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Background: The gut microbiome and fecal metabolites have been found to influence sarcopenia, but whether there are potential bacteria that can alleviate sarcopenia has been under-investigated, and the molecular mechanism remains unclear., Methods: To investigate the relationships between the gut microbiome, fecal metabolites and sarcopenia, subjects were selected from observational multi-ethnic study conducted in Western China. Sarcopenia was diagnosed according to the criteria of the Asian Working Group for Sarcopenia 2014. The gut microbiome was profiled by shotgun metagenomic sequencing. Untargeted metabolomic analysis was performed to analyse the differences in fecal metabolites. We investigated bacterium with the greatest relative abundance difference between healthy individuals and sarcopenia patients, and the differences in metabolites associated with the bacteria, to verify its effects on muscle mass and function in a mouse model., Results: The study included 283 participants (68.90% females, mean age: 66.66 years old) with and without sarcopenia (141 and 142 participants, respectively) and from the Han (98 participants), Zang (88 participants) and Qiang (97 participants) ethnic groups. This showed an overall reduction (15.03% vs. 20.77%, P = 0.01) of Prevotella copri between the sarcopenia and non-sarcopenia subjects across the three ethnic groups. Functional characterization of the differential bacteria showed enrichment (odds ratio = 15.97, P = 0.0068) in branched chain amino acid (BCAA) metabolism in non-sarcopenia group. A total of 13 BCAA and their derivatives have relatively low levels in sarcopenia. In the in vivo experiment, we found that the blood BCAA level was higher in the mice gavaged with live P. copri (LPC) (P < 0.001). The LPC mice had significantly longer wire and grid hanging time (P < 0.02), longer time on rotor (P = 0.0001) and larger grip strength (P < 0.0001), indicating better muscle function. The weight of gastrocnemius mass and rectus femoris mass (P < 0.05) was higher in LPC mice. The micro-computed tomography showed a larger leg area (P = 0.0031), and a small animal analyser showed a higher lean mass ratio in LPC mice (P = 0.0157), indicating higher muscle mass., Conclusions: The results indicated that there were lower levels of both P. copri and BCAA in sarcopenia individuals. In vivo experiments, gavage with LPC could attenuate muscle mass and function decline, indicating alleviating sarcopenia. This suggested that P. copri may play a therapeutic potential role in the management of sarcopenia., (© 2023 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC.)

Sarcopenia is a progressive muscle disease characterized by the loss of skeletal muscle mass, strength, function, and physical performance. Since the disease code was assigned, attention has been focused on natural products that can protect against muscle atrophy. Cibotium barometz (Cibotium Rhizome) has been used as an herbal medicine for the treatment of bone or joint diseases in Asian countries. However, no studies have identified the mechanism of action of Cibotium Rhizome on muscle atrophy related to sarcopenia at the site of myotubes. The aim of this study was to investigate the improvement effect of the ethanol extract of Cibotium Rhizome (ECR) on dexamethasone-induced muscle atrophy in an in vitro cell model, i.e., the C2C12 myotubes. High-performance liquid chromatography was performed to examine the phytochemicals in ECR. Seven peaks in the ECR were identified, corresponding to the following compounds: protocatechuic acid, (+)-catechin hydrate, p -coumaric acid, ellagic acid, chlorogenic acid, caffeic acid, and ferulic acid. In atrophy-like conditions induced by 100 μM dexamethasone for 24 h in C2C12, ECR increased the expression of the myosin heavy chain, p-Akt, the p-mammalian target of rapamycin (mTOR), p-p70S6K, and repressed the expression of regulated in development and DNA damage responses 1 (REDD1), kruppel-like factor 15 (KLF 15), muscle atrophy F-box, and muscle-specific RING finger protein-1 in C2C12. In addition, ECR alleviated dexamethasone-induced muscle atrophy by repressing REDD1 and KLF15 transcription in C2C12 myotubes, indicating the need for further studies to provide a scientific basis for the development of useful therapeutic agents using ECR to alleviate the effects of skeletal muscle atrophy or sarcopenia.

Aging is a complex biological process which can be associated with skeletal muscle degradation leading to sarcopenia. The aim of this study consisted i) to determine the oxidative and inflammatory status of sarcopenic patients and ii) to clarify the impact of oxidative stress on myoblasts and myotubes. To this end, various biomarkers of inflammation (C-reactive protein (CRP), TNF-α, IL-6, IL-8, leukotriene B4 (LTB4)) and oxidative stress (malondialdehyde, conjugated dienes, carbonylated proteins and antioxidant enzymes: catalase, superoxide dismutase, glutathione peroxidase) as well as oxidized derivatives of cholesterol formed by cholesterol autoxidation (7-ketocholesterol, 7β-hydroxycholesterol), were analyzed. Apelin, a myokine which contributes to muscle strength, was also quantified. To this end, a case-control study was conducted to evaluate the RedOx and inflammatory status in 45 elderly subjects (23 non-sarcopenic; 22 sarcopenic) from 65 years old and higher. SARCopenia-Formular (SARC-F) and Timed Up and Go (TUG) tests were used to distinguish between sarcopenic and non-sarcopenic subjects. By using red blood cells, plasma and/or serum, we observed in sarcopenic patients an increased activity of major antioxidant enzymes (superoxide dismutase, glutathione peroxidase, catalase) associated with lipid peroxidation and protein carbonylation (increased level of malondialdehyde, conjugated dienes and carbonylated proteins). Higher levels of 7-ketocholesterol and 7β-hydroxycholesterol were also observed in the plasma of sarcopenic patients. Significant differences were only observed with 7β-hydroxycholesterol. In sarcopenic patients comparatively to non-sarcopenic subjects, significant increase of CRP, LTB4 and apelin were observed whereas similar levels of TNF-α, IL-6 and IL-8 were found. The increased plasma level of 7-ketocholesterol and 7β-hydroxycholesterol in sarcopenic patients led us to study the cytotoxic effect of these oxysterols on undifferentiated (myoblasts) and differentiated (myotubes) murine C2C12 cells. With the fluorescein diacetate and sulforhodamine 101 assays, an induction of cell death was observed both on undifferentiated and differentiated cells: the cytotoxic effects were less pronounced with 7-ketocholesterol. In addition, IL-6 secretion was never detected whatever the culture conditions, TNF-α secretion was significantly increased on undifferentiated and differentiated C2C12 cells treated with 7-ketocholesterol- and 7β-hydroxycholesterol, and IL-8 secretion was increased on differentiated cells. 7-ketocholesterol- and 7β-hydroxycholesterol-induced cell death was strongly attenuated by α-tocopherol and Pistacia lentiscus L. seed oil both on myoblasts and/or myotubes. TNF-α and/or IL-8 secretions were reduced by α-tocopherol and Pistacia lentiscus L. seed oil. Our data support the hypothesis that the enhancement of oxidative stress observed in sarcopenic patients could contribute, especially via 7β-hydroxycholesterol, to skeletal muscle atrophy and inflammation via cytotoxic effects on myoblasts and myotubes. These data bring new elements to understand the pathophysiology of sarcopenia and open new perspectives for the treatment of this frequent age-related disease., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2023. Published by Elsevier Ltd.)

