Multiple pathological fractures and muscle atrophy caused by a parathyroid carcinoma with postoperative hungry bone syndrome: A case report.

BACKGROUND: Parathyroid carcinoma (PC) is a rare endocrine malignancy causing pathological changes such as abnormal bone metabolism, elevated serum calcium, and impaired renal function, and uncontrollable hypercalcemia is the main cause of death in PC patients. The diagnosis of PC is challenging and relying on postoperative histopathology. Radical surgery at the first time is the only effective therapy to cure PC. Hungry bone syndrome (HBS) is a relatively uncommon complication of parathyroidectomy characterized by profound and prolonged hypocalcemia, timely electrolyte monitoring and alternative interventional protocols can prevent symptomatic hypocalcemia. CASE: A 57-year-old man presented with multiple pathological fractures and muscle atrophy as the main symptoms accompanied by bone pain, hypercalcemia, elevated parathyroid hormone (PTH), and an enlarged left-sided neck mass. After consultation of multidisciplinary team, he was treated conservatively with plaster bandage fixation and infusion of intravenous zoledronic acid; and then complete resection of parathyroid mass + removal of involved tissue structures + left thyroid and isthmus lobectomy + lymph node dissection in the VI region in left neck were performed. The postoperative histopathology suggested a diagnosis of parathyroid carcinoma. Calcium and fluid supplementation and oral levothyroxine tablets were given postoperatively. Unexpectedly, the patient's PTH level decreased rapidly at 24 h postoperative, and serum calcium and phosphorus decreased continuously, and he felt numb around perioral sites and fingertips, which considered to be postoperative HBS complicated by parathyroidectomy. Then, a large amount of calcium supplementation and vitamin D were given timely and the patient got better at 1 month postoperatively. At 9-month postoperative, his bone pain and fatigue were significantly relieved compared with before with calcium, phosphorus, and PTH levels at normal range. CONCLUSION: The possibility of parathyroid disease, particularly PC, should be considered in the presence of multiple pathological fractures, muscle atrophy, generalized bone pain, hypercalcemia, and clear neck mass. Radical resection of the tumor lesions at the first surgery is a key element affecting the prognosis of PC, and the effective management of preoperative hypercalcemia and postoperative HBS is also of great significance for improving prognosis.

Lactobacillus gasseri BNR17 Ameliorates Dexamethasone-Induced Muscle Loss in BALB/c Mice and C2C12 Myotubes.

This study aimed to investigate the effects and mechanism of Lactobacillus gasseri BNR17, a probiotic strain isolated from human breast milk, on dexamethasone-induced muscle loss in mice and cultured myotubes. BALB/c mice were intraperitoneally injected with dexamethasone, and orally administered L. gasseri BNR17 for 21 days. L. gasseri BNR17 treatment ameliorated dexamethasone-induced decline in muscle function, as evidenced by an increase in forelimb grip strength, treadmill running time, and rotarod retention time in both female and male mice. In addition, L. gasseri BNR17 treatment significantly increased the mass of the gastrocnemius and quadriceps muscles. Dual-energy X-ray absorptiometry showed a significant increase in lean body mass and a decrease in fat mass in both whole body and hind limb after treatment with L. gasseri BNR17. It was found that L. gasseri BNR17 treatment downregulated serum myostatin level and the protein degradation pathway composed of muscle-specific ubiquitin E3 ligases, MuRF1 and MAFbx, and their transcription factor FoxO3. In contrast, L. gasseri BNR17 treatment upregulated serum insulin-like growth factor-1 level and Akt-mTOR-p70S6K signaling pathway involved in protein synthesis in muscle. As a result, L. gasseri BNR17 treatment significantly increased the levels of major muscular proteins such as myosin heavy chain and myoblast determination protein 1. Consistent with in vivo results, L. gasseri BNR17 culture supernatant significantly ameliorated dexamethasone-induced C2C12 myotube atrophy in vitro. In conclusion, L. gasseri BNR17 ameliorates muscle loss by downregulating the protein degradation pathway and upregulating the protein synthesis pathway.

Astaxanthin Ameliorates Skeletal Muscle Atrophy in Mice With Cancer Cachexia.

