the differentiation of satellite stem cells both in vivo and in vitro and improved the regenerative capacity of injured muscle [96,97]. Therefore, royal jelly treatment might reduce the progression of age-related muscular atrophy [59]. Future RCTs that evaluate the effect of bee products on muscle qualities and motor performance in humans should be properly designed to include biological markers of motor functioning along with behavioral measures.\nMultifactorial conditions such as sarcopenia should be addressed by multimodal interventions. Nutrition and physical exercise are key strategies that can preserve muscle mass and function in older adults both in clinical and community settings [21]. Thus, it might be helpful to compare the effect of combining bee products with other conventional treatments such as other dietary elements and exercise given that factors such as physical activity and diet can interfere with or promote the effect of bee products on muscle qualities and disorders that underlie muscle weakness [105,106]. Fat mass increases with age, especially after age-related hormonal decline (e.g., after menopause), and it activates inflammatory processes that disturb body physiology [172]. In this regard, supplementing obese rats with milk naturally enriched with PUFA and polyphenols from propolis increased gastrocnemius muscle mass and tended to increase the mass of the soleus muscle. It decreased the diameter of adipocytes and tended to decrease serum levels of low-density lipoprotein. These findings suggest a role of propolis-enriched milk in the mitigation of sarcopenic obesity, albeit it had no effect on body weight [105]. On the other side, many studies show that exercise has significantly improved muscle mass and strength in sarcopenic seniors [4,42,132,173]. Propolis treatment of undifferentiated L6 myoblast selectively stimulated IL-6 production and inhibited pathological cytokines such as interleukin (IL)-1β and TNF-α [108]. This interesting in vitro investigation indicates that propolis can mimic the mechanism through which exercise induces skeletal muscle remodeling [23,114]. Evidence from preclinical studies shows that concurrent treatment of rats on endurance training with royal jelly enhanced mitochondrial adaptation in muscles that combine both type I and type II fibers such as the soleus muscle whereas neither royal jelly alone nor exercise alone could influence the activity of mitochondrial enzymes in that muscle [106]. Moreover, bee pollen and propolis treatment of rats on exhaustive exercise increased the production of antioxidant enzymes, blocked the production of free radicals, promoted glycogen use in the skeletal muscle and liver, and restored muscle fiber structure [90,109].\nIn most studies, whole royal jelly, bee pollen, and propolis were used. However, these products appeared in different forms e.g., neat vs processed bee pollen [90], water [109] vs ethanolic extracts [110] of propolis, lyophilized [98,99] and crude [97] vs enzyme-treated [59,95,96,97] royal jelly. Both processed bee pollen [36] and pRJ [97,106] had better effects compared with crude bee pollen and royal jelly. In addition, a large group of constituents of royal jelly and propolis were used such as 10-HDA [54,106], CAPE [69,101,102,103], artepillin C, coumaric acid, kaempferide [70], boropinic acid, 4-geranyloxyferulic acid, 7-isopentenyloxycoumarin, and auraptene [69]. 10-HDA was the only element in royal jelly that was tested in skeletal muscle. It enhanced glucose uptake via AMPK phosphorylation [106]. It also restored body weight, restored skeletal muscle mass (only in males), and reduced fat mass (only in females) in aged rats undergoing chronic stress [54]. CAPE is one of the most investigated compounds in propolis: it enhanced skeletal muscle glucose uptake [111], inhibited cytokine and ROS production, prevented protein carbonylation, lipid peroxidation, and muscle proteolysis [101,102,103]. The effects of whole ethanolic extracts of propolis and CAPE on glucose uptake in skeletal muscle were comparable to those of insulin [69,109,111]. More, investigations of the effect of flavonoids and oxyprenylated phenylpropanoids abundant in ethanolic extracts of propolis on glucose uptake in skeletal muscle revealed superior effects of kaempferide [70], 4-geranyloxyferulic acid, and auraptene. Among 5 oxyprenylated phenylpropanoids derived from propolis, auraptene most potently activated GLUT4 translocation and accelerated glucose influx into skeletal muscle cells. Measurement of the incorporated amounts of these compounds into myotubes indicated that auraptene had the highest bioavailability among other effective compounds [69].\nMatters concerning dosage and duration of treatment remain issues of concern should these compounds be used to prevent and treat sarcopenia. In addition, the effect of other active ingredients of bee products on skeletal muscle pathologies is worth investigation. For instance, MRJPs are reported to contribute to most therapeutic properties of royal jelly due to their rich amino acid content (up to 578 amino acids) [47]. In the meantime, the literature documents a potent regulatory effect of amino acids on skeletal muscle protein turnover [6,131,132]. Nonetheless, the effect of MRJPs on skeletal muscle were not studied until now.\nDespite the details illustrated in this review, many questions remain unanswered. The most important question among all is which bee product or bee component can produce the best benefits against skeletal muscle senescence and under which circumstances? Sarcopenia is the result of several interrelated factors such as neuromuscular dysfunction, oxidative stress, metabolic alterations, poor blood supply, hormonal deficiencies (e.g., sex hormones), chronic inflammation, and lifestyle choices (e.g., physical inactivity and unhealthy diet) [21]. The effect of bee products on some of these factors are underaddressed (e.g., neuromuscular dysfunction, muscle blood supply, and gut microbiome) while some other have not been explored yet (e.g., sex steroids and their association with muscular function)."}