An association between the loss of skeletal muscle mass and obesity in the geriatric population has been identified as a disease known as sarcopenic obesity. Therefore, therapeutic/preventive interventions are needed to ameliorate sarcopenia. The present study investigates the effect of azilsartan (AZL) on skeletal muscle loss in High-Fat Diet (HFD)-induced sarcopenic obese (SO) rats. Four- and fourteen-months male Sprague Dawley rats were used and randomized in control and azilsartan treatment. 14 months animals were fed with HFD for four months and labeled as HFD-fed SO rats. Young & old rats received 0.5% carboxymethyl cellulose as a vehicle/AZL (8 mg/kg, per oral) treatment for six weeks. Grip strength and body composition analysis were performed after the last dose of AZL. Serum and gastrocnemius (GN)muscles were collected after animal sacrifice. AZL treatment significantly increased lean muscle mass, grip strength, myofibrillar protein, and antioxidant (superoxide dismutase & nitric oxide) levels in SO rats. AZL also restored the muscle biomarkers (creatine kinase, myostatin & testosterone), and insulin levels. AZL improves cellular, and ultracellular muscle structure and prevents type I to type II myofiber transitions in SO rats. Further, immunohistochemistry results showed increased expressions of pAkt and reduced expression of MuRF-1 and TNF-α exhibiting that AZL intervention could decrease protein degradation in SO rats. In conclusion, present results showed that AZL significantly increased lean mass, and restored muscle biomarkers, and muscle architecture. Taken together, the aforementioned findings suggest that azilsartan could be a possible therapeutic approach to reduce muscle wasting in sarcopenic obesity., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objective: To determine the effectiveness of whey protein (WP) supplementation during resistance exercise training (RET) vs. RET with or without placebo supplementation on skeletal muscle mass, strength, and physical performance in older people with Sarcopenia., Methods: Electronic searches in the PubMed, Embase, Scopus, Web of Science, LILACS, SPORTDiscus, Epistemonikos, and CINAHL databases were performed until 20 January 2023. Randomized clinical trials conducted on sarcopenic adults aged 60 or older were included. The studies had to compare the effectiveness of the addition of supplements based on concentrated, isolated, or hydrolyzed whey protein during RET and compare it with RET with or without placebo supplementation on skeletal muscle mass and strength changes. The study selection process, data extraction, and risk of bias assessment were carried out by two independent reviewers., Results: Seven randomized clinical trials (591 participants) were included, and five of them provided data for quantitative synthesis. The overall pooled standardized mean difference (SMD) estimate showed a small effect size in favor of RET plus WP for skeletal muscle mass according to appendicular muscle index, with statistically significant differences compared with RET with or without the placebo group (SMD = 0.24; 95% CI, 0.05 to 0.42; p = 0.01; I 2 = 0%, p = 0.42). The overall pooled mean difference (MD) estimate showed a significant difference of +2.31 kg (MD = 2.31 kg; 95% CI, 0.01 to 4.6; p = 0.05; I 2 = 81%, p < 0.001) in handgrip strength in the RET plus WP group compared with the RET group with or without placebo. The narrative synthesis revealed discordance between the results of the studies on physical performance., Conclusions: WP supplementation during RET is more effective in increasing handgrip strength and skeletal muscle mass in older people with Sarcopenia compared with RET with or without placebo supplementation. However, the effect sizes were small, and the MD did not exceed the minimally important clinical difference. The quality of the evidence was low to very low according, to the GRADE approach. Further research is needed in this field.

Oxidative stress, inflammation, mitochondrial dysfunction, reduced protein synthesis, and increased proteolysis are all critical factors in the process of muscle atrophy. In particular, oxidative stress is the key factor that triggers skeletal muscle atrophy. It is activated in the early stages of muscle atrophy and can be regulated by various factors. The mechanisms of oxidative stress in the development of muscle atrophy have not been completely elucidated. This review provides an overview of the sources of oxidative stress in skeletal muscle and the correlation of oxidative stress with inflammation, mitochondrial dysfunction, autophagy, protein synthesis, proteolysis, and muscle regeneration in muscle atrophy. Additionally, the role of oxidative stress in skeletal muscle atrophy caused by several pathological conditions, including denervation, unloading, chronic inflammatory diseases (diabetes mellitus, chronic kidney disease, chronic heart failure, and chronic obstructive pulmonary disease), sarcopenia, hereditary neuromuscular diseases (spinal muscular atrophy, amyotrophic lateral sclerosis, and Duchenne muscular dystrophy), and cancer cachexia, have been discussed. Finally, this review proposes the alleviation oxidative stress using antioxidants, Chinese herbal extracts, stem cell and extracellular vesicles as a promising therapeutic strategy for muscle atrophy. This review will aid in the development of novel therapeutic strategies and drugs for muscle atrophy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Sarcopenia, the age-related loss of muscle strength and mass or quality, is a common condition with major adverse consequences. Although the pathophysiology is incompletely understood, there are common mechanisms between sarcopenia and the phenomenon of accelerated ageing seen in diabetes mellitus. Drugs currently used to treat type 2 diabetes mellitus may have mechanisms of action that are relevant to the prevention and treatment of sarcopenia, for those with type 2 diabetes and those without diabetes. This review summarises shared pathophysiology between sarcopenia and diabetes mellitus, including the effects of advanced glycation end products, mitochondrial dysfunction, chronic inflammation and changes to the insulin signalling pathway. Cellular and animal models have generated intriguing, albeit mixed, evidence that supports possible beneficial effects on skeletal muscle function for some classes of drugs used to treat diabetes, including metformin and SGLT2 inhibitors. Most human observational and intervention evidence for the effects of these drugs has been derived from populations with type 2 diabetes mellitus, and there is a need for intervention studies for older people with, and at risk of, sarcopenia to further investigate the balance of benefit and risk in these target populations. Not all diabetes treatments will be safe to use in those without diabetes because of variable side effects across classes. However, some agents [including glucagon-like peptide (GLP)-1 receptor agonists and SGLT2 inhibitors] have already demonstrated benefits in populations without diabetes, and it is these agents, along with metformin, that hold out the most promise for further investigation in sarcopenia., (© 2023. The Author(s).)

Sex differences in muscle aging are poorly understood, but could be crucial for the optimization of sarcopenia-related interventions. To gain insight into potential sex differences in muscle aging, we recruited young (23 ± 2 years, 13 males and 13 females) and old (80 ± 3.5 years, 28 males and 26 females) participants. Males and females in both groups were highly matched, and vastus lateralis muscle parameters of old versus young participants were compared for each sex separately, focusing on gene expression. The overall gene expression profiles separated the sexes, but similar gene expression patterns separated old from young participants in males and females. Genes were indeed regulated in the same direction in both sexes during aging; however, the magnitude of differential expression was sex specific. In males, oxidative phosphorylation was the top-ranked differentially expressed process, and in females, this was cell growth mediated by AKT signaling. Findings from RNA-seq data were studied in greater detail using alternative approaches. In addition, we confirmed our data using publicly available data from three independent human studies. In conclusion, top-ranked pathways differ between males and females, but were present and altered in the same direction in both sexes. We conclude that the same processes are associated with skeletal muscle aging in males and females, but the differential expression of those processes in old vs. young participants is sex specific., (© 2023. The Author(s).)

Sarcopenia, a progressive disease characterized by a decline in muscle strength, quality, and mass, affects aging population worldwide, leading to increased morbidity and mortality. Besides resistance exercise, various nutritional strategies, including omega-3 polyunsaturated fatty acid (n-3 PUFA) supplementation, have been sought to prevent this condition. This narrative review summarizes the current evidence on the effect and mechanism of n-3 PUFA on musculoskeletal health. Despite conflicting evidence, n-3 PUFA is suggested to benefit muscle mass and volume, with more evident effects with higher supplementation dose (>2 g/day). n-3 PUFA supplementation likely improves handgrip and quadriceps strength in the elderly. Improved muscle functions, measured by walking speed and time-up-to-go test, are also observed, especially with longer duration of supplementation (>6 months), although the changes are small and unlikely to be clinically meaningful. Lastly, n-3 PUFA supplementation may positively affect muscle protein synthesis response to anabolic stimuli, alleviating age-related anabolic resistance. Proposed mechanisms by which n-3 PUFA supplementation improves muscle health include 1. anti-inflammatory properties, 2. augmented expression of mechanistic target of rapamycin complex 1 (mTORC1) pathway, 3. decreased intracellular protein breakdown, 4. improved mitochondrial biogenesis and function, 5. enhanced amino acid transport, and 6. modulation of neuromuscular junction activity. In conclusion, n-3 PUFAs likely improve musculoskeletal health related to sarcopenia, with suggestive effect on muscle mass, strength, physical performance, and muscle protein synthesis. However, the interpretation of the findings is limited by the small number of participants, heterogeneity of supplementation regimens, and different measuring protocols.