Astaxanthin (AST) is a natural marine carotenoid with a variety of biological activities. This study aimed to demonstrate the possible mechanisms by which AST improves skeletal muscle atrophy in cancer cachexia. In this study, the effects of different doses of AST (30 mg/kg b.w., 60 mg/kg b.w. and 120 mg/kg b.w.) on skeletal muscle functions were explored in mice with cancer cachexia. The results showed that AST (30, 60 and 120 mg/kg b.w.) could effectively protect cachexia mice from body weight and skeletal muscle loss. AST dose-dependently ameliorated the decrease in myofibres cross-sectional area and increased the expression of myosin heavy chain (MHC). AST treatment decreased both the serum and muscle level of IL-6 but not TNF-α in C26 tumor-bearing cachexia mice. Moreover, AST alleviated skeletal muscle atrophy by decreasing the expression of two muscle-specific E3 ligases MAFBx and MuRF-1. AST improved mitochondrial function by downregulating the levels of muscle Fis1, LC3B and Bax, upregulating the levels of muscle Mfn2 and Bcl-2. In conclusion, our study show that AST might be expected to be a nutritional supplement for cancer cachexia patients.

Niacin supplementation attenuates the regression of three-dimensional capillary architecture in unloaded female rat skeletal muscle.

Inactivity can lead to muscle atrophy and capillary regression in skeletal muscle. Niacin (NA), known for inducing hypermetabolism, may help prevent this capillary regression. In this study involving adult female Sprague-Dawley rats, the animals were randomly assigned to one of four groups: control (CON), hindlimb unloading (HU), NA, and HU with NA supplementation (HU + NA). For a period of 2 weeks, the rats in the HU and HU + NA groups underwent HU, while those in the NA and HU + NA groups received NA (750 mg/kg) twice daily through oral administration. The results demonstrated that HU lowered capillary number, luminal diameter, and capillary volume, as well as decreased succinate dehydrogenase activity, slow fiber composition, and PGC-1α expression within the soleus muscle. However, NA supplementation prevented these alterations in capillary structure due to unloading by stimulating PGC-1α factors and inhibiting mitochondrial dysfunction. Therefore, NA supplementation could serve as a potential therapeutic approach for preserving the capillary network and mitochondrial metabolism of muscle fibers during periods of inactivity.

Identification of Peucedanum japonicum Thunb. extract components and their protective effects against dexamethasone-induced muscle atrophy.

BACKGROUND: Peucedanum japonicum Thunb. (PJ) is a vegetable widely consumed in East Asia and is known to have anticancer and anti-inflammatory effects. However, the effect of PJ on muscle atrophy remains elusive. PURPOSE: This study aimed to investigate the effect of PJ and its active compound on dexamethasone (DEX)-induced muscle atrophy. METHODS: We performed qualitative and quantitative analysis of PJ using ultra-performance liquid chromatography-mass spectrometry tandem mass spectrometry (UPLC-MS/MS) and high-performance liquid chromatography (HPLC), respectively. The efficacy of PJ and its main compound 4-caffeoylquinic acid (CQA) on muscle atrophy was evaluated in DEX-induced myotube atrophy and DEX-induced muscle atrophy in mouse myoblasts (C2C12) and C57BL/6 mice, in vitro and in vivo, respectively. RESULTS: The UPLC-MS/MS and HPLC data showed that the concentration of 4-CQA in PJ was 18.845 mg/g. PJ and 4-CQA treatments significantly inhibited DEX-induced myotube atrophy by decreasing protein synthesis and glucocorticoid translocation to the nucleus in C2C12 myotubes. In addition, PJ enhanced myogenesis by upregulating myogenin and myogenic differentiation 1 in C2C12 cells. PJ supplementation effectively increased muscle function and mass, downregulated atrogenes, and decreased proteasome activity in C57BL/6 mice. Additionally, PJ effectively decreased the nuclear translocation of forkhead transcription factor 3 alpha by inhibiting glucocorticoid receptor. CONCLUSION: Overall, PJ and its active compound 4-CQA alleviated skeletal muscle atrophy by inhibiting protein degradation. Hence, our findings present PJ as a potential novel pharmaceutical candidate for the treatment of muscle atrophy.

Exploring the Potential of Crassostrea nippona Hydrolysates as Dietary Supplements for Mitigating Dexamethasone-Induced Muscle Atrophy in C2C12 Cells.