{"project":"LitCovid-PD-HP","denotations":[{"id":"T70","span":{"begin":993,"end":1009},"obj":"Phenotype"},{"id":"T71","span":{"begin":1234,"end":1257},"obj":"Phenotype"},{"id":"T72","span":{"begin":1355,"end":1373},"obj":"Phenotype"},{"id":"T73","span":{"begin":1492,"end":1506},"obj":"Phenotype"},{"id":"T74","span":{"begin":2450,"end":2464},"obj":"Phenotype"},{"id":"T75","span":{"begin":3993,"end":4000},"obj":"Phenotype"},{"id":"T76","span":{"begin":4019,"end":4033},"obj":"Phenotype"},{"id":"T77","span":{"begin":4040,"end":4052},"obj":"Phenotype"},{"id":"T78","span":{"begin":5115,"end":5129},"obj":"Phenotype"},{"id":"T79","span":{"begin":6894,"end":6910},"obj":"Phenotype"},{"id":"T80","span":{"begin":7509,"end":7514},"obj":"Phenotype"},{"id":"T81","span":{"begin":7995,"end":8009},"obj":"Phenotype"},{"id":"T82","span":{"begin":8400,"end":8416},"obj":"Phenotype"},{"id":"T83","span":{"begin":9201,"end":9216},"obj":"Phenotype"},{"id":"T84","span":{"begin":9796,"end":9803},"obj":"Phenotype"},{"id":"T85","span":{"begin":13886,"end":13902},"obj":"Phenotype"}],"attributes":[{"id":"A70","pred":"hp_id","subj":"T70","obj":"http://purl.obolibrary.org/obo/HP_0025464"},{"id":"A71","pred":"hp_id","subj":"T71","obj":"http://purl.obolibrary.org/obo/HP_0003202"},{"id":"A72","pred":"hp_id","subj":"T72","obj":"http://purl.obolibrary.org/obo/HP_0000855"},{"id":"A73","pred":"hp_id","subj":"T73","obj":"http://purl.obolibrary.org/obo/HP_0003202"},{"id":"A74","pred":"hp_id","subj":"T74","obj":"http://purl.obolibrary.org/obo/HP_0003202"},{"id":"A75","pred":"hp_id","subj":"T75","obj":"http://purl.obolibrary.org/obo/HP_0001513"},{"id":"A76","pred":"hp_id","subj":"T76","obj":"http://purl.obolibrary.org/obo/HP_0003202"},{"id":"A77","pred":"hp_id","subj":"T77","obj":"http://purl.obolibrary.org/obo/HP_0004395"},{"id":"A78","pred":"hp_id","subj":"T78","obj":"http://purl.obolibrary.org/obo/HP_0003202"},{"id":"A79","pred":"hp_id","subj":"T79","obj":"http://purl.obolibrary.org/obo/HP_0025464"},{"id":"A80","pred":"hp_id","subj":"T80","obj":"http://purl.obolibrary.org/obo/HP_0002664"},{"id":"A81","pred":"hp_id","subj":"T81","obj":"http://purl.obolibrary.org/obo/HP_0003202"},{"id":"A82","pred":"hp_id","subj":"T82","obj":"http://purl.obolibrary.org/obo/HP_0003202"},{"id":"A83","pred":"hp_id","subj":"T83","obj":"http://purl.obolibrary.org/obo/HP_0001324"},{"id":"A84","pred":"hp_id","subj":"T84","obj":"http://purl.obolibrary.org/obo/HP_0001513"},{"id":"A85","pred":"hp_id","subj":"T85","obj":"http://purl.obolibrary.org/obo/HP_0025464"}],"text":"5. Discussion\nAge-related deteriorations in skeletal muscle are multifactorial in nature, which contributes to the high failure rates of drugs designed to target sarcopenia. Thus, there is a strong need for new therapeutic agents that express multidimensional effects in order to provide physically frail elders a chance to restore their health and QoL [21]. Given the scarcity of human trials using bee products among physically frail and sarcopenic subjects, cell culture and animal studies may provide useful information about the effect of bee products on skeletal muscle and help identifying their probable mechanism of action. Both in vivo and in vitro studies indicate that substances produced by honey bees such as royal jelly, bee pollen, and propolis can positively modulate basic cellular functions of myoblasts as well as mature myocytes. These products seem to be promising anti-sarcopenic agents because they can promote muscle protein synthesis [36,104], decrease mitochondrial oxidative stress [36,90,106], mitigate inflammation [38,90,101,108,115], improve muscular blood supply [102,110], enhance peripheral motor conduction [113], accelerate the removal of AGEs [38], counteract catabolism, and decrease markers of skeletal muscle atrophy [97,101,102,103].\nOne of the major pathologies underlying age-related skeletal muscle failure is insulin resistance, which alters glucose metabolism [3,4,21,118,130,164]. Numerous studies signify that bee products may protect against muscle wasting by correcting metabolic dysregulations in skeletal muscle via activation of some of the key nutrient sensing molecules [69,96,100,106,109,111]. In this respect, bee pollen permitted mTORC1 to mitigate anabolic resistance through the regulation of muscle protein and muscle growth in malnourished sarcopenic old rats [36]. Royal jelly and CAPE restored muscle mass and metabolism through activation of AKT, a substrate of mTOR [96,111]. Polyphenols in propolis [70], CAPE [111], and 10-HDA [106] activated AMPK resulting in enhanced skeletal muscle glucose uptake. In the meantime, royal jelly improved mitochondrial biogenesis in skeletal muscle via activation of AMPK [106]. AMPK and mTOR are master regulators of metabolism and autophagy [2,165]; they keep muscle integrity by stimulating protein synthesis [21,22]. Accordingly, all these findings denote that bee products represent a promising nutritional strategy that can tackle skeletal muscle wasting in old age by correcting its underling metabolic causes. However, the detailed physiological processes involved still need to be deeply unraveled in further investigations.\nThe activity of mTOR depends mainly on the bioavailability of essential amino acids in addition to many other molecules in the cellular microenvironment [136]. Evidence from preclinical and human studies confirms that ingestion of essential amino acids increases their cellular bioavailability, which is associated with upregulation of the activity of the nutrient sensing mTORC1 kinase following its translocation from the cytosol to the surface of lysosomes [135,136]. Research shows that ingestion of small amounts of essential amino acids (6.8 g) by healthy older adults could stimulate muscle protein synthesis by activating mTORC1 signaling even without involvement in resistance exercise training [137]. Other factors affect the capacity of essential amino acids to stimulate muscle protein synthesis. Amino acid bioavailability depends to a great extent on the bacterial strains of resident gut microbiome, which can either promote amino acid loss by degrading them or substantially contribute to their availability by producing some of them e.g., lysine [152]. Furthermore, amino acid supplements in old age do not enhance muscle protein metabolism, combat anabolic resistance, or improve muscle condition under sedentary conditions [25,166].