The effects of supplementation with whey protein alone or with vitamin D on sarcopenia-related outcomes in older adults are unclear. We aimed to assess the effect of whey protein supplementation alone or with vitamin D on lean mass (LM), strength, and function in older adults with or without sarcopenia or frailty. We searched PubMed, Web of Science, and SCOPUS databases. Randomized controlled trials (RCT) that investigated the effect of whey protein supplementation with or without vitamin D on sarcopenia outcomes in healthy and sarcopenic or frail older adults were included. Standardized mean differences (SMDs) were calculated for LM, muscle strength, and physical function data. The analysis showed that whey protein supplementation had no effect on LM and muscle strength; nevertheless, a significant improvement was found in physical function (SMD = 0.561; 95% confidence interval [CIs]: 0.256, 0.865, n = 33), particularly gait speed (GS). On the contrary, whey protein supplementation significantly improved LM (SMD = 0.982; 95% CI: 0.228, 1.736; n = 11), appendicular lean mass and physical function (SMD = 1.211; 95% CI: 0.588, 1.834; n = 16), and GS in sarcopenic/frail older adults. By contrast, co-supplementation with vitamin D enhanced LM gains (SMD =0.993; 95% CI: 0.112, 1.874; n = 11), muscle strength (SMD =2.005; 95% CI: 0.975, 3.035; n = 11), and physical function (SMD = 3.038; 95% CI: 2.196, 3.879; n = 18) significantly. Muscle strength and physical function improvements after whey protein supplementation plus vitamin D were observed without resistance exercise (RE) and short study duration subgroups. Moreover, the combination of whey protein and vitamin D with RE did not enhance the effect of RE. Whey protein supplementation improved LM and function in sarcopenic/frail older adults but had no positive effect in healthy older persons. By contrast, our meta-analysis showed that co-supplementation with whey protein and vitamin D is effective, particularly in healthy older adults, which is likely owing, we propose, to the correction of vitamin D insufficiency or deficiency. The trial was registered at https://inplasy.com as INPLASY202240167., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Klotho is known for its age-suppressing function and has been implicated in sarcopenia pathology. It has recently been proposed that the adenosine A2B receptor plays a crucial role in skeletal muscle energy expenditure. However, the association between Klotho and A2B remains elusive. In this study, Klotho knockout mice, aged 10 weeks, and wild-type mice, aged 10 and 64 weeks, were used for comparison in indicators of sarcopenia (n = 6 for each group). PCR was performed to confirm the mice genotypes. Skeletal muscle sections were analyzed using hematoxylin and eosin staining as well as immunohistochemistry staining. The skeletal muscle cross-sectional area was significantly reduced in Klotho knockout mice and wild-type mice, aged 64 weeks, when compared with wild-type mice, aged 10 weeks, with a decreased percentage of type IIa and IIb myofibers. Likely impaired regenerative capacity, as reflected by the reduction of paired box 7 (Pax7)- and myogenic differentiation protein 1 (MyoD)-positive cells, was also observed in Klotho knockout mice and aged wild-type mice. 8-Hydroxy-2-deoxyguanosine expression was enhanced with Klotho knockout and aging, indicating higher oxidative stress. Adenosine A2B signaling was impaired, with a lower expression of the A2B receptor and the cAMP-response element binding protein in Klotho knockout and aged mice. The present study provides the novel finding that sarcopenia involves adenosine signaling under the influence of Klotho knockout., (Copyright © 2023 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Skeletal muscle is essential for human locomotion as well as maintaining metabolic homeostasis. Age-related reduction in skeletal muscle mass, strength, and function (i.e., sarcopenia) is a result of pathophysiological processes that include inflammation, alteration of molecular signaling for muscle protein synthesis and degradation, changes in insulin sensitivity, as well as altered skeletal muscle satellite cell activity. Finding strategies to mitigate skeletal muscle loss with age is deemed paramount as the percentage of the population continues to shift towards having more older adults with sarcopenia. Recent research indicates omega-3 fatty acid supplementation can influence anabolic or catabolic pathways in skeletal muscle. Our brief review will provide a synopsis of some underlying mechanisms that may be attributed to omega-3 fatty acid supplementation's effects on skeletal muscle. We will approach this review by focusing on cell culture, animal (pre-clinical models), and human studies evaluating omega-3 fatty acid supplementation, with suggestions for future research. In older adults, omega-3 fatty acids may possess some potential to modify pathophysiological pathways associated with sarcopenia; however, it is highly likely that omega-3 fatty acids need to be combined with other anabolic interventions to effectively ameliorate sarcopenia.

Age-dependent loss of skeletal muscle mass and function is a feature of sarcopenia, and increases the risk of many aging-related metabolic diseases. Here, we report phenotypic and single-nucleus transcriptomic analyses of non-human primate skeletal muscle aging. A higher transcriptional fluctuation was observed in myonuclei relative to other interstitial cell types, indicating a higher susceptibility of skeletal muscle fiber to aging. We found a downregulation of FOXO3 in aged primate skeletal muscle, and identified FOXO3 as a hub transcription factor maintaining skeletal muscle homeostasis. Through the establishment of a complementary experimental pipeline based on a human pluripotent stem cell-derived myotube model, we revealed that silence of FOXO3 accelerates human myotube senescence, whereas genetic activation of endogenous FOXO3 alleviates human myotube aging. Altogether, based on a combination of monkey skeletal muscle and human myotube aging research models, we unraveled the pivotal role of the FOXO3 in safeguarding primate skeletal muscle from aging, providing a comprehensive resource for the development of clinical diagnosis and targeted therapeutic interventions against human skeletal muscle aging and the onset of sarcopenia along with aging-related disorders., (©The Author(s) 2022. Published by Oxford University Press on behalf of Higher Education Press.)

Background: This narrative review describes foundational and emerging evidence of how dietary protein intakes may influence muscle-related attributes of older adults., Methods: PubMed was used to identify pertinent research., Results: Among medically stable older adults, protein intakes below the recommended dietary allowance (RDA) (0.8 g/kg body weight [BW]/d) exacerbate age-related reductions in muscle size, quality, and function. Dietary patterns with total protein intakes at or moderately above the RDA, including one or preferably more meals containing sufficient dietary protein to maximize protein anabolism, promote muscle size and function. Some observational studies suggest protein intakes from 1.0 to 1.6 g/kg BW/d may promote greater muscle strength and function more so than muscle size. Experimental findings from randomized controlled feeding trials indicate protein intakes greater than the RDA (averaging ~1.3 g/kg BW/d) do not influence indices of lean body mass or muscle and physical functions with non-stressed conditions, but positively influence changes in lean body mass with purposeful catabolic (energy restriction) or anabolic (resistance exercise training) stressors. Among older adults with diagnosed medical conditions or acute illness, specialized protein or amino acid supplements that stimulate muscle protein synthesis and improve protein nutritional status may attenuate the loss of muscle mass and function and improve survival of malnourished patients. Observational studies favor animal versus plant protein sources for sarcopenia-related parameters., Conclusions: Quantity, quality, and patterning of dietary protein consumed by older adults with varied metabolic states, and hormonal and health status influence the nutritional needs and therapeutic use of protein to support muscle size and function., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aims: Sarcopenia is an age-related syndrome characterized by a gradual loss of the muscle mass, strength, and function. It is associated with a high risk of adverse consequences such as poorer quality of life, falls, disability and mortality among the elderly. The aim in this study is to investigate the pathological mechanism of sarcopenia., Main Methods: The aging of skeletal muscle was investigated by the D-galactose induced accelerated aging model combining with constrained motion. After 10 weeks, muscle function and gastrocnemius muscle index, and morphology of muscle fibers were evaluated, and myostatin, IGF-1 and ATP in skeletal muscle were also determined. Then the mechanism of aging-related skeletal muscle dysfunctions was investigated based on untargeted serum metabolomics and 16S rRNA gene sequencing. Four key metabolites were validated by the D-galactose-induced C2C12 senescent cell model in vitro., Key Findings: Results showed that gastrocnemius muscle mass was decreased significantly, morphology of muscle fibers was altered, and muscle function was damaged in the aged group. Furthermore, increased MSTN, and decreased IGF-1 and ATP were also observed in the aging skeletal muscle. Importantly, alteration of the key pathways including riboflavin biosynthesis and energy metabolism contributed to the aging of skeletal muscle. Four key metabolites, including riboflavin, α-ketoglutaric acid and two dicarboxylic acids, which were involved in these metabolic pathways, could promote the proliferation of C2C12 cells., Significance: These findings provide novel insights into pathological mechanism of sarcopenia, and will facilitate the development of therapeutic and preventive strategies for sarcopenia., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interests., (Copyright © 2023. Published by Elsevier Inc.)