Muscle atrophy is a detrimental and injurious condition that leads to reduced skeletal muscle mass and disruption of protein metabolism. Oyster (Crassostrea nippona) is a famous and commonly consumed shellfish in East Asia and has become a popular dietary choice worldwide. The current investigation evaluated the efficacy of C. nippona against muscle atrophy, which has become a severe health issue. Mammalian skeletal muscles are primarily responsible for efficient metabolism, energy consumption, and body movements. The proteins that regulate muscle hypertrophy and atrophy are involved in muscle growth. C. nippona extracts were enzymatically hydrolyzed using alcalase (AOH), flavourzyme (FOH), and protamex (POH) to evaluate their efficacy in mitigating dexamethasone-induced muscle damage in C2C12 cells in vitro. AOH exhibited notable cell proliferative abilities, promoting dose-dependent myotube formation. These results were further solidified by protein expression analysis. Western blot and gene expression analysis via RT-qPCR demonstrated that AOH downregulated MuRF-1, Atrogin, Smad 2/3, and Foxo-3a, while upregulating myogenin, MyoD, myosin heavy chain expression, and mTOR, key components of the ubiquitin-proteasome and mTOR signaling pathways. Finally, this study suggests that AOH holds promise for alleviating dexamethasone-induced muscle atrophy in C2C12 cells in vitro, offering insights for developing functional foods targeting conditions akin to sarcopenia.

Macamide, a component of maca (Lepidium meyenii Walp) lipophilic extract, enhances myogenic differentiation via AKT/p38 signaling and attenuates dexamethasone-induced muscle atrophy.

Maca (Lepidium meyenii) is a plant that grows in the central Andes region of Peru, and it has been reported to have various bioactive functions, such as improving or preventing osteoporosis, sexual dysfunction, and memory impairment. In this study, maca roots of various colors (yellow, red, or black) were extracted using different polar solvents (PE, HEX, or BuOH) to compare their effects on muscle differentiation. Among them, the red maca lipophilic extract, which showed the most effectiveness, was chosen for further investigation. Our results show that RMLE enhances muscle differentiation by inducing MyoD-E2A heterodimerization through the activation of the AKT/p38 pathway. Additionally, RMLE attenuated dexamethasone-induced muscle atrophy by inhibiting nuclear translocation of FoxO3a and expression of E3-ligase (MAFbx and MURF1) in vitro and in vivo. Therefore, based on these results suggest that lipophilic extract of maca, which can abundantly contain nonpolar compounds, macamides, can enhance the functional properties of maca in alleviating muscle homeostasis.

Cannabidiol protects C2C12 myotubes against cisplatin-induced atrophy by regulating oxidative stress.

Cancer and chemotherapy induce a severe loss of muscle mass (known as cachexia), which negatively impact cancer treatment and patient survival. The aim of the present study was to investigate whether cannabidiol (CBD) administration may potentially antagonize the effects of cisplatin in inducing muscle atrophy, using a model of myotubes in culture. Cisplatin treatment resulted in a reduction of myotube diameter (15.7 ± 0.3 vs. 22.2 ± 0.5 µm, P < 0.01) that was restored to control level with 5 µM CBD (20.1 ± 0.4 µM, P < 0.01). Protein homeostasis was severely altered with a ≈70% reduction in protein synthesis (P < 0.01) and a twofold increase in proteolysis (P < 0.05) in response to cisplatin. Both parameters were dose dependently restored by CBD cotreatment. Cisplatin treatment was associated with increased thiobarbituric acid reactive substances (TBARS) content (0.21 ± 0.03 to 0.48 ± 0.03 nmol/mg prot, P < 0.05), catalase activity (0.24 ± 0.01 vs. 0.13 ± 0.02 nmol/min/µg prot, P < 0.01), whereas CBD cotreatment normalized TBARS content to control values (0.22 ± 0.01 nmol/mg prot, P < 0.01) and reduced catalase activity (0.17 ± 0.01 nmol/min/µg prot, P < 0.05). These changes were associated with increased mRNA expression of GPX1, SOD1, SOD2, and CAT mRNA expression in response to cisplatin (P < 0.01), which was corrected by CBD cotreatment (P < 0.05). Finally, cisplatin treatment increased the mitochondrial protein content of NDUFB8, UQCRC2, COX4, and VDAC1 (involved in mitochondrial respiration and apoptosis), and CBD cotreatment restored their expression to control values. Altogether, our results demonstrated that CBD antagonize the cisplatin-induced C2C12 myotube atrophy and could be used as an adjuvant in the treatment of cancer cachexia to help maintain muscle mass and improve patient quality of life.NEW & NOTEWORTHY In an in vitro model, cisplatin treatment led to myotube atrophy associated with dysregulation of protein homeostasis and increased oxidative stress, resulting in increased apoptosis. Cotreatment with cannabidiol was able to prevent this phenotype by promoting protein homeostasis and reducing oxidative stress.