\nAccording to Table 1, different models of skeletal muscle injury (e.g., natural aging [96], sarcopenic obesity [54], AGE-induced muscle wasting [38], malnutrition-related muscle loss [36], exhaustive exercise [90,109], etc.) were used to evaluate the effect of bee products on skeletal muscle. The effects of bee products on muscle mass varied considerably: some studies reported that bee products increased muscle mass [36,54,90,96,100,105,113] and improved physical performance [95,96,97,98,99] while others could not or did not depict any significant change in muscle mass [38,102,103,104,110,117]. However, the latter revealed major beneficial effects related to the biology of skeletal muscle aging such as improved muscle protein deposition [104], enhanced activity of mitochondrial enzymes [106], decreased muscle infiltration by inflammatory cells, decreased muscle proteolysis, lowered lipid peroxidation and protein carbonylation [102,103], increased microvascular blood supply, heightened production of antioxidants [110], and increased clearance of AGEs from skeletal muscle [38]. These findings suggest that bee products may prevent the development of sarcopenia if supplemented earlier before the occurrence of muscle atrophy. In this regard, supplementing young football players with royal jelly for two months resulted in a significant increase in muscle and bone mass compared with control players who did not receive royal jelly [167].\nAs for the effect of bee products on sarcopenia in humans, we could locate only one randomized control trial (RCT), which examined the effect of pRJ (1.2 g/d or 4.8 g/d over 1 year) on muscle strength among institutionalized aged population. This study revealed no significant effect of pRJ on the tested muscular functions: handgrip strength, six-minute walk test, timed up and go test, and standing on one leg with eyes closed [59]. Nonetheless, such outcome indexes may not be sufficient to evaluate the overall effect of royal jelly on muscular performance and quality. In addition, the literature documents gut microbiome alterations-related to muscle loss in institutionalized old adults compared with older adults living in the community, which might affect the efficacy of nutritional therapies in this particular group [164,168,169].\nThe relation between muscle mass or strength and physical function in old people is not as direct or clear as originally presumed. Existing knowledge indicates that muscle strength may be intact in people with muscle loss. Likewise, decreased muscle strength may not necessarily alter physical performance [21,170]. Research notes that selection of interventions that merely increase muscle mass and/or strength entails ignoring valuable therapies that contribute to various biological processes of muscle recovery by interfering with pathologies conducive to muscle loss. More, combining functional measures of muscle performance with different comprehensive biomarkers (e.g., of metabolism, inflammation, oxidative stress, etc.) in skeletal muscle and the whole body may identify therapies that can positively affect muscle qualities independent of mass increase [21]. In support of this argument, treating sarcopenic elderly with oral amino acids (which represent only one ingredient of royal jelly or bee pollen) significantly increased whole-body lean mass 6 and 18 months after treatment as indicated by dual-energy X-ray absorptiometry. This effect was attributed to enhancement of insulin sensitivity and anabolism as portrayed by significant reductions in fasting blood glucose, serum insulin, HOMA-IR, and serum tumor necrosis factor-α (TNF-α) as well as increase of serum level of IGF-1 and IGF-1/TNF-α ratio [171]. Animal studies lend further support to those reports. For instance, royal jelly had no effect on muscle differentiation genes (myogenic differentiation 1 (MyoD), myogenein, myostatin) in sarcopenic mice, indicating that royal jelly may not improve age-related deterioration of muscle strength—once it occurs. On the other hand, royal jelly significantly reduced the progression of muscle atrophy by decreasing the expression of catabolism genes E3 ubiquitin ligases MuRF1 and atrogin-1 in old mice to levels similar to those in young mice [97]. Royal jelly also stimulated the differentiation of satellite stem cells both in vivo and in vitro and improved the regenerative capacity of injured muscle [96,97]. Therefore, royal jelly treatment might reduce the progression of age-related muscular atrophy [59]. Future RCTs that evaluate the effect of bee products on muscle qualities and motor performance in humans should be properly designed to include biological markers of motor functioning along with behavioral measures.\nMultifactorial conditions such as sarcopenia should be addressed by multimodal interventions. Nutrition and physical exercise are key strategies that can preserve muscle mass and function in older adults both in clinical and community settings [21]. Thus, it might be helpful to compare the effect of combining bee products with other conventional treatments such as other dietary elements and exercise given that factors such as physical activity and diet can interfere with or promote the effect of bee products on muscle qualities and disorders that underlie muscle weakness [105,106]. Fat mass increases with age, especially after age-related hormonal decline (e.g., after menopause), and it activates inflammatory processes that disturb body physiology [172]. In this regard, supplementing obese rats with milk naturally enriched with PUFA and polyphenols from propolis increased gastrocnemius muscle mass and tended to increase the mass of the soleus muscle. It decreased the diameter of adipocytes and tended to decrease serum levels of low-density lipoprotein. These findings suggest a role of propolis-enriched milk in the mitigation of sarcopenic obesity, albeit it had no effect on body weight [105]. On the other side, many studies show that exercise has significantly improved muscle mass and strength in sarcopenic seniors [4,42,132,173]. Propolis treatment of undifferentiated L6 myoblast selectively stimulated IL-6 production and inhibited pathological cytokines such as interleukin (IL)-1β and TNF-α [108]. This interesting in vitro investigation indicates that propolis can mimic the mechanism through which exercise induces skeletal muscle remodeling [23,114]. Evidence from preclinical studies shows that concurrent treatment of rats on endurance training with royal jelly enhanced mitochondrial adaptation in muscles that combine both type I and type II fibers such as the soleus muscle whereas neither royal jelly alone nor exercise alone could influence the activity of mitochondrial enzymes in that muscle [106]. Moreover, bee pollen and propolis treatment of rats on exhaustive exercise increased the production of antioxidant enzymes, blocked the production of free radicals, promoted glycogen use in the skeletal muscle and liver, and restored muscle fiber structure [90,109].