Table 1.
Characteristics of Included Pre-Clinical and Clinical Studies Examining the Effect of Royal Jelly, Propolis, Bee Pollen, and their Constituents on Skeletal Muscle (N of studies = 24).
| Bee Products/Their Constituents | Animal Model/Cell Line | Experimental Design | Outcome Measures | Results and Possible Related Mechanisms | References |
|---|---|---|---|---|---|
|
In vitro Royal jelly and pRJ (500 μg/mL: 1, 2, 3, and 5 d) In vivo Dietary royal jelly and pRJ (1% and 5% for 3 months) |
In vitro SC isolated from aged mice In vivo 21-months old male C57BL/6 mice as a mouse model of sarcopenia |
In vitro EG1: royal jelly treated SC EG2: pRJ treated SC CG: untreated SC In vivo EG1 and EG2: aged mice on 1% and 5% royal jelly, respectively EG3 and EG4: aged mice on 1% and 5% pRJ, respectively CG: untreated aged mice |
In vitro SC proliferation and differentiation into myotubes and AKT signaling. In vivo No of SC, skeletal muscle weight, grip strength, regenerative capacity of injured muscle, and serum IGF-1. |
In vitro pRJ enhanced SC proliferation rate and differentiation into myotubes through activation of AKT signaling. In vivo Royal jelly and pRJ significantly increased the number of SC, weight of skeletal muscle, grip strength, regenerative capacity of injured skeletal muscle, and IGF-1 serum level. |
[96] |
| Intragastric 10-HDA (1.6 mM/kg body weight) |
In vitro L6 myotubes obtained from Osaka biobank In vivo 7-weeks old male C57BL/6J mice |
In vitro EG: 10-HDA CG1: AICAR (1 mM) CG2: DMSO (0.1%) In vivo EG: 10-HDA (1.6 mM) CG1: gum Arabic (5%) |
Glucose uptake, AMPK signaling, and Glut4 translocation. | 10-HDA increased glucose uptake into L6 myotubes following AMPK activation and Glut4 translocation to the plasma membrane. AMPK activation was induced by the upstream kinase Ca²/calmodulin-dependent kinase β, independent of changes in AMP:ATP ratio and the liver kinase B1 pathway. | [106] |
| Intragastric royal jelly and pRJ (0.7 and 1.4 mg/kg body weight/d/90 d) | D-galactose induced mouse model of aging | EG1 and EG2: mice on 0.7 and 1.4 mg RJ, respectively EG3 and EG4: mice on 0.7 and 1.4 mg RJ hydrolysate, respectively CG: untreated mice |
Antioxidant enzymes, body weight, muscular performance, memory, and learning. | Both doses of pRJ prevented age-related locomotor decline, preserved body weight, enhanced memory and learning, increased antioxidant enzyme activity, and inhibited the production of lipid peroxides. | [95] |
| Oral 10-HDA (12-60 mg/kg body weight/d/4 months) | Obese old rats and stressed mice as models of sarcopenia and depression (male and female Sprague-Dawley and 2-months old male and female BALB/c) | EG1 and EG2: aged obese rats on 10-HDA (12 or 24 mg/kg/d for 3.5 months) EG3 and EG4: stressed BALB/c mice on 10-HDA (30 or 60 mg/kg/d for 4 months) CG1 and CG2: untreated aged obese rats and untreated stressed BALB/c mice |
Body weight, weight of abdominal adipose tissue, and muscle mass. | 10-HDA significantly increased weight gain and weight maintenance in aged rats/mice undergoing behavioral stress without any change in diet consumption. It also significantly decreased adipose tissue in female animals and increased muscle mass in male rodents compared with untreated controls. | [54] |
| Dietary royal jelly and pRJ + MF powder diet (0.05% or 0.5%) | 6-months old male HET mouse model of severe sarcopenia (background strains: BALB/c, C57BL/6, C3H, and DBA/2) | EG1 and EG2: HET mice on 0.05% and 0.5% royal jelly, respectively EG3 and EG4: HET mice on 0.05% and 0.5% pRJ, respectively CG1: untreated HET mice CG2: untreated young mice |