Effects of exercise, metformin, and combination treatments on type 2 diabetic mellitus-induced muscle atrophy in db/db mice: Crosstalk between autophagy and the proteasome

Both exercise and metformin are common effective clinical treatments of type 2 diabetic mellitus. This study investigated the functional role of exercise, metformin, and combination treatment on type 2 diabetic mellitus–induced muscle atrophy. In this experiment, a total of 10 BKS mice were set as the control group. A total of 40 BKS-db/db mice were randomly divided into the control group (db/db); the exercise intervention group (db/db + Ex), which ran on a treadmill at 7–12 m/min, 30–40 min/day, 5 days/week; the metformin administration group (db/db + Met), which was administered 300 mg/kg of metformin solution by gavage daily; and the exercise combined with metformin administration group (db/db + Ex + Met). After 8 weeks of intervention, their tibialis anterior muscles were removed. The levels of insulin signaling pathway proteins, ubiquitin proteasome, and autophagic lysosome–associated proteins were detected using western blot, the expression of MuRF1 and Atrogin-1 was detected using immunohistochemical staining, and the degradation of autophagosomes was detected using double-labeled immunofluorescence. The db/db mice exhibited reduced insulin sensitivity and inhibition of the autophagic–lysosome system, the ubiquitin–proteasome system was activated, and protein degradation was exacerbated, leading to skeletal muscle atrophy. Exercise and metformin and their combined interventions can increase insulin sensitivity, whereas exercise alone showed more effective in inhibiting the ubiquitin–proteasome system, improving autophagy levels, and alleviating skeletal muscle atrophy. Compared with metformin, exercise demonstrated superior improvement of muscle atrophy by promoting the synthesis and degradation of autophagy through the AMPK/ULK1 pathway. However, the combination treatment exhibits no synergistic effect on muscle atrophy. (AU)

Ursolic acid alleviates cancer cachexia by inhibiting STAT3 signaling pathways in C2C12 myotube and CT26 tumor-bearing mouse model.

Cancer cachexia, a multi-organ disorder resulting from tumor and immune system interactions, prominently features muscle wasting and affects the survival of patients with cancer. Ursolic acid (UA) is known for its antioxidant, anti-inflammatory, and anticancer properties. However, its impact on cancer cachexia remains unexplored. This study aimed to assess the efficacy of UA in addressing muscle atrophy and organ dysfunction in cancer cachexia and reveal the mechanisms involved. UA dose-dependently ameliorated C2C12 myotube atrophy. Mechanistically, it inhibited the expression of muscle-specific RING finger containing protein 1 (MURF1) and the phosphorylation of signal transducer and activator of transcription 3 (STAT3), and upregulated the mRNA or protein levels of myogenic differentiation antigen and myogenin in cultured C2C12 myotubes treated with conditioned medium. In vivo, UA protected CT26 tumor-bearing mice against loss of body weight, as well as increased skeletal muscle and epididymal fat without affecting tumor growth. Additionally, UA increased food intake in CT26 tumor-bearing mice. The mRNA expression of tumor necrosis-α and interleukin 6 was significantly downregulated in the intestine, gastrocnemius, and heart tissues following 38 d UA administration. UA treatment reversed the levels of myocardial function indicators, including creatine kinase, creatine kinase-MB, lactate dehydrogenase, car-dial troponin T, and glutathione. Finally, UA treatment significantly inhibited the expression of MURF1, the phosphorylation of nuclear factor kappa-B p65, and STAT3 in the gastrocnemius muscle and heart tissues of cachexic mice. Our findings suggest that UA is a promising natural compound for developing dietary supplements for cancer cachexia therapy owing to its anti-catabolic effects.