\nIn most studies, whole royal jelly, bee pollen, and propolis were used. However, these products appeared in different forms e.g., neat vs processed bee pollen [90], water [109] vs ethanolic extracts [110] of propolis, lyophilized [98,99] and crude [97] vs enzyme-treated [59,95,96,97] royal jelly. Both processed bee pollen [36] and pRJ [97,106] had better effects compared with crude bee pollen and royal jelly. In addition, a large group of constituents of royal jelly and propolis were used such as 10-HDA [54,106], CAPE [69,101,102,103], artepillin C, coumaric acid, kaempferide [70], boropinic acid, 4-geranyloxyferulic acid, 7-isopentenyloxycoumarin, and auraptene [69]. 10-HDA was the only element in royal jelly that was tested in skeletal muscle. It enhanced glucose uptake via AMPK phosphorylation [106]. It also restored body weight, restored skeletal muscle mass (only in males), and reduced fat mass (only in females) in aged rats undergoing chronic stress [54]. CAPE is one of the most investigated compounds in propolis: it enhanced skeletal muscle glucose uptake [111], inhibited cytokine and ROS production, prevented protein carbonylation, lipid peroxidation, and muscle proteolysis [101,102,103]. The effects of whole ethanolic extracts of propolis and CAPE on glucose uptake in skeletal muscle were comparable to those of insulin [69,109,111]. More, investigations of the effect of flavonoids and oxyprenylated phenylpropanoids abundant in ethanolic extracts of propolis on glucose uptake in skeletal muscle revealed superior effects of kaempferide [70], 4-geranyloxyferulic acid, and auraptene. Among 5 oxyprenylated phenylpropanoids derived from propolis, auraptene most potently activated GLUT4 translocation and accelerated glucose influx into skeletal muscle cells. Measurement of the incorporated amounts of these compounds into myotubes indicated that auraptene had the highest bioavailability among other effective compounds [69].\nMatters concerning dosage and duration of treatment remain issues of concern should these compounds be used to prevent and treat sarcopenia. In addition, the effect of other active ingredients of bee products on skeletal muscle pathologies is worth investigation. For instance, MRJPs are reported to contribute to most therapeutic properties of royal jelly due to their rich amino acid content (up to 578 amino acids) [47]. In the meantime, the literature documents a potent regulatory effect of amino acids on skeletal muscle protein turnover [6,131,132]. Nonetheless, the effect of MRJPs on skeletal muscle were not studied until now.\nDespite the details illustrated in this review, many questions remain unanswered. The most important question among all is which bee product or bee component can produce the best benefits against skeletal muscle senescence and under which circumstances? Sarcopenia is the result of several interrelated factors such as neuromuscular dysfunction, oxidative stress, metabolic alterations, poor blood supply, hormonal deficiencies (e.g., sex hormones), chronic inflammation, and lifestyle choices (e.g., physical inactivity and unhealthy diet) [21]. The effect of bee products on some of these factors are underaddressed (e.g., neuromuscular dysfunction, muscle blood supply, and gut microbiome) while some other have not been explored yet (e.g., sex steroids and their association with muscular function)."}

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Discussion\nAge-related deteriorations in skeletal muscle are multifactorial in nature, which contributes to the high failure rates of drugs designed to target sarcopenia. Thus, there is a strong need for new therapeutic agents that express multidimensional effects in order to provide physically frail elders a chance to restore their health and QoL [21]. Given the scarcity of human trials using bee products among physically frail and sarcopenic subjects, cell culture and animal studies may provide useful information about the effect of bee products on skeletal muscle and help identifying their probable mechanism of action. Both in vivo and in vitro studies indicate that substances produced by honey bees such as royal jelly, bee pollen, and propolis can positively modulate basic cellular functions of myoblasts as well as mature myocytes. These products seem to be promising anti-sarcopenic agents because they can promote muscle protein synthesis [36,104], decrease mitochondrial oxidative stress [36,90,106], mitigate inflammation [38,90,101,108,115], improve muscular blood supply [102,110], enhance peripheral motor conduction [113], accelerate the removal of AGEs [38], counteract catabolism, and decrease markers of skeletal muscle atrophy [97,101,102,103].\nOne of the major pathologies underlying age-related skeletal muscle failure is insulin resistance, which alters glucose metabolism [3,4,21,118,130,164]. Numerous studies signify that bee products may protect against muscle wasting by correcting metabolic dysregulations in skeletal muscle via activation of some of the key nutrient sensing molecules [69,96,100,106,109,111]. In this respect, bee pollen permitted mTORC1 to mitigate anabolic resistance through the regulation of muscle protein and muscle growth in malnourished sarcopenic old rats [36]. Royal jelly and CAPE restored muscle mass and metabolism through activation of AKT, a substrate of mTOR [96,111]. Polyphenols in propolis [70], CAPE [111], and 10-HDA [106] activated AMPK resulting in enhanced skeletal muscle glucose uptake. In the meantime, royal jelly improved mitochondrial biogenesis in skeletal muscle via activation of AMPK [106]. AMPK and mTOR are master regulators of metabolism and autophagy [2,165]; they keep muscle integrity by stimulating protein synthesis [21,22]. Accordingly, all these findings denote that bee products represent a promising nutritional strategy that can tackle skeletal muscle wasting in old age by correcting its underling metabolic causes. However, the detailed physiological processes involved still need to be deeply unraveled in further investigations.