Background: Skeletal muscle is sensitive to bile acids (BA) because it expresses the TGR5 receptor for BA. Cholic (CA) and deoxycholic (DCA) acids induce a sarcopenia-like phenotype through TGR5-dependent mechanisms. Besides, a mouse model of cholestasis-induced sarcopenia was characterised by increased levels of serum BA and muscle weakness, alterations that are dependent on TGR5 expression. Mitochondrial alterations, such as decreased mitochondrial potential and oxygen consumption rate (OCR), increased mitochondrial reactive oxygen species (mtROS) and unbalanced biogenesis and mitophagy, have not been studied in BA-induced sarcopenia., Methods: We evaluated the effects of DCA and CA on mitochondrial alterations in C 2 C 12 myotubes and a mouse model of cholestasis-induced sarcopenia. We measured mitochondrial mass by TOM20 levels and mitochondrial DNA; ultrastructural alterations by transmission electronic microscopy; mitochondrial biogenesis by PGC-1α plasmid reporter activity and protein levels by western blot analysis; mitophagy by the co-localisation of the MitoTracker and LysoTracker fluorescent probes; mitochondrial potential by detecting the TMRE probe signal; protein levels of OXPHOS complexes and LC3B by western blot analysis; OCR by Seahorse measures; and mtROS by MitoSOX probe signals., Results: DCA and CA caused a reduction in mitochondrial mass and decreased mitochondrial biogenesis. Interestingly, DCA and CA increased LC3II/LC3I ratio and decreased autophagic flux concordant with raised mitophagosome-like structures. In addition, DCA and CA decreased mitochondrial potential and reduced protein levels in OXPHOS complexes I and II. The results also demonstrated that DCA and CA decreased basal, ATP-linked, FCCP-induced maximal respiration and spare OCR. DCA and CA also reduced the number of cristae. In addition, DCA and CA increased the mtROS. In mice with cholestasis-induced sarcopenia, TOM20, OXPHOS complexes I, II and III, and OCR were diminished. Interestingly, the OCR and OXPHOS complexes were correlated with muscle strength and bile acid levels., Conclusion: Our results showed that DCA and CA decreased mitochondrial mass, possibly by reducing mitochondrial biogenesis, which affects mitochondrial function, thereby altering potential OCR and mtROS generation. Some mitochondrial alterations were also observed in a mouse model of cholestasis-induced sarcopenia characterised by increased levels of BA, such as DCA and CA., (© 2023. The Author(s).)

Sarcopenia is characterized by an age-related loss of skeletal muscle mass and function and has been recognized as a clinical disease by the World Health Organization since 2016. Substantial evidence has suggested that dietary modification can be a feasible tool to combat sarcopenia. Among various natural dietary ingredients, the present study focused on botanical and marine extracts, phytochemicals, and probiotics. Aims of this review were (1) to provide basic concepts including the definition, diagnosis, prevalence, and adverse effects of sarcopenia, (2) to describe possible pathological mechanisms including protein homeostasis imbalance, inflammation, mitochondrial dysfunction, and satellite cells dysfunction, and (3) to analyze recent experimental studies reporting potential biological functions against sarcopenia. A recent literature review for dietary ingredients demonstrated that protein homeostasis is maintained via an increase in the PI3K/Akt pathway and/or a decrease in the ubiquitin-proteasome system. Regulation of inflammation has primarily targeted inhibition of NF-κB signaling. Elevated Pgc-1α or Pax7 expression reverses mitochondrial or satellite cell dysfunction. This review provides the current knowledge on dietary components with the potential to assist sarcopenia prevention and/or treatment. Further in-depth studies are required to elucidate the role of and develop various dietary materials for healthier aging, particularly concerning muscle health.