Gromwell (Lithospermum erythrorhizon) Attenuates High-Fat-Induced Skeletal Muscle Wasting by Increasing Protein Synthesis and Mitochondrial Biogenesis.

Gromwell (Lithospermum erythrorhizon, LE) can mitigate obesity-induced skeletal muscle atrophy in C2C12 myotubes and high-fat diet (HFD)-induced obese mice. The purpose of this study was to investigate the anti-skeletal muscle atrophy effects of LE and the underlying molecular mechanism. C2C12 myotubes were pretreated with LE or shikonin, and active component of LE, for 24 h and then treated with 500 µM palmitic acid (PA) for an additional 24 h. Additionally, mice were fed a HFD for 8 weeks to induced obesity, and then fed either the same diet or a version containing 0.25% LE for 10 weeks. LE attenuated PA-induced myotubes atrophy in differentiated C2C12 myotubes. The supplementation of LE to obese mice significantly increased skeletal muscle weight, lean body mass, muscle strength, and exercise performance compared with those in the HFD group. LE supplementation not only suppressed obesity-induced skeletal muscle lipid accumulation, but also downregulated TNF-α and atrophic genes. LE increased protein synthesis in the skeletal muscle via the mTOR pathway. We observed LE induced increase of mitochondrial biogenesis and upregulation of oxidative phosphorylation related genes in the skeletal muscles. Furthermore, LE increased the expression of peroxisome proliferator-activated receptor-gamma coactivator-1 alpha and the phosphorylation of adenosine monophosphate-activated protein kinase. Collectively, LE may be useful in ameliorating the detrimental effects of obesity-induced skeletal muscle atrophy through the increase of protein synthesis and mitochondrial biogenesis of skeletal muscle.

Steamed Ginseng Berry Powder Ameliorates Skeletal Muscle Atrophy via Myogenic Effects.

Sarcopenia is an age-related loss of muscle mass and function for which there is no approved pharmacological treatment. We tested direct efficacy by evaluating grip strength improvement in a sarcopenia mouse model rather than drug screening, which inhibits specific molecular mechanisms. Various physiological functions of ginseng berries are beneficial to the human body. The present study aimed to evaluate the efficacy and safety of steamed ginseng berry powder (SGBP). SGBP administration increased myotube diameter and suppressed the mRNA expression of sarcopenia-inducing molecules. SGBP also reduced the levels of inflammatory transcription factors and cytokines that are known to induce sarcopenia. Oral administration of SGBP improved muscle mass and physical performance in a mouse model of sarcopenia. In summary, our data suggest that SGBP is a novel therapeutic candidate for the amelioration of muscle weakness, including sarcopenia.

Ashwagandha Ethanol Extract Attenuates Sarcopenia-Related Muscle Atrophy in Aged Mice.

The investigation focused on the impact of Withania somnifera (ashwagandha) extract (WSE) on age-related mechanisms affecting skeletal muscle sarcopenia-related muscle atrophy in aged mice. Beyond evaluating muscular aspects, the study explored chronic low-grade inflammation, muscle regeneration, and mitochondrial biogenesis. WSE administration, in comparison to the control group, demonstrated no significant differences in body weight, diet, or water intake, affirming its safety profile. Notably, WSE exhibited a propensity to reduce epidermal and abdominal fat while significantly increasing muscle mass at a dosage of 200 mg/kg. The muscle-to-fat ratio, adjusted for body weight, increased across all treatment groups. WSE administration led to a reduction in the pro-inflammatory cytokines TNF-α and IL-1ß, mitigating inflammation-associated muscle atrophy. In a 12-month-old mouse model equivalent to a 50-year-old human, WSE effectively preserved muscle strength, stabilized grip strength, and increased muscle tissue weight. Positive effects were observed in running performance and endurance. Mechanistically, WSE balanced muscle protein synthesis/degradation, promoted fiber differentiation, and enhanced mitochondrial biogenesis through the IGF-1/Akt/mTOR pathway. This study provides compelling evidence for the anti-sarcopenic effects of WSE, positioning it as a promising candidate for preventing sarcopenia pending further clinical validation.

Dietary supplementation with inulin improves burn-induced skeletal muscle atrophy by regulating gut microbiota disorders.