\nThe activity of mTOR depends mainly on the bioavailability of essential amino acids in addition to many other molecules in the cellular microenvironment [136]. Evidence from preclinical and human studies confirms that ingestion of essential amino acids increases their cellular bioavailability, which is associated with upregulation of the activity of the nutrient sensing mTORC1 kinase following its translocation from the cytosol to the surface of lysosomes [135,136]. Research shows that ingestion of small amounts of essential amino acids (6.8 g) by healthy older adults could stimulate muscle protein synthesis by activating mTORC1 signaling even without involvement in resistance exercise training [137]. Other factors affect the capacity of essential amino acids to stimulate muscle protein synthesis. Amino acid bioavailability depends to a great extent on the bacterial strains of resident gut microbiome, which can either promote amino acid loss by degrading them or substantially contribute to their availability by producing some of them e.g., lysine [152]. Furthermore, amino acid supplements in old age do not enhance muscle protein metabolism, combat anabolic resistance, or improve muscle condition under sedentary conditions [25,166].\nAccording to Table 1, different models of skeletal muscle injury (e.g., natural aging [96], sarcopenic obesity [54], AGE-induced muscle wasting [38], malnutrition-related muscle loss [36], exhaustive exercise [90,109], etc.) were used to evaluate the effect of bee products on skeletal muscle. The effects of bee products on muscle mass varied considerably: some studies reported that bee products increased muscle mass [36,54,90,96,100,105,113] and improved physical performance [95,96,97,98,99] while others could not or did not depict any significant change in muscle mass [38,102,103,104,110,117]. However, the latter revealed major beneficial effects related to the biology of skeletal muscle aging such as improved muscle protein deposition [104], enhanced activity of mitochondrial enzymes [106], decreased muscle infiltration by inflammatory cells, decreased muscle proteolysis, lowered lipid peroxidation and protein carbonylation [102,103], increased microvascular blood supply, heightened production of antioxidants [110], and increased clearance of AGEs from skeletal muscle [38]. These findings suggest that bee products may prevent the development of sarcopenia if supplemented earlier before the occurrence of muscle atrophy. In this regard, supplementing young football players with royal jelly for two months resulted in a significant increase in muscle and bone mass compared with control players who did not receive royal jelly [167].\nAs for the effect of bee products on sarcopenia in humans, we could locate only one randomized control trial (RCT), which examined the effect of pRJ (1.2 g/d or 4.8 g/d over 1 year) on muscle strength among institutionalized aged population. This study revealed no significant effect of pRJ on the tested muscular functions: handgrip strength, six-minute walk test, timed up and go test, and standing on one leg with eyes closed [59]. Nonetheless, such outcome indexes may not be sufficient to evaluate the overall effect of royal jelly on muscular performance and quality. In addition, the literature documents gut microbiome alterations-related to muscle loss in institutionalized old adults compared with older adults living in the community, which might affect the efficacy of nutritional therapies in this particular group [164,168,169].\nThe relation between muscle mass or strength and physical function in old people is not as direct or clear as originally presumed. Existing knowledge indicates that muscle strength may be intact in people with muscle loss. Likewise, decreased muscle strength may not necessarily alter physical performance [21,170]. Research notes that selection of interventions that merely increase muscle mass and/or strength entails ignoring valuable therapies that contribute to various biological processes of muscle recovery by interfering with pathologies conducive to muscle loss. More, combining functional measures of muscle performance with different comprehensive biomarkers (e.g., of metabolism, inflammation, oxidative stress, etc.) in skeletal muscle and the whole body may identify therapies that can positively affect muscle qualities independent of mass increase [21]. In support of this argument, treating sarcopenic elderly with oral amino acids (which represent only one ingredient of royal jelly or bee pollen) significantly increased whole-body lean mass 6 and 18 months after treatment as indicated by dual-energy X-ray absorptiometry. This effect was attributed to enhancement of insulin sensitivity and anabolism as portrayed by significant reductions in fasting blood glucose, serum insulin, HOMA-IR, and serum tumor necrosis factor-α (TNF-α) as well as increase of serum level of IGF-1 and IGF-1/TNF-α ratio [171]. Animal studies lend further support to those reports. For instance, royal jelly had no effect on muscle differentiation genes (myogenic differentiation 1 (MyoD), myogenein, myostatin) in sarcopenic mice, indicating that royal jelly may not improve age-related deterioration of muscle strength—once it occurs. On the other hand, royal jelly significantly reduced the progression of muscle atrophy by decreasing the expression of catabolism genes E3 ubiquitin ligases MuRF1 and atrogin-1 in old mice to levels similar to those in young mice [97]. Royal jelly also stimulated the differentiation of satellite stem cells both in vivo and in vitro and improved the regenerative capacity of injured muscle [96,97]. Therefore, royal jelly treatment might reduce the progression of age-related muscular atrophy [59]. Future RCTs that evaluate the effect of bee products on muscle qualities and motor performance in humans should be properly designed to include biological markers of motor functioning along with behavioral measures.