No of blood cells and Pax7 SC, albumin, AST, ALT, T-CHO, TG, expression of muscle genes (MyoD, myogenein, myostatin) and catabolic genes (E3 ubiquitin ligases MuRF1, and atrogin-1). Behavioral tests: grip strength, wire hang, rotarod, and horizontal bar tests. | RJ and pRJ significantly delayed age-related impairment of motor functions, positively improved physical performance of treated mice in 4 types of tests (grip strength, wire hang, horizontal bar, and rotarod), lowered age-related muscular atrophy, increased No of Pax7 SC markers, and suppressed catabolic genes. | [97] |
| Intragastric royal jelly (100 mg/kg body weight/d/8 weeks) | 10-months old male Sprague-Dawley on HFD as a rat model of sarcopenic obesity | EG1: aged rats on royal jelly and HFD EG2: aged rats on royal jelly CG1: untreated young rats CG2: untreated aged rats CG3: untreated old rats on HFD |
Serum levels of T-CHO, TG, HDL-c, LDL-c, insulin, HOMA-IR. Skeletal muscle TG levels. Serum and adipose tissue levels of TNFR1. Percentage of weight gain of the body, abdominal fat, and tibialis anterior and hind limb muscles. | Royal jelly significantly decreased insulin levels, HOMA-IR, TNFR1 in serum and adipose tissue, serum lipids, muscle TG levels, body weight gain and abdominal fat weight and significantly increased the weight of hind limb muscle in aged rats on HFD compared with aged mice on HFD only. | [100] |
| Oral royal jelly (1.0 mg/g body weight/d/3 weeks) | 6–7 weeks old ICR mice | EG: endurance exercise + royal jelly CG1: sedentary rats on royal jelly CG2: endurance exercise+ distilled water CG3: sedentary rats on distilled water |
CS, β-HAD, and activities of AMPK and acetyl-CoA carboxylase in the soleus, plantaris, and tibialis anterior muscles. | Royal jelly increased CS and β-HAD maximal activities in the soleus muscle compared with all CGs but failed to affect these enzymes in the plantaris and tibialis anterior muscles of sedentary mice compared with CG2. Royal jelly effects in the soleus muscle were mediated by AMPK and acetyl-CoA carboxylase activity. |
[106] |
| Gavage/oral lyophilized royal jelly (50 and 100 mg/kg body weight/d/8 weeks) | 18-months old (naturally aging) Wistar male rats as a model of aging | EG1 and EG2: aged rats on royal jelly 50 and 100 mg, respectively CG: aged rats on gavage solution of 0.9% NaCl. |
Learning, spatial memory, and motor performance on Morris water maze. | Royal jelly improved learning, spatial memory, and motor performance e.g., increased the number of crossings, swimming speed, and swimming distance. | [98,99] |
| Oral pRJ (1.2 or 4.8 g/d over 1 year) | Institutionalized older adults (mean age: 78.5 ± 7.5 years, N = 199, N males = 99, N females = 95) | EG1 and EG2: pRJ (1.2 and 4.8 g/d), respectively CG: placebo |
Handgrip strength, six-minute walk test, timed up and go test, and standing on one leg with eyes closed. | pRJ had no significant effect on handgrip strength, six-minute walk test, timed up and go test, and standing on one leg with eyes closed. | [59] |
| Brazilian propolis extract (100 μg/mL/4-12 h) |
In vitro Differentiated myoblast C2C12 cells and RAW264 macrophages isolated from mice |
EGs: propolis (100 μg/mL) CG1: ethanol (0.008%) CG2: DMSO (0.08%). CG3: IKK inhibitor (BMS-345541) |
IL-6, LIF, CCL-2, CCL-5, CXCL-10, VEGF-A, COX2, MMP-12, migration of RAW264 macrophages, and activities of MAIL/IκBζ and NF-κB. | Propolis (at 8h) induced RAW264 macrophage migration, activated MAIL/IκBζ and NF-κB proteins p50 and p65, and increased levels of VEGF-A, COX-2, MMP-12, CCL-2, CCL-5, CCL-10, LIF, and IL-6. Propolis inhibited the production of IL-1β and TNF-α. | [108] |
| CAPE (1 and 10 μM/3 min-12 h) |
In vitro Differentiated L6 myoblast cells isolated from rats |
EGs: CAPE (1, 10 μM) CG1: insulin (100 nM) CG2: AICAR |
2-Deoxyglucose uptake, AMPK and AKT signaling. | CAPE (10 μM/1h) increased 2-Deoxyglucose uptake (same as insulin) and activated AMPK (same as AICAR, an AMPK activator). CAPE (10 μM/3 min) activated AKT in a PI3K-dependent manner. | [111] |