Aging is associated with impairment of multiple organs, including skeletal muscle and heart. In this study, we investigated whether resveratrol, an activator of an NAD + -dependent protein deacetylase Sirtuin-1 (SIRT1), attenuates age-related sarcopenia and cardiomyocyte hypertrophy in mice. Treatment of mice with resveratrol (0.4 g/kg diet) from 28 weeks of age for 32 weeks prevented aging-associated shortening of rotarod riding time. In the tibialis anterior (TA) muscle, histogram analysis showed that the atrophic muscle was increased in 60-week-old (wo) mice compared with 20-wo mice, which was attenuated by resveratrol. In the heart, resveratrol attenuated an aging-associated increase in the cardiomyocyte diameter. Acetylated proteins were increased and autophagic activity was reduced in the TA muscle of 60-wo mice compared with those of 20-wo mice. Resveratrol treatment reduced levels of acetylated proteins and restored autophagic activity in the TA muscle. Aging-related reduction in myocardial autophagy was also suppressed by resveratrol. Skeletal muscle-specific SIRT1 knockout mice showed increases in acetylated proteins and atrophic muscle fibers and reduced autophagic activity in the TA muscle. These results suggest that activation of SIRT1 by treatment with resveratrol suppresses sarcopenia and cardiomyocyte hypertrophy by restoration of autophagy in mice., Competing Interests: Competing interests The authors declare no competing interests., (Copyright © 2023 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Background: Mitochondrial dysfunction has been implicated in sarcopenia. 31 P magnetic resonance spectroscopy (MRS) enables non-invasive measurement of adenosine triphosphate (ATP) synthesis rates to probe mitochondrial function. Here, we assessed muscle energetics in older sarcopenic and non-sarcopenic men and compared with muscle biopsy-derived markers of mitochondrial function., Methods: Twenty Chinese men with sarcopenia (SARC, age = 73.1 ± 4.1 years) and 19 healthy aged and sex-matched controls (CON, age = 70.3 ± 4.2 years) underwent assessment of strength, physical performance, and magnetic resonance imaging. Concentrations of phosphocreatine (PCr), ATP and inorganic phosphate (Pi) as well as muscle pH were measured at rest and during an interleaved rest-exercise protocol to probe muscle mitochondrial function. Results were compared to biopsy-derived mitochondrial complex activity and expression to understand underlying metabolic perturbations., Results: Despite matched muscle contractile power (strength/cross-sectional area), the ATP contractile cost was higher in SARC compared with CON (low-intensity exercise: 1.06 ± 0.59 vs. 0.57 ± 0.22, moderate: 0.93 ± 0.43 vs. 0.58 ± 0.68, high: 0.70 ± 0.57 vs. 0.43 ± 0.51 mmol L -1  min -1  bar -1  cm -2 , P = 0.003, <0.0001 and <0.0001, respectively). Post-exercise mitochondrial oxidative synthesis rates (a marker of mitochondrial function) tended to be longer in SARC but did not reach significance (17.3 ± 6.4 vs. 14.6 ± 6.5 mmol L -1  min -1 , P = 0.2). However, relative increases in end-exercise ADP in SARC (31.8 ± 9.9 vs. 24.0 ± 7.3 mmol L -1 , P = 0.008) may have been a compensatory mechanism. Mitochondrial complex activity was found to be associated with exercise-induced drops in PCr [citrate synthetase activity (CS), Spearman correlation rho = -0.42, P = 0.03] and end-exercise ADP (complex III, rho = -0.52, P = 0.01; CS rho = -0.45, P = 0.02; SDH rho = -0.45, P = 0.03), with CS also being strongly associated with the PCr recovery rate following low intensity exercise (rho = -0.47, P = 0.02), and the cost of contraction at high intensity (rho = -0.54, P = 0.02). Interestingly, at high intensity, the fractional contribution of oxidative phosphorylation to exercise was correlated with activity in complex II (rho = 0.5, P = 0.03), CS (rho = 0.47, P = 0.02) and SDH (rho = 0.46, P = 0.03), linking increased mitochondrial complex activity with increased ability to generate energy through oxidative pathways., Conclusions: This study used 31 P MRS to assess ATP utilization and resynthesis in sarcopenic muscle and demonstrated abnormal increases in the energy cost during exercise and perturbed mitochondrial energetics in recovery. Associations between mitochondrial complex activity and the fractional contribution to energy requirement during exercise indicate increased ability to generate energy oxidatively in those with better mitochondrial complex activity., (© 2023 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Spaceflight and its associated stressors, such as microgravity, radiation exposure, confinement, circadian derailment and disruptive workloads represent an unprecedented type of exposome that is entirely novel from an evolutionary stand point. Within this perspective, we aimed to review the effects of prolonged spaceflight on immune-neuroendocrine systems, brain and brain-gut axis, cardiovascular system and musculoskeletal apparatus, highlighting in particular the similarities with an accelerated aging process. In particular, spaceflight-induced muscle atrophy/sarcopenia and bone loss, vascular and metabolic changes, hyper and hypo reaction of innate and adaptive immune system appear to be modifications shared with the aging process. Most of these modifications are mediated by molecular events that include oxidative and mitochondrial stress, autophagy, DNA damage repair and telomere length alteration, among others, which directly or indirectly converge on the activation of an inflammatory response. According to the inflammaging theory of aging, such an inflammatory response could be a driver of an acceleration of the normal, physiological rate of aging and it is likely that all the systemic modifications in turn lead to an increase of inflammaging in a sort of vicious cycle. The most updated countermeasures to fight these modifications will be also discussed in the light of their possible application not only for astronauts' benefit, but also for older adults on the ground., Competing Interests: Declaration of conflicts of interest The authors declare no conflicts of interest., (Copyright © 2023. Published by Elsevier B.V.)

The quality of skeletal muscle is maintained by a balance between protein biosynthesis and degradation. Disruption in this balance results in sarcopenia. However, its underlying mechanisms remain underinvestigated. Selenoprotein P (SeP; encoded by Selenop in mice) is a hepatokine that is upregulated in type 2 diabetes and aging and causes signal resistances via reductive stress. We created immobilized muscle atrophy model in Selenop knockout (KO) mice. Immobilization (IMM) significantly reduced cross-sectional areas and the size of skeletal muscle fibers, which were ameliorated in KO mice. IMM upregulated the genes encoding E3 ubiquitin ligases and their upstream FoxO1, FoxO3, and KLF15 transcription factors in the skeletal muscle, which were suppressed in KO mice. These findings suggest a possible involvement of SeP-mediated reductive stress in physical inactivity-mediated sarcopenia, which may be a therapeutic target against sarcopenia. NEW & NOTEWORTHY Selenoprotein P (SeP) is a hepatokine that is upregulated in type 2 diabetes and aging and causes signal resistances via reductive stress. Immobilization (IMM) significantly reduced skeletal muscle mass in mice, which was prevented in SeP knockout (KO) mice. IMM-induced Foxos/KLF15-atrogene upregulation was suppressed in the skeletal muscle of KO mice. These findings suggest that SeP-mediated reductive stress is involved in and may be a therapeutic target for physical inactivity-mediated muscle atrophy.

This study aimed to identify the serum metabolites associated with sarcopenic risk in Japanese patients with type 2 diabetes, determine the effect of dietary protein intake on the serum metabolic profile, and examine its association with sarcopenia. Ninety-nine Japanese patients with type 2 diabetes were included, and sarcopenic risk was defined as low muscle mass or strength. Seventeen serum metabolites were quantified after gas chromatography-mass spectrometry analysis. The relationship between dietary protein intake and the metabolites concerning sarcopenia was analyzed, and the factors affecting sarcopenic risk were clarified. Twenty-seven patients were classified as being at risk of sarcopenia, the same as the general risk, which was associated with older age, a longer duration of the disease, and a lower body mass index. Low levels of leucine and glutamic acid were significantly associated with low muscle strength ( p = 0.002 and p < 0.001, respectively), and leucine was also associated with muscle mass ( p = 0.001). Lower levels of glutamic acid had higher odds of sarcopenic risk after being adjusted for age and HbA1c (adjusted OR 4.27, 95% CI 1.07-17.11, p = 0.041), but not for leucine. Leucine and glutamic acid can serve as useful biomarkers for sarcopenia, highlighting potential targets for its prevention.

Apelin, as a cardiokine/myokine, is emerging as an important regulator of cardiac and skeletal muscle homeostasis. Loss of apelin signaling results in premature cardiac aging and sarcopenia. However, the contribution of apelin to peak athletic performance remains largely elusive. In this paper, we assessed the impact of maximal cardiorespiratory exercise testing on the plasma apelin levels of 58 male professional soccer players. Circulating apelin-13 and apelin-36, on average, increased transiently after a single bout of treadmill exercise; however, apelin responses (Δapelin = peak - baseline values) showed a striking interindividual variability. Baseline apelin-13 levels were inversely correlated with those of Δapelin-13 and Δapelin-36. Δapelin-13 showed a positive correlation with the maximal metabolic equivalent, relative maximal O 2 consumption, and peak circulatory power, whereas such an association in the case of Δapelin-36 could not be detected. In conclusion, we observed a pronounced individual-to-individual variation in exercise-induced changes in the plasma levels of apelin-13 and apelin-36. Since changes in plasma apelin-13 levels correlated with the indicators of physical performance, whole-body oxygen consumption and pumping capability of the heart, apelin, as a novel exerkine, may be a determinant of peak athletic performance.