\nMultifactorial conditions such as sarcopenia should be addressed by multimodal interventions. Nutrition and physical exercise are key strategies that can preserve muscle mass and function in older adults both in clinical and community settings [21]. Thus, it might be helpful to compare the effect of combining bee products with other conventional treatments such as other dietary elements and exercise given that factors such as physical activity and diet can interfere with or promote the effect of bee products on muscle qualities and disorders that underlie muscle weakness [105,106]. Fat mass increases with age, especially after age-related hormonal decline (e.g., after menopause), and it activates inflammatory processes that disturb body physiology [172]. In this regard, supplementing obese rats with milk naturally enriched with PUFA and polyphenols from propolis increased gastrocnemius muscle mass and tended to increase the mass of the soleus muscle. It decreased the diameter of adipocytes and tended to decrease serum levels of low-density lipoprotein. These findings suggest a role of propolis-enriched milk in the mitigation of sarcopenic obesity, albeit it had no effect on body weight [105]. On the other side, many studies show that exercise has significantly improved muscle mass and strength in sarcopenic seniors [4,42,132,173]. Propolis treatment of undifferentiated L6 myoblast selectively stimulated IL-6 production and inhibited pathological cytokines such as interleukin (IL)-1β and TNF-α [108]. This interesting in vitro investigation indicates that propolis can mimic the mechanism through which exercise induces skeletal muscle remodeling [23,114]. Evidence from preclinical studies shows that concurrent treatment of rats on endurance training with royal jelly enhanced mitochondrial adaptation in muscles that combine both type I and type II fibers such as the soleus muscle whereas neither royal jelly alone nor exercise alone could influence the activity of mitochondrial enzymes in that muscle [106]. Moreover, bee pollen and propolis treatment of rats on exhaustive exercise increased the production of antioxidant enzymes, blocked the production of free radicals, promoted glycogen use in the skeletal muscle and liver, and restored muscle fiber structure [90,109].\nIn most studies, whole royal jelly, bee pollen, and propolis were used. However, these products appeared in different forms e.g., neat vs processed bee pollen [90], water [109] vs ethanolic extracts [110] of propolis, lyophilized [98,99] and crude [97] vs enzyme-treated [59,95,96,97] royal jelly. Both processed bee pollen [36] and pRJ [97,106] had better effects compared with crude bee pollen and royal jelly. In addition, a large group of constituents of royal jelly and propolis were used such as 10-HDA [54,106], CAPE [69,101,102,103], artepillin C, coumaric acid, kaempferide [70], boropinic acid, 4-geranyloxyferulic acid, 7-isopentenyloxycoumarin, and auraptene [69]. 10-HDA was the only element in royal jelly that was tested in skeletal muscle. It enhanced glucose uptake via AMPK phosphorylation [106]. It also restored body weight, restored skeletal muscle mass (only in males), and reduced fat mass (only in females) in aged rats undergoing chronic stress [54]. CAPE is one of the most investigated compounds in propolis: it enhanced skeletal muscle glucose uptake [111], inhibited cytokine and ROS production, prevented protein carbonylation, lipid peroxidation, and muscle proteolysis [101,102,103]. The effects of whole ethanolic extracts of propolis and CAPE on glucose uptake in skeletal muscle were comparable to those of insulin [69,109,111]. More, investigations of the effect of flavonoids and oxyprenylated phenylpropanoids abundant in ethanolic extracts of propolis on glucose uptake in skeletal muscle revealed superior effects of kaempferide [70], 4-geranyloxyferulic acid, and auraptene. Among 5 oxyprenylated phenylpropanoids derived from propolis, auraptene most potently activated GLUT4 translocation and accelerated glucose influx into skeletal muscle cells. Measurement of the incorporated amounts of these compounds into myotubes indicated that auraptene had the highest bioavailability among other effective compounds [69].\nMatters concerning dosage and duration of treatment remain issues of concern should these compounds be used to prevent and treat sarcopenia. In addition, the effect of other active ingredients of bee products on skeletal muscle pathologies is worth investigation. For instance, MRJPs are reported to contribute to most therapeutic properties of royal jelly due to their rich amino acid content (up to 578 amino acids) [47]. In the meantime, the literature documents a potent regulatory effect of amino acids on skeletal muscle protein turnover [6,131,132]. Nonetheless, the effect of MRJPs on skeletal muscle were not studied until now.\nDespite the details illustrated in this review, many questions remain unanswered. The most important question among all is which bee product or bee component can produce the best benefits against skeletal muscle senescence and under which circumstances? Sarcopenia is the result of several interrelated factors such as neuromuscular dysfunction, oxidative stress, metabolic alterations, poor blood supply, hormonal deficiencies (e.g., sex hormones), chronic inflammation, and lifestyle choices (e.g., physical inactivity and unhealthy diet) [21]. The effect of bee products on some of these factors are underaddressed (e.g., neuromuscular dysfunction, muscle blood supply, and gut microbiome) while some other have not been explored yet (e.g., sex steroids and their association with muscular function)."}

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Discussion\nAge-related deteriorations in skeletal muscle are multifactorial in nature, which contributes to the high failure rates of drugs designed to target sarcopenia. Thus, there is a strong need for new therapeutic agents that express multidimensional effects in order to provide physically frail elders a chance to restore their health and QoL [21]. Given the scarcity of human trials using bee products among physically frail and sarcopenic subjects, cell culture and animal studies may provide useful information about the effect of bee products on skeletal muscle and help identifying their probable mechanism of action. Both in vivo and in vitro studies indicate that substances produced by honey bees such as royal jelly, bee pollen, and propolis can positively modulate basic cellular functions of myoblasts as well as mature myocytes. These products seem to be promising anti-sarcopenic agents because they can promote muscle protein synthesis [36,104], decrease mitochondrial oxidative stress [36,90,106], mitigate inflammation [38,90,101,108,115], improve muscular blood supply [102,110], enhance peripheral motor conduction [113], accelerate the removal of AGEs [38], counteract catabolism, and decrease markers of skeletal muscle atrophy [97,101,102,103].