| Boropinic acid, 4-geranyloxyferulic acid, 7-isopentenyloxycoumarin, auraptene (0.1, 1, 10 μM), and raw Italian propolis (0.001–1 mg/mL) |
In vitro Differentiated L6 myoblast cells isolated from rats |
EGs: boropinic acid, 4-geranyloxyferulic acid, 7-isopentenyloxycoumarin, auraptene (0.1, 1, 10 μM), and propolis (0.001–1 mg/mL) CG1: insulin (0.1 μM) CG2: DMSO |
GLUT4-mediated glucose uptake and GLUT4 translocation. | Propolis (1.0 and 1 mg/mL), 4-geranyloxyferulic acid, 7-isopentenyloxycoumarin, and auraptene significantly increased glucose uptake and GLUT4 translocation. | [69] |
|
In vitro A single oral dose of Brazilian propolis extract (250 mg/kg body weight) In vivo Artepillin C, coumaric acid, and kaempferide (1–104 ng/mL for 15 min) |
In vitro Differentiated L6 myoblast cells isolated from rats In vivo 5-weeks old male ICR mice |
EGs: artepillin C, coumaric acid, and kaempferide (1, 10 μM), and propolis (1–104 ng/mL) CG1: insulin (100 nM) CG2: AICAR CG3: DMSO |
2-Deoxyglucose uptake, OGTT, maltase and sucrase-isomaltase activities in epithelial cells of the small intestinal, phosphorylation of AMPK, PI3K, AKT, AS160, IR, and GLUT4 translocation. | Polyphenols in propolis activated PI3K and AMPK signaling pathways and promoted GLUT4 translocation in L6 myotubes though only kaempferide increased glucose uptake. Propolis extract (In vitro, 1 μg) and In vivo significantly promoted the phosphorylation of IR, PI3K, and AMPK and increased GLUT4 translocation in rat skeletal muscle and subsequently decreased postprandial blood glucose levels. Propolis extract had no effect on α-glucosidase activity in the small intestine. |
[70] |
| Gavage CAPE (5 and 10 mg/kg/d/5 d) | 6-7-weeks old male adult Wistar rats | EG: CAPE + eccentric exercise CG1: normal rats + propylene glycol in saline CG2: acute eccentric treadmill exercise |
Serum creatine kinase levels, IL-1β, MCP-1, COX-2, iNOS, leukocyte infiltration, and the extent of muscle fiber damage (vacuolization and fragmentation). | CAPE decreased serum creatine kinase, protein nitrotyrosine, PARP activity, MDA, leukocyte infiltration, skeletal muscle cell fragmentation and vacuolization, muscle levels of COX2, iNOS, IL-1β, MCP-1, and p65NF-κB activity to levels in resting CG1 compared with CG2. | [101] |
| Dietary propolis (0.1% over 20 weeks) | MGO-induced muscle wasting in male C57BL/6NCr mice (4-weeks old) | EG: propolis + MGO CG1: MGO only CG2: propolis only CG3: untreated mice |
Weight of EDL and soleus muscles, soleus and EDL levels of AGEs, inflammation-related molecules, and activity of glyoxalase 1. | Propolis had no effect on MGO-induced loss of EDL muscle but tended to increase the weight of the soleus muscle regardless of MGO treatment. Propolis decreased muscular levels of AGEs, IL-1β, IL-6, TLR4 and enhanced the activity of glyoxalase 1. |
[38] |
| Dietary crude propolis (0.2% over 2 or 5 weeks) | HFD-induced muscle wasting in male C57BL/6 mice (4-weeks old) | EG: propolis + HFD CG1: HFD only CG2: untreated mice |
16S rRNA of gut microbiota, serum levels of LPS, triacylglycerols and glucose, and skeletal muscle levels of inflammatory cytokine TLR4 expression. | Propolis (5 weeks) significantly decreased serum triacylglycerols, glucose, circulating LPS and down-regulated the expression TLR4 and inflammatory cytokine in muscle. It countereacted the effect of HFD on gut microbiota. | [116] |
| Oral propolis water extract (50 mg/kg body weight/d/6 weeks) | 6-weeks old Sprague-Dawley rats | EG: propolis + eccentric exercise CG1: only eccentric exercise CG2: no treatment |