Background and Aim: Although liver diseases, including non-alcoholic steatohepatitis, are associated with skeletal muscle atrophy, the mechanism behind their association has not been fully elucidated. In this study, the effects of aging and non-alcoholic steatohepatitis on the skeletal muscle, and the interaction between the liver and muscle were investigated using a diet-induced non-alcoholic steatohepatitis model in senescence-accelerated mice., Methods: A total of four groups of senescence-accelerated mice and the control mice were fed either a non-alcoholic steatohepatitis-inducing or control diet, and their livers and skeletal muscles were removed for examinations., Results: In the senescence-accelerated/non-alcoholic steatohepatitis group, serum level of alanine aminotransferase was markedly elevated and histopathology of non-alcoholic steatohepatitis was significant. Skeletal muscles were also markedly atrophied. The expression of the ubiquitin ligase Murf1 in the muscle was significantly increased with muscle atrophy, while that of Tnfa was not significantly different. In contrast, the hepatic Tnfa expression and serum TNF-α levels were significantly increased in the senescence-accelerated/non-alcoholic steatohepatitis group. These results suggest that liver-derived TNF-α might promote muscle atrophy associated with steatohepatitis and aging through Murf-1. The metabolomic analysis of skeletal muscle indicated higher spermidine and lower tryptophan levels in the steatohepatitis-diet group., Conclusions: The findings of this study revealed an aspect of liver-muscle interaction, which might be important in developing treatments for sarcopenia associated with liver diseases., (© 2023 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Sarcopenia, an illness condition usually characterized by a loss of skeletal muscle mass and muscle strength or function, is often associated with neurodegenerative diseases, such as Alzheimer's disease (AD), a common type of dementia, leading to memory loss and other cognitive impairment. However, the underlying mechanisms for their associations and relationships are less well understood. The App , a Mendelian gene for early-onset AD, encodes amyloid precursor protein (APP), a transmembrane protein enriched at both the neuromuscular junction (NMJ) and synapses in the central nervous system (CNS). Here, in this review, we highlight APP and its family members' physiological functions and Swedish mutant APP (APP swe )'s pathological roles in muscles and NMJ. Understanding APP's pathophysiological functions in muscles and NMJ is likely to uncover insights not only into neuromuscular diseases but also AD. We summarize key findings from the burgeoning literature, which may open new avenues to investigate the link between muscle cells and brain cells in the development and progression of AD and sarcopenia.

The skeletal muscle is a dynamic organ composed of contractile muscle fibers, connective tissues, blood vessels and nerve endings. Its main function is to provide motility to the body, but it is also deeply involved in systemic metabolism and thermoregulation. The skeletal muscle frequently encounters microinjury or trauma, which is primarily repaired by the coordinated actions of muscle stem cells (satellite cells, SCs), fibro-adipogenic progenitors (FAPs), and multiple immune cells, particularly macrophages. During aging, however, the capacity of skeletal muscle to repair and regenerate declines, likely contributing to sarcopenia, an age-related condition defined as loss of muscle mass and function. Recent studies have shown that resident macrophages in skeletal muscle are highly heterogeneous, and their phenotypes shift during aging, which may exacerbate skeletal muscle deterioration and inefficient regeneration. In this review, we highlight recent insight into the heterogeneity and functional roles of macrophages in skeletal muscle regeneration, particularly as it declines with aging.

A decline in muscle mass and function represents one of the most problematic changes associated with aging, and has dramatic effects on autonomy and quality of life. Several factors contribute to the inexorable process of sarcopenia, such as mitochondrial and autophagy dysfunction, and the lack of regeneration capacity of satellite cells. The physiologic decline in muscle mass and in motoneuron functionality associated with aging is exacerbated by the sedentary lifestyle that accompanies elderly people. Regular physical activity is beneficial to most people, but the elderly need well-designed and carefully administered training programs that improve muscle mass and, consequently, both functional ability and quality of life. Aging also causes alteration in the gut microbiota composition associated with sarcopenia, and some advances in research have elucidated that interventions via the gut microbiota-muscle axis have the potential to ameliorate the sarcopenic phenotype. Several mechanisms are involved in vitamin D muscle atrophy protection, as demonstrated by the decreased muscular function related to vitamin D deficiency. Malnutrition, chronic inflammation, vitamin deficiencies, and an imbalance in the muscle-gut axis are just a few of the factors that can lead to sarcopenia. Supplementing the diet with antioxidants, polyunsaturated fatty acids, vitamins, probiotics, prebiotics, proteins, kefir, and short-chain fatty acids could be potential nutritional therapies against sarcopenia. Finally, a personalized integrated strategy to counteract sarcopenia and maintain the health of skeletal muscles is suggested in this review.

Sarcopenia, a decrease in skeletal muscle mass and function caused by aging, impairs mobility, raises the risk of fractures, diabetes, and other illnesses, and severely affects a senior's quality of life. Nobiletin (Nob), polymethoxyl flavonoid, has various biological effects, such as anti-diabetic, anti-atherogenic, anti-inflammatory, anti-oxidative, and anti-tumor properties. In this investigation, we hypothesized that Nob potentially regulates protein homeostasis to prevent and treat sarcopenia. To investigate whether Nob could block skeletal muscle atrophy and elucidate its underlying molecular mechanism, we used the D-galactose-induced (D-gal-induced) C57BL/6J mice for 10 weeks to establish a skeletal muscle atrophy model. The findings demonstrated that Nob increased body weight, hindlimb muscle mass, lean mass and improved the function of skeletal muscle in D-gal-induced aging mice. Nob improved myofiber sizes and increased skeletal muscle main proteins composition in D-gal-induced aging mice. Notably, Nob activated mTOR/Akt signaling to increase protein synthesis and inhibited FOXO3a-MAFbx/MuRF1 pathway and inflammatory cytokines, thereby reducing protein degradation in D-gal-induced aging mice. In conclusion, Nob attenuated D-gal-induced skeletal muscle atrophy. It is a promising candidate for preventing and treating age-associated atrophy of skeletal muscles.

Sarcopenic obesity (SO) is defined as a combination of obesity and sarcopenia, leading to serious health consequences. However, a lack of suitable animal models has hampered research into this disorder. 12-month-old Sprague-Dawley rats were given a high fat content (HFD, SO group) or standard diet (DC groups) for 28 weeks (until 20 months of age). In addition, 2-month-old rats were fed a standard diet as an age control (YC group) until they reached 10 months of age. At the end of the intervention, quadriceps development in the rats was monitored using magnetic resonance examinations and MR spectroscopy. Age-related changes in muscle mass and strength, histopathology, HFD-induced adiposity, and metabolic disturbances were compared between the three groups. Comparing with DC group, rats of SO (20 months, and fed by high-fat diet) exhibited a more prominent loss of muscle mass and strength, a more pronounced decline in myofibre number, IFM, increase in myocyte apoptosis accompanied with increased visceral fat, remarkable glycolipid metabolic disorders, and insulin resistance. However, DC group rats (20 months with standard diet) only showed a decline in quadriceps cross-sectional area/body weight, forelimb grip strength, myofibre cross-sectional area and number, and intermyofibrillar mitochondria number (IFM), increased myocyte apoptosis, without significant metabolic disorder compared with YC group rats. After verifying, SO animal model was successfully set up by HFD induced obesity concomitant with aging-related sarcopenia., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Sarcopenia, a disorder that involves the generalized loss of skeletal muscle strength and mass, was formally recognized as a disease by its inclusion in the International Classification of Diseases in 2016. Sarcopenia typically affects older people, but younger individuals with chronic disease are also at risk. The risk of sarcopenia is high (with a prevalence of ≥25%) in individuals with rheumatoid arthritis (RA), and this rheumatoid sarcopenia is associated with increased likelihood of falls, fractures and physical disability, in addition to the burden of joint inflammation and damage. Chronic inflammation mediated by cytokines such as TNF, IL-6 and IFNγ contributes to aberrant muscle homeostasis (for instance, by exacerbating muscle protein breakdown), and results from transcriptomic studies have identified dysfunction of muscle stem cells and metabolism in RA. Progressive resistance exercise is an effective therapy for rheumatoid sarcopenia but it can be challenging or unsuitable for some individuals. The unmet need for anti-sarcopenia pharmacotherapies is great, both for people with RA and for otherwise healthy older adults., (© 2023. Springer Nature Limited.)