Inulin, as a prebiotic, could modulate the gut microbiota. Burn injury leads to gut microbiota disorders and skeletal muscle catabolism. Therefore, whether inulin can improve burn-induced muscle atrophy by regulating microbiota disorders remains unknown. This study aimed to clarify that inulin intake alleviates gut microbiota disorders and skeletal muscle atrophy in burned rats. Rats were divided into the sham group, burn group, prebiotic inulin intervention group, and pseudo-aseptic validation group. A 30% total body surface area (TBSA) third-degree burn wound on dorsal skin was evaluated in all groups except the sham group. Animals in the intervention group received 7 g/L inulin. Animals in the validation group received antibiotic cocktail and inulin treatment. In our study inulin intervention could significantly alleviate the burn-induced skeletal muscle mass decrease and skeletal myoblast cell apoptosis. Inulin intake increased the abundances of Firmicutes and Actinobacteria but decreased the abundance of Proteobacteria. The biosynthesis of amino acids was the most meaningful metabolic pathway distinguishing the inulin intervention group from the burn group, and further mechanistic studies have shown that inulin can promote the phosphorylation of the myogenesis-related proteins PI3K, AKT and P70S6K and activate PI3K/AKT signaling for protein synthesis. In conclusion, inulin alleviated burn induced muscle atrophy through PI3K/AKT signaling and regulated gut microbiota dysbiosis.

Protective Effect of Whole Wheat on Muscle Atrophy in C2C12 Cells via Akt/FoxO1 Signaling Pathways.

Skeletal muscles are important for body movement, postural maintenance, and energy metabolism. Muscle atrophy is caused by various factors, including lack of exercise, age, genetics, and malnutrition, leading to the loss of muscle mass. The Akt/FoxO signaling pathway plays a key role in the regulation of muscle protein synthesis and degradation. Whole wheat contains functional ingredients that may indirectly contribute to muscle health and function and can help prevent or slow the progression of muscle atrophy. In this study, the protective effects of three wheat cultivars (Seodun, Ol, and Shinmichal 1) against hydrogen peroxide-induced muscle atrophy in C2C12 cells were investigated. We found that whole-wheat treatment reduced reactive oxygen species production, prevented glutathione depletion, and increased myotube diameter, thereby reducing muscle atrophy by activating myoblast differentiation. Generally, "Shinmichal 1" exhibited the highest activation of the Akt/FoxO signaling pathway. In contrast, "Seodun" showed similar or slightly higher activities than those of the H2O2-treated only group. In conclusion, whole wheat exerts a protective effect against muscle atrophy by activating the Akt/FoxO signaling pathway. This study indicates that whole wheat may help prevent muscle atrophy.

Effects of amino acid supplementation on muscle mass, muscle performance and functional capacity in subjects undergoing total knee arthroplasty: a systematic review of randomized clinical trials.

The aim of the present study was to summarize the effectiveness of amino acid supplementation on muscle strength, muscle volume, and functional capacity in patients undergoing total knee arthroplasty. For this, in November 2022, a search was carried out in the PubMed, Cochrane Library, and EMBASE databases, identifying a total of 2182 documents, of which only 4 were included in the present review. The included studies had 148 participants (47 men and 101 women), with a minimum age of 53 and a maximum of 92 years, and supplementation times of 13 to 30 days (1 to 3 times a day). For the results, in relation to muscle performance, when comparing the control and experimental groups, greater muscle atrophy was observed in the pre- and post-moments of the control group, in relation to the experimental group. In addition, studies suggest a good tendency for muscle mass gain, and improvement in the functional capacities of patients who used supplementation. Therefore, the use of amino acids after TKA surgery reduces muscle atrophy, which preserves muscle mass and leads to better performance in tests of strength and functional capacity, when compared to the use of a placebo.

Oral glutamine supplementation relieves muscle loss in immobilized rats, altering p38MAPK and FOXO3a signaling pathways.