Blood levels of glucose and insulin, MDA, SOD, GPX, and CAT in the liver and in the tissue of the liver and the gastrocnemius muscle. | Serum levels of glucose and insulin were significantly lower in EG and CG1 than CG2. Glycogen level in skeletal muscle was higher in EG and CG1 than CG2. Skeletal muscle levels of MDA were lower in EG than CG1 and CG2. Liver levels of SOD as well as gastrocnemius muscle levels of SOD, GPX and CAT were higher in EG only. | [109] |
| Gavage naturally-enriched milk with PUFA and propolis polyphenols (PUFA/P-M: 5 mL/kg body weight /85 d) | 21-d old male Wistar rats | EG: HFD + PUFA/P-M CG1: HFD + water CG2: HFD + whole milk CG3: HFD + PUFA milk CG 4: standard chow + water N.B. All treatments were repeated in absence of HFD |
Weight gain, mass of internal organs and the soleus and gastrocnemius muscles, and glucose tolerance. | Among all treatments in obese rats, only PUFA/P-m increased gastrocnemius muscle mass (tended to increase soleus muscle mass) and mesenteric fat and tended to lower LDL levels. It decreased the size of adipocytes compared with all groups except PUFA milk with no effect on body weight. | [105] |
| Dietary propolis 4% (105 d) | Nile tilapia in net cages (males only) | EG: propolis rich diet CG: propolis free diet |
Muscle morphometry and myostatin gene expression. | Propolis diet had no effect on muscle growth or myostatin gene expression at 35, 70, and 105 d. | [117] |
| Dietary propolis (1, 2, 3 and 4 g/kg of feed/45 d) | Nile tilapia post-larvae and fingerlings in tanks | EG: propolis rich diet CG: propolis free diet |
Final weight, total and standard body length, survival, body composition, and intestinal villus height. | Propolis supplementation had no effect on weight, total and standard length, survival, and intestinal villus height. However, 2.6 g propolis/kg of feed significantly improved body protein deposition and body condition factor—an estimate of future growth. | [104] |
| Intraperitoneal CAPE (10 μM/kg 1 h before ischemia reperfusion) | Adult male Wistar rats undergoing ischemia reperfusion | EG: ischemia reperfusion + CAPE CG1: ischemia reperfusion CG2: sham |
Neutrophil infiltration, serum creatine kinase, serum and gastrocnemius muscle levels of protein carbonyl, xanthine oxidase, and adenosine deaminase. | CAPE reduced neutrophil infiltration and serum creatine kinase as well as protein carbonyl, xanthine oxidase, and adenosine deaminase levels in the blood and gastrocnemius muscle. | [102,103] |
| Gavage propolis (1 g/kg body weight/d/2 weeks) | Adult male Wistar rats with 2-week hind limb unloading (HU) | EG: HU rats + propolis CG1: normal rats + propolis CG2: normal rats CG3: untreated HU rats |
Soleus muscle weight, FCSA, myofiber number, apoptosis of endothelial cells, capillary to muscle fiber ratio, capillary number, luminal diameter, and capillary volume, levels of ROS, SOD-1, anti-angiogenic factors, and pro-angiogenic factors. | Propolis had no effect on soleus muscle weight or FCSA. However, the relative soleus muscle-to-body weight and the capillary to muscle fiber ratio of the soleus muscle were significantly higher in EG than in CG3. Propolis decreased the number of apoptotic endothelial cells, improved levels of SOD-1, ROS, and VEGF leading to increased capillary number, luminal diameter, and capillary volume in the EG to the levels of CG1 and CG2, which were all significantly different from CG3. | [110] |
| Gavage propolis (200-mg/kg body weight/d/28 d) | Adult female Wistar rats undergoing crush injuries of the sciatic nerve | EG: propolis CG1: curcumin CG2: methylprednisolone CG3: sham rats CG4: untreated rats with sciatic nerve injury |
Gastrocnemius muscle mass, motor function, nerve fiber myelination, and nerve conduction. | Propolis and curcumin significantly restored gastrocnemius muscle mass, improved walking, nerve fiber myelination, and motor conduction to the gastrocnemius muscle compared with CG4. | [113] |