Sarcopenic obesity (SO) is characterized by atrophic skeletal muscle impairment (sarcopenia) and obesity, which is associated with adverse outcomes of morbidity and mortality in elderly people. We investigated the effects of melatonin and exercise training on SO in 32-week-old senescence-accelerated mouse-prone-8 (SAMP8) mice fed a normal diet or a high-fat diet for 16 weeks. Melatonin, exercise, or melatonin and exercise for 8 weeks displayed reductions in the SO-induced impairment of skeletal muscle function and atrophy. Specifically, a decrease in mitochondrial calcium retention capacity in skeletal muscles observed in the HFD-con group was attenuated in melatonin and/or exercise intervention groups. More importantly, HFD-con mice displayed a lower number of Pax7+ satellite cells (SCs) and higher expression of p16 ink than P8ND mice, which were attenuated by melatonin and/or exercise interventions. The cellular senescence in SC-derived primary myoblasts from HFD-con mice was significantly attenuated in myoblasts from the melatonin and/or exercise groups, which was reproduced in a senescence model of H 2 O 2 -treated C2C12 myoblasts. Our results suggest that melatonin and exercise training attenuate SO-induced skeletal muscle dysfunction, at least in part, through preserving the SC pool by inhibiting cellular senescence and attenuating mitochondrial dysfunction.

With increasing life expectancy, the related disorders of bone loss, metabolic dysregulation and sarcopenia have become major health threats to the elderly. Each of these conditions is prevalent in patients with chronic kidney disease (CKD), particularly in more advanced stages. Our current understanding of the bone-muscle interaction is beyond mechanical coupling, where bone and muscle have been identified as interrelated secretory organs, and regulation of both bone and muscle metabolism occurs through osteokines and myokines via autocrine, paracrine and endocrine systems. This review appraises the current knowledge regarding biochemical crosstalk between bone and muscle, and considers recent progress related to the role of osteokines and myokines in CKD, including modulatory effects of physical exercise and potential therapeutic targets to improve musculoskeletal health in CKD patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wong and McMahon.)

Introduction: Diabetic sarcopenia (DS) is characterized by muscle atrophy, slower nerve conduction, reduced maximum tension generated by skeletal muscle contraction, and slower contraction rate. Hence, DS can cause limb movement degeneration, slow movement, reduced balance, reduced metabolic rate, falls, fractures, etc. Moreover, the relevant early biological metabolites and their pathophysiological mechanism have yet to be characterized., Method: The current cross-sectional study employed serum metabolomics analysis to screen potential noninvasive biomarkers in patients with diabetic sarcopenia. A total of 280 diabetic patients were enrolled in the study (n = 39 sarcopenia [DS], n = 241 without sarcopenia [DM]). Ten patients were randomly selected from both groups. Non-targeted metabolomic analysis was performed by ultra-high-performance liquid chromatography-electrospray ionization tandem mass spectrometry., Results: A total of 632 differential metabolites were identified, including 82 that were significantly differentially abundant ( P < 0.05, VIP > 1, FC > 1.2 or FC < 0.8). Compared with the DM group, the contents of pentadecanoic acid, 5'-methylthioadenosine (5'-MTA), N,N-dimethylarginine (asymmetric dimethylarginine, ADMA), and glutamine in the DS group were significantly increased, while that of isoxanthohumol was decreased., Discussion: Based on receiver operating characteristic curve analysis, pentadecanoic acid, 5'-MTA, ADMA, and glutamine may serve as potential biomarkers of DS. Moreover, ATP-binding cassette (ABC) transporters and the mammalian target of the rapamycin signaling pathway were found to potentially have important regulatory roles in the occurrence and development of DS (P < 0.05). Collectively, the differential metabolites identified in this study provide new insights into the underlying pathophysiology of DS and serve as a basis for therapeutic interventions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Tan, Liu, Yang, Li, Yu, Zhao, Fu, Yu, Han and Cheng.)

Sarcopenia associated with aging and obesity is characterized by the atrophy of fast-twitch muscle fibers and an increase in intramuscular fat deposits. However, the mechanism of fast-twitch fiber-specific atrophy remains unclear. In this study, we aimed to assess the effect of palmitic acid (PA), the most common fatty acid component of human fat, on muscle fiber type, focusing on the expression of fiber-type-specific myosin heavy chain (MHC). Myotubes differentiated from C2C12 myoblasts were treated with PA. The PA treatment inhibited myotube formation and hypertrophy while reducing the gene expression of MHC IIb and IIx, specific isoforms of fast-twitch fibers. Consistent with this, a significant suppression of MHC IIb protein expression in PA-treated cells was observed. A reporter assay using plasmids containing the MHC IIb gene promoter revealed that the PA-induced reduction in MHC IIb gene expression was caused by the suppression of MyoD transcriptional activity through its phosphorylation. Treatment with a specific protein kinase C (PKC) inhibitor recovered the reduction in MHC IIb gene expression levels in PA-treated cells, suggesting the involvement of the PA-induced activation of PKC. Thus, PA selectively suppresses the mRNA and protein expression of fast-twitch MHC by modulating MyoD activity. This finding provides a potential pathogenic mechanism for age-related sarcopenia.

Increase in body fat contributes to loss of function and changes in skeletal muscle, accelerating sarcopenia, a phenomenon known as sarco-obesity or sarcopenic obesity. Studies suggest that obesity decreases the skeletal muscle (SM)'s ability to oxidize glucose, increases fatty acid oxidation and reactive oxygen species production, due to mitochondrial dysfunction. Exercise improves mitochondrial dysfunction in obesity; however, it is not known if exercise regulates the mitochondrial unfolded protein response (UPRmt) in the SM. Our study aimed to determine the mito-nuclear UPRmt in response to exercise in a model of obesity, and how this response is associated with the improvement in SM functioning after exercise training. C57BL/6 mice were fed a normal diet and high-fat diet (HFD) for 12 weeks. After 8 weeks, animals were subdivided into sedentary and exercised for the remaining 4 weeks. Grip strength and maximal velocity of mice submitted to HFD improved after training. Our results show an increase in the activation of UPRmt after exercise while in obese mice, proteostasis is basally decreased but shows a more pronounced increase with exercise. These results correlate with improvement in the circulating triglycerides, suggesting mitochondrial proteostasis could be protective and could be related to mitochondrial fuel utilization in SM.

Sarcopenia increases with age, and an underlying mechanism needs to be determined to help with designing more effective treatments. This study aimed to determine whether 1,25(OH) 2 D 3 deficiency could cause cellular senescence and a senescence-associated secretory phenotype (SASP) in skeletal muscle cells to induce sarcopenia, whether GATA4 could be upregulated by 1,25(OH) 2 D 3 deficiency to promote SASP, and whether Bmi-1 reduces the expression of GATA4 and GATA4-dependent SASP induced by 1,25(OH) 2 D 3 deficiency in skeletal muscle cells. Bioinformatics analyses with RNA sequencing data in skeletal muscle from physiologically aged and young mice were conducted. Skeletal muscles from 2-month-old young and 2-year-old physiologically aged wild-type (WT) mice and 8-week-old WT, Bmi-1 mesenchymal transgene (Bmi-1 Tg ), Cyp27b1 homozygous (Cyp27b1 -/- ), and Bmi-1 Tg Cyp27b1 -/- mice were observed for grip strength, cell senescence, DNA damage, and NF-κB-mediated SASP signaling of skeletal muscle. We found that muscle-derived Bmi-1 and vitamin D receptor (VDR) decreased with physiological aging, and DNA damage and GATA4-dependent SASP activation led to sarcopenia. Furthermore, 1,25(OH) 2 D 3 deficiency promoted DNA damage-induced GATA4 accumulation in muscles. GATA4 upregulated Rela at the region from -1448 to -1412 bp at the transcriptional level to cause NF-κB-dependent SASP for aggravating cell senescence and muscular dysfunction and sarcopenia. Bmi-1 overexpression promoted the ubiquitination and degradation of GATA4 by binding RING1B, which prevented cell senescence, SASP, and dysfunctional muscle, and improved sarcopenia induced by 1,25(OH) 2 D 3 deficiency. Thus, Bmi-1 overexpression improves sarcopenia induced by 1,25(OH) 2 D 3 deficiency, downregulates GATA4-dependent Rela transcription, and sequentially inhibits GATA4-dependent SASP in muscle cells. Therefore, Bmi-1 overexpression could be used for translational gene therapy for the ubiquitination of GATA4 and prevention of sarcopenia. © 2023 American Society for Bone and Mineral Research (ASBMR)., (© 2023 American Society for Bone and Mineral Research (ASBMR).)