BACKGROUND: Skeletal muscle synthesizes, stores, and releases body L-glutamine (GLN). Muscle atrophy due to disabling diseases triggers the activation of proteolytic and pro-apoptotic cell signaling, thus impairing the body's capacity to manage GLN content. This situation has a poor therapeutic prognosis. OBJECTIVE: Evaluating if oral GLN supplementation can attenuate muscle wasting mediated by elevated plasma cortisol and activation of caspase-3, p38MAPK, and FOXO3a signaling pathways in soleus and gastrocnemius muscles of rats submitted to 14-day bilateral hindlimbs immobilization. METHODS: Animals were randomly distributed into six groups: non-immobilized rats (Control), control orally supplemented with GLN (1 g kg-1) in solution with L-alanine (ALA: 0.61 g kg-1; GLN+ALA), control orally supplemented with dipeptide L-alanyl-L-glutamine (DIP; 1.49 g kg-1), hindlimbs immobilized rats (IMOB), IMOB orally GLN+ALA supplemented (GLN+ALA-IMOB), and IMOB orally DIP supplemented (DIP-IMOB). Plasma and muscle GLN concentration, plasma cortisol level, muscle caspase-3 activity, muscle p38MAPK and FOXO3a protein content (total and phosphorylated forms), and muscle cross-sectional area (CSA) were measured. RESULTS: Compared to controls, IMOB rats presented: a) increased plasma cortisol levels; b) decreased plasma and muscle GLN concentration; c) increased muscle caspase-3 activity; d) increased total and phosphorylated p38MAPK protein content; e) increased FOXO3a and decreased phosphorylated FOXO3a protein content; f) reduced muscle weight and CSA befitting to atrophy. Oral supplementation with GLN+ALA and DIP was able to significantly attenuate these effects. CONCLUSIONS: These findings attest that oral GLN supplementation in GLN+ALA solution or DIP forms attenuates rats' skeletal muscle mass wasting caused by disuse-mediated muscle atrophy.

Fuzhuan brick tea extract ameliorates obesity-induced skeletal muscle atrophy by alleviating mitochondrial dysfunction in mice.

Fuzhuan brick tea (FBT) is a post-fermented tea fermented by the fungus Eurotium cristatum and is mainly produced in Hunan Province, China. Our previous study revealed that FBT extract prevents obesity by increasing energy expenditure and mitochondrial content in mice. Therefore, in this study, we hypothesized that FBT extract could be effective in alleviating obesity-induced muscle atrophy by addressing mitochondrial dysfunction, and aimed to explore the underlying molecular mechanism of FBT extract in high-fat diet-induced obese mice. FBT extract increased skeletal muscle weight and size, myosin heavy chain isoforms, and muscle performance in obese mice. Additionally, FBT extract reduced obesity-induced intramuscular lipids, skeletal muscle inflammation, and the expression of skeletal muscle atrophy markers, and increased the expression of fibronectin type III domain-containing protein 5 in skeletal muscles. Obesity-induced skeletal muscle mitochondrial dysfunction was improved by FBT extract as analyzed through mitochondrial morphology, fatty acid oxidation, respiratory chain complexes, and mitochondrial dynamics and biogenesis. Epigallocatechin, a major bioactive compound in FBT extract, attenuated palmitic acid-induced muscle atrophy by regulating mitochondrial functions in C2C12 cells. In conclusion, FBT extract may prevent obesity-induced muscle atrophy by alleviating mitochondrial dysfunction in mice.

Electroacupuncture Promotes Skeletal Muscle Myogenic Differentiation and Protein Synthesis by Reducing Let-7c-5p Levels.