\nOne of the major pathologies underlying age-related skeletal muscle failure is insulin resistance, which alters glucose metabolism [3,4,21,118,130,164]. Numerous studies signify that bee products may protect against muscle wasting by correcting metabolic dysregulations in skeletal muscle via activation of some of the key nutrient sensing molecules [69,96,100,106,109,111]. In this respect, bee pollen permitted mTORC1 to mitigate anabolic resistance through the regulation of muscle protein and muscle growth in malnourished sarcopenic old rats [36]. Royal jelly and CAPE restored muscle mass and metabolism through activation of AKT, a substrate of mTOR [96,111]. Polyphenols in propolis [70], CAPE [111], and 10-HDA [106] activated AMPK resulting in enhanced skeletal muscle glucose uptake. In the meantime, royal jelly improved mitochondrial biogenesis in skeletal muscle via activation of AMPK [106]. AMPK and mTOR are master regulators of metabolism and autophagy [2,165]; they keep muscle integrity by stimulating protein synthesis [21,22]. Accordingly, all these findings denote that bee products represent a promising nutritional strategy that can tackle skeletal muscle wasting in old age by correcting its underling metabolic causes. However, the detailed physiological processes involved still need to be deeply unraveled in further investigations.\nThe activity of mTOR depends mainly on the bioavailability of essential amino acids in addition to many other molecules in the cellular microenvironment [136]. Evidence from preclinical and human studies confirms that ingestion of essential amino acids increases their cellular bioavailability, which is associated with upregulation of the activity of the nutrient sensing mTORC1 kinase following its translocation from the cytosol to the surface of lysosomes [135,136]. Research shows that ingestion of small amounts of essential amino acids (6.8 g) by healthy older adults could stimulate muscle protein synthesis by activating mTORC1 signaling even without involvement in resistance exercise training [137]. Other factors affect the capacity of essential amino acids to stimulate muscle protein synthesis. Amino acid bioavailability depends to a great extent on the bacterial strains of resident gut microbiome, which can either promote amino acid loss by degrading them or substantially contribute to their availability by producing some of them e.g., lysine [152]. Furthermore, amino acid supplements in old age do not enhance muscle protein metabolism, combat anabolic resistance, or improve muscle condition under sedentary conditions [25,166].\nAccording to Table 1, different models of skeletal muscle injury (e.g., natural aging [96], sarcopenic obesity [54], AGE-induced muscle wasting [38], malnutrition-related muscle loss [36], exhaustive exercise [90,109], etc.) were used to evaluate the effect of bee products on skeletal muscle. The effects of bee products on muscle mass varied considerably: some studies reported that bee products increased muscle mass [36,54,90,96,100,105,113] and improved physical performance [95,96,97,98,99] while others could not or did not depict any significant change in muscle mass [38,102,103,104,110,117]. However, the latter revealed major beneficial effects related to the biology of skeletal muscle aging such as improved muscle protein deposition [104], enhanced activity of mitochondrial enzymes [106], decreased muscle infiltration by inflammatory cells, decreased muscle proteolysis, lowered lipid peroxidation and protein carbonylation [102,103], increased microvascular blood supply, heightened production of antioxidants [110], and increased clearance of AGEs from skeletal muscle [38]. These findings suggest that bee products may prevent the development of sarcopenia if supplemented earlier before the occurrence of muscle atrophy. In this regard, supplementing young football players with royal jelly for two months resulted in a significant increase in muscle and bone mass compared with control players who did not receive royal jelly [167].\nAs for the effect of bee products on sarcopenia in humans, we could locate only one randomized control trial (RCT), which examined the effect of pRJ (1.2 g/d or 4.8 g/d over 1 year) on muscle strength among institutionalized aged population. This study revealed no significant effect of pRJ on the tested muscular functions: handgrip strength, six-minute walk test, timed up and go test, and standing on one leg with eyes closed [59]. Nonetheless, such outcome indexes may not be sufficient to evaluate the overall effect of royal jelly on muscular performance and quality. In addition, the literature documents gut microbiome alterations-related to muscle loss in institutionalized old adults compared with older adults living in the community, which might affect the efficacy of nutritional therapies in this particular group [164,168,169].\nThe relation between muscle mass or strength and physical function in old people is not as direct or clear as originally presumed. Existing knowledge indicates that muscle strength may be intact in people with muscle loss. Likewise, decreased muscle strength may not necessarily alter physical performance [21,170]. Research notes that selection of interventions that merely increase muscle mass and/or strength entails ignoring valuable therapies that contribute to various biological processes of muscle recovery by interfering with pathologies conducive to muscle loss. More, combining functional measures of muscle performance with different comprehensive biomarkers (e.g., of metabolism, inflammation, oxidative stress, etc.) in skeletal muscle and the whole body may identify therapies that can positively affect muscle qualities independent of mass increase [21]. In support of this argument, treating sarcopenic elderly with oral amino acids (which represent only one ingredient of royal jelly or bee pollen) significantly increased whole-body lean mass 6 and 18 months after treatment as indicated by dual-energy X-ray absorptiometry. This effect was attributed to enhancement of insulin sensitivity and anabolism as portrayed by significant reductions in fasting blood glucose, serum insulin, HOMA-IR, and serum tumor necrosis factor-α (TNF-α) as well as increase of serum level of IGF-1 and IGF-1/TNF-α ratio [171]. Animal studies lend further support to those reports. For instance, royal jelly had no effect on muscle differentiation genes (myogenic differentiation 1 (MyoD), myogenein, myostatin) in sarcopenic mice, indicating that royal jelly may not improve age-related deterioration of muscle strength—once it occurs. On the other hand, royal jelly significantly reduced the progression of muscle atrophy by decreasing the expression of catabolism genes E3 ubiquitin ligases MuRF1 and atrogin-1 in old mice to levels similar to those in young mice [97]. Royal jelly also stimulated the differentiation of satellite stem cells both in vivo and in vitro and improved the regenerative capacity of injured muscle [96,97]. Therefore, royal jelly treatment might reduce the progression of age-related muscular atrophy [59]. Future RCTs that evaluate the effect of bee products on muscle qualities and motor performance in humans should be properly designed to include biological markers of motor functioning along with behavioral measures.