| Dietary fresh monofloral bee pollen 5% or 10% (3 weeks) | Malnourished old male Wistar rats (22-month-old) | EG1 and EG2: refeeding diet + bee pollen 5% and 10%, respectively CG1: refeeding diet CG2: no treatment CG3: untreated normal weight rats |
Body weight and composition, muscle mass, muscle protein synthesis rate, plasma cytokines, mitochondrial enzyme activity, and mTOR/p70S6kinase/4eBP1 signaling. | Bee pollen restored visceral and subcutaneous adipose tissues and increased plantaris and gastrocnemius muscle mass. 10% pollen restored the levels of cytokines to normal, boosted muscle protein synthesis, and increased complex IV activity while both 5% and 10% increased the activity CS and the phosphorylation of mTOR/p70S6kinase/4eBP1 signaling. | [36] |
| Oral crude and processed monofloral Indian mustard bee pollen (100, 200, and 300 mg/kg body weight/4 weeks) | Adult male Wistar rats and Swiss albino mice | EG1: neat bee pollen + acute eccentric swimming EG2: processed bee pollen + acute eccentric swimming CG1: no treatment CG2: bee pollen only CG3: acute eccentric swimming + vehicle gum acacia |
Body weight, relative weight of the gastrocnemius muscle, SOD, GSH, MDA, NO, total protein content, lipid peroxidation, myostatin mRNA, β-actin, mitochondrial complex I, II, III, and IV enzyme activity. | Crude (300 mg/kg) and processed (200 and 300 mg/kg) bee pollen prevented myofiber fragmentation and restored body weight and the relative weight of the gastrocnemius muscle as well as mitochondrial complex-I, -II, -III, and -IV enzyme activity to normal (CG1 and CG2) compared with CG3. Both bee pollen treatments decreased MDA, NO, total protein content, lipid peroxidation, and myostatin and increased SOD and GSH in skeletal muscle. | [90] |
N.B. All studies were conducted in vivo unless otherwise indicated. pRJ: protease-treated royal jelly, No: number, SC: Satellite cells, EG: experimental group, CG: control group, min: minute, d: day, h: hour, IGF-1: Insulin growth factor 1, AKT: Serine/threonine protein kinase, AS160: AKT substrate of 160 kDa, BALB/c: Bagg albino, 10-HDA: 10-Hydroxy-decanoic acid, ROS: reactive oxygen species, HET: genetically heterogeneous mice, AST: aspartate aminotransferase, ALT: alanine aminotransferase, T-CHO: total cholesterol, TLR4: toll-like receptors 4, TG: triglyceride, HFD: high fat diet, LPS: lipopolysaccharide, HDL: high density lipoprotein, LDL: low density lipoprotein, HOMA-IR: homeostatic model assessment of insulin resistance, PUFA: polyunsaturated fatty acids, TNFR1: tumor necrosis factor receptor 1, HU: hind limb unloading, IKK: IκB kinase, DMSO: dimethyle sulfoxoide, AICAR: 5-aminoimidazole-4-carboxamide ribonucleoside, CAPE: caffeic acid phenethyl ester, AGEs: advanced glycation end products, MMP-12: metalloproteinase-12, MyoD: myogenic differentiation 1; VEGF: vascular endothelial growth factor, NF-κB: nuclear factor kappa B, MDA: malondialdehyde, SOD: superoxide dismutase, CAT: catalase, and GPX: glutathione peroxidase, LIF: leukemia inhibitory factor, CXCL-10: chemokine (C-X-C motif) ligand 10, CCL: C-C chemokine ligand, MCP-1: monocyte chemotactic protein-1, COX-2: cyclooxygenase-2, iNOS: inducible nitric oxide synthase, PARP: poly (ADP-ribose) polymerase, AMPK: adenosine monophosphate activated protein kinase, PI3K: phosphatidylinositol 3-kinase, IR: insulin receptor, GLUT4: glucose transporter 4, OGTT: Oral Glucose Tolerance Test, FCSA: fiber cross-sectional area, mTOR: mammalian target of rapamycin, p70S6kinase: P70 ribosomal proteins S6 kinase, 4eBP1: eukaryotic translation initiation 4E-binding protein 1, SOD: superoxide dismutase, GSH: glutathione, MDA: malonaldehyde, NO: nitric oxide, MGO: methylglyoxal, EDL: extensor digitorum longus, IL-6: interleukin-6, IL-1β: interleukin-1β, TLR4: toll-like receptor 4, CS: citrate synthase, β-HAD: β-hydroxyacyl coenzyme A dehydrogenase.