Objective: Acupuncture with low-frequency electrical stimulation (Acu-LFES) can attenuate muscle atrophy. Previous studies have found that Acu-LFES reduces the let-7 family in serum exosomes. This study explored the effects of let-7c-5p in chronic kidney disease (CKD) muscle atrophy. Methods: A total of 24 mice were randomly divided into control group, Acu-LFES group, CKD group, and CKD/Acu-LFES group (n = 6/group). The 5/6 nephrectomy was performed to establish the CKD model in mice. After 20 weeks, the Acu-LFES group and CKD/Acu-LFES group were treated with electroacupuncture at the "Zu San Li" and "Yang Ling Quan" bilaterally points for 15 minutes once. Surface sensing of translation (SUnSET), Reverse Transcription-quantitative PCR(RT-qPCR), immunofluorescence staining, and Western blot were performed to examine each group's state of protein production and myogenic differentiation. we knocked down or exogenously expressed let-7c-5p in C2C12 myoblast, RT-qPCR, and Western blot were performed to examine protein synthesis and myogenic differentiation. Results: The protein expressions of MyoD and Myogenin (MyoG) were decreased in the CKD group (P = .029 and P = .026) concomitant with a decrease in the muscle fiber cross-sectional area. Acu-LFES prevented muscle atrophy in CKD mice. The protein expressions of MyoD and MyoG were increased in the CKD/Acu-LFES group (P = .006 and P = .001). In muscle of CKD mice, IGF1, IGF1R, IRS1, phosphorylated mTOR and P70S6K proteins were decreased compared with control muscle (P = .001, P = .007, P < .001, P < .001 and P < .001), whereas atrogin-1/MAFbx and MuRF1 were dramatically increased (P < .001). Acu-LFES reversed these phenomena, indicating IGF1/mTOR signaling pathway was induced to promote muscle protein synthesis and myogenic differentiation. Meanwhile, Acu-LFES caused a decrease of let-7c-5p in skeletal muscle of CKD mice (P = .034). Inhibiting let-7c-5p promoted C2C12 myogenic differentiation (P = .002 and P = .001) and increased IGF1, IGF1R, IRS1 levels while upregulating mTOR and P70S6K phosphorylation (P < .001, P = .002, P = .009, P < .001 and P = .007). It is interesting to observe that the abundance of atrogin-1/MAFbx and MuRF-1 was unaffected by let-7c-5p (P > .05). Conclusions: Acu-LFES-reduced expression of let-7c-5p can ameliorate CKD-induced skeletal muscle atrophy by upregulating the IGF1/mTOR signaling pathway, which enhances skeletal muscle protein synthesis and myogenic differentiation. Let-7c-5p may be a potential regulator for the treatment of muscle atrophy.

Jakyak-gamcho-tang, a decoction of Paeoniae Radix and Glycyrrhizae Radix et Rhizoma, ameliorates dexamethasone-induced muscle atrophy and muscle dysfunction.

BACKGROUND: Although chronic treatment with glucocorticoids, such as dexamethasone, is frequently associated with muscle atrophy, effective and safe therapeutics for treating muscle atrophy remain elusive. Jakyak-gamcho-tang (JGT), a decoction of Paeoniae Radix and Glycyrrhizae Radix et Rhizoma, has long been used to relieve muscle tension and control muscle cramp-related pain. However, the effects of JGT on glucocorticoid-induced muscle atrophy are yet to be comprehensively clarified. PURPOSE: The objective of the current study was to validate the protective effect of JGT in dexamethasone-induced muscle atrophy models and elucidate its underlying mechanism through integrated in silico - in vitro - in vivo studies. STUDY DESIGN AND METHODS: Differential gene expression was preliminarily analyzed using the RNA-seq data to determine the effects of JGT on C2C12 myotubes. The protective effects of JGT were further validated in dexamethasone-treated C2C12 myotubes by assessing cell viability, myotube integrity, and mitochondrial function or in C57BL/6 N male mice with dexamethasone-induced muscle atrophy by evaluating muscle mass and physical performance. Transcriptomic pathway analysis was also performed to elucidate the underlying mechanism. RESULTS: Based on preliminary gene set enrichment analysis using the RNA-seq data, JGT regulated various pathways related to muscle differentiation and regeneration. Dexamethasone-treated C2C12 myotubes and muscle tissues of atrophic mice displayed substantial muscle protein degradation and muscle loss, respectively, which was efficiently alleviated by JGT treatment. Importantly, JGT-mediated protective effects were associated with observations such as preservation of mitochondrial function, upregulation of myogenic signaling pathways, including protein kinase B/mammalian target of rapamycin/forkhead box O3, inhibition of ubiquitin-mediated muscle protein breakdown, and downregulation of inflammatory and apoptotic pathways induced by dexamethasone. CONCLUSION: To the best of our knowledge, this is the first report to demonstrate that JGT could be a potential pharmaceutical candidate to prevent muscle atrophy induced by chronic glucocorticoid treatment, highlighting its known effects for relieving muscle spasms and pain. Moreover, transcriptomic pathway analysis can be employed as an efficient in silico tool to predict novel pharmacological candidates and elucidate molecular mechanisms underlying the effects of herbal medications comprising diverse biologically active ingredients.