\nMultifactorial conditions such as sarcopenia should be addressed by multimodal interventions. Nutrition and physical exercise are key strategies that can preserve muscle mass and function in older adults both in clinical and community settings [21]. Thus, it might be helpful to compare the effect of combining bee products with other conventional treatments such as other dietary elements and exercise given that factors such as physical activity and diet can interfere with or promote the effect of bee products on muscle qualities and disorders that underlie muscle weakness [105,106]. Fat mass increases with age, especially after age-related hormonal decline (e.g., after menopause), and it activates inflammatory processes that disturb body physiology [172]. In this regard, supplementing obese rats with milk naturally enriched with PUFA and polyphenols from propolis increased gastrocnemius muscle mass and tended to increase the mass of the soleus muscle. It decreased the diameter of adipocytes and tended to decrease serum levels of low-density lipoprotein. These findings suggest a role of propolis-enriched milk in the mitigation of sarcopenic obesity, albeit it had no effect on body weight [105]. On the other side, many studies show that exercise has significantly improved muscle mass and strength in sarcopenic seniors [4,42,132,173]. Propolis treatment of undifferentiated L6 myoblast selectively stimulated IL-6 production and inhibited pathological cytokines such as interleukin (IL)-1β and TNF-α [108]. This interesting in vitro investigation indicates that propolis can mimic the mechanism through which exercise induces skeletal muscle remodeling [23,114]. Evidence from preclinical studies shows that concurrent treatment of rats on endurance training with royal jelly enhanced mitochondrial adaptation in muscles that combine both type I and type II fibers such as the soleus muscle whereas neither royal jelly alone nor exercise alone could influence the activity of mitochondrial enzymes in that muscle [106]. Moreover, bee pollen and propolis treatment of rats on exhaustive exercise increased the production of antioxidant enzymes, blocked the production of free radicals, promoted glycogen use in the skeletal muscle and liver, and restored muscle fiber structure [90,109].\nIn most studies, whole royal jelly, bee pollen, and propolis were used. However, these products appeared in different forms e.g., neat vs processed bee pollen [90], water [109] vs ethanolic extracts [110] of propolis, lyophilized [98,99] and crude [97] vs enzyme-treated [59,95,96,97] royal jelly. Both processed bee pollen [36] and pRJ [97,106] had better effects compared with crude bee pollen and royal jelly. In addition, a large group of constituents of royal jelly and propolis were used such as 10-HDA [54,106], CAPE [69,101,102,103], artepillin C, coumaric acid, kaempferide [70], boropinic acid, 4-geranyloxyferulic acid, 7-isopentenyloxycoumarin, and auraptene [69]. 10-HDA was the only element in royal jelly that was tested in skeletal muscle. It enhanced glucose uptake via AMPK phosphorylation [106]. It also restored body weight, restored skeletal muscle mass (only in males), and reduced fat mass (only in females) in aged rats undergoing chronic stress [54]. CAPE is one of the most investigated compounds in propolis: it enhanced skeletal muscle glucose uptake [111], inhibited cytokine and ROS production, prevented protein carbonylation, lipid peroxidation, and muscle proteolysis [101,102,103]. The effects of whole ethanolic extracts of propolis and CAPE on glucose uptake in skeletal muscle were comparable to those of insulin [69,109,111]. More, investigations of the effect of flavonoids and oxyprenylated phenylpropanoids abundant in ethanolic extracts of propolis on glucose uptake in skeletal muscle revealed superior effects of kaempferide [70], 4-geranyloxyferulic acid, and auraptene. Among 5 oxyprenylated phenylpropanoids derived from propolis, auraptene most potently activated GLUT4 translocation and accelerated glucose influx into skeletal muscle cells. Measurement of the incorporated amounts of these compounds into myotubes indicated that auraptene had the highest bioavailability among other effective compounds [69].\nMatters concerning dosage and duration of treatment remain issues of concern should these compounds be used to prevent and treat sarcopenia. In addition, the effect of other active ingredients of bee products on skeletal muscle pathologies is worth investigation. For instance, MRJPs are reported to contribute to most therapeutic properties of royal jelly due to their rich amino acid content (up to 578 amino acids) [47]. In the meantime, the literature documents a potent regulatory effect of amino acids on skeletal muscle protein turnover [6,131,132]. Nonetheless, the effect of MRJPs on skeletal muscle were not studied until now.\nDespite the details illustrated in this review, many questions remain unanswered. The most important question among all is which bee product or bee component can produce the best benefits against skeletal muscle senescence and under which circumstances? Sarcopenia is the result of several interrelated factors such as neuromuscular dysfunction, oxidative stress, metabolic alterations, poor blood supply, hormonal deficiencies (e.g., sex hormones), chronic inflammation, and lifestyle choices (e.g., physical inactivity and unhealthy diet) [21]. The effect of bee products on some of these factors are underaddressed (e.g., neuromuscular dysfunction, muscle blood supply, and gut microbiome) while some other have not been explored yet (e.g., sex steroids and their association with muscular function)."}