Skeletal muscle has a robust endocrine function as a powerful organ and can secrete and release cytokines or polypeptides known as myokines. These myokines have significant regulatory effects on signal transduction in skeletal muscle and the metabolism of peripheral tissues and organs and exert biological effects via autocrine, paracrine, or endocrine forms. Obesity and aging cause myokine secretion dysregulation, and hastening sarcopenic obesity (SO) development. Exercise is currently an excellent intervention and prevention method for SO. Meanwhile, exercise impacts many organs and tissues. These organs and tissues will produce various myokines in response to movement and metabolism throughout the body to govern muscle differentiation, growth, and remodeling. According to accumulating data, exercise can increase the release of myokines from diverse tissues into the blood and postpone the SO onset and progression by influencing protein metabolism, inflammation, mitochondrial quality control, and other mechanisms., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Only in recent years, thanks to a precision medicine-based approach, have treatments tailored to the sex of each patient emerged in clinical trials. In this regard, both striated muscle tissues present significant differences between the two sexes, which may have important consequences for diagnosis and therapy in aging and chronic illness. In fact, preservation of muscle mass in disease conditions correlates with survival; however, sex should be considered when protocols for the maintenance of muscle mass are designed. One obvious difference is that men have more muscle than women. Moreover, the two sexes differ in inflammation parameters, particularly in response to infection and disease. Therefore, unsurprisingly, men and women respond differently to therapies. In this review, we present an up-to-date overview on what is known about sex differences in skeletal muscle physiology and disfunction, such as disuse atrophy, age-related sarcopenia, and cachexia. In addition, we summarize sex differences in inflammation which may underly the aforementioned conditions because pro-inflammatory cytokines deeply affect muscle homeostasis. The comparison of these three conditions and their sex-related bases is interesting because different forms of muscle atrophy share common mechanisms; for instance, those responsible for protein dismantling are similar although differing in terms of kinetics, severity, and regulatory mechanisms. In pre-clinical research, exploring sexual dimorphism in disease conditions could highlight new efficacious treatments or recommend implementation of an existing one. Any protective factors discovered in one sex could be exploited to achieve lower morbidity, reduce the severity of the disease, or avoid mortality in the opposite sex. Thus, the understanding of sex-dependent responses to different forms of muscle atrophy and inflammation is of pivotal importance to design innovative, tailored, and efficient interventions.

Sarcopenia is a condition in which muscle mass, strength, and performance decrease with age. It is associated with chronic diseases such as diabetes, cardiovascular disease, and hypertension, and contributes to an increase in mortality. Because managing sarcopenia is critical for maintaining good health and quality of life for the elderly, the condition has sparked concern among many researchers. To counteract sarcopenia, intake of protein is an important factor, while a lack of either protein or vitamin D is a major cause of sarcopenia. In addition, essential amino acids, leucine, β-hydroxy β-methylbutyrate (HMB), creatine, and citrulline are used as supplements for muscle health and are suggested as alternatives for controlling sarcopenia. There are many studies on such proteins and supplements, but it is necessary to actually organize the types, amounts, and methods by which proteins and supplements should be consumed to inhibit sarcopenia. In this study, the efficacy of proteins and supplements for controlling sarcopenia according to human clinical studies is summarized to provide suggestions about how the elderly may consume proteins, amino acids, and other supplements.

Sarcopenia is a syndrome of age-related loss of muscle mass and strength that seriously affects human health, and there are currently no effective drugs to treat the disease. Linolenic acid as a common n-3 polyunsaturated fatty acid (n-3 PUFA) is known to have many beneficial functions. Some studies have found that n-3 PUFA might have the potential to improve sarcopenia. In this study, Caenorhabditis elegans ( C. elegans ) was used as a model animal to investigate the effects of linolenic acid on C. elegans muscles. The results showed that 50 μg mL -1 linolenic acid significantly improved sarcopenia by repairing mitochondrial function by promoting mitophagy and fighting oxidative stress ( p < 0.05). This included the increase of the expression of the mitophagy gene pink-1 and DAF-16/FOXO transcription factors, respectively, by linolenic acid. This study could provide some evidence for the application of n-3 PUFA in improving sarcopenia.

Skeletal muscle atrophy is prevalent in a myriad of pathological conditions, such as diabetes, denervation, long-term immobility, malnutrition, sarcopenia, obesity, Alzheimer's disease, and cachexia. This is a critically important topic that has significance in the health of the current society, particularly older adults. The most damaging effect of muscle atrophy is the decreased quality of life from functional disability, increased risk of fractures, decreased basal metabolic rate, and reduced bone mineral density. Most skeletal muscle in humans contains slow oxidative, fast oxidative, and fast glycolytic muscle fiber types. Depending on the pathological condition, either oxidative or glycolytic muscle type may be affected to a greater extent. This review article discusses the prevalence of skeletal muscle atrophy and several mechanisms, with an emphasis on high-fat, high-sugar diet patterns, obesity, and diabetes, but including other conditions such as sarcopenia, Alzheimer's disease, cancer cachexia, and heart failure.

Aquaporins (AQPs) are water channels in the cell membrane that regulate osmosis in response to rapid changes in intracellular and extracellular fluid concentration caused by extrinsic factors. While there are so many studies on the association of AQPs with muscular atrophy, sarcopenia, and Duchenne muscular dystrophy (DMD), the expression of AQP has not been verified in naturally aging mice or humans. Notably, due to the characteristics of AQPs, the difference in function cannot be evaluated without extrinsic factors such as acute water restriction. The purpose of this study was to investigate the changes in AQPs expression and function due to natural aging under acute water restriction conditions in aging mice. The expression of AQP4 was shown to decrease with aging similar to previous studies. However, for the first time, this study results confirmed that AQP1 expression increased in aging mice. In addition, the expression of Aqp1 decreased in the acute water restricted group compared to the control group after acute water restriction in aging mice. These results suggest that although the expression of AQP1 increases with aging, its function is reduced. We also confirmed that overexpression of Aqp1 can inhibit myotube differentiation and that knockdown can promote myotube differentiation through in vitro experiments. In conclusion, based on our results, we suggest that the AQP1 is an important factor in sarcopenia caused by natural aging accompanied by chronic dehydration., (© 2022. The Author(s) under exclusive licence to University of Navarra.)

Background: Sarcopenia, the age-related decline in skeletal muscle mass and function, diminishes life quality in elderly people. Improving the capacity of skeletal muscle differentiation is expected to counteract sarcopenia. However, the mechanisms underlying skeletal muscle differentiation are complex, and effective therapeutic targets are largely unknown., Methods: The human Gene Expression Omnibus database, aged mice and primary skeletal muscle cells were used to assess the expression level of pyruvate dehydrogenase B (PDHB) in human and mouse aged state. d-Galactose (d-gal)-induced sarcopenia mouse model and two classic cell models (C2C12 and HSkMC) were used to assess the myogenic effect of PDHB and the underlying mechanisms via immunocytochemistry, western blotting, quantitative real-time polymerase chain reaction, RNA interference or overexpression, dual-luciferase reporter assay, RNA sequencing and untargeted metabolomics., Results: We identified that a novel target PDHB promoted myogenic differentiation. PDHB expression decreased in aged mouse muscle relative to the young state (-50% of mRNA level, P < 0.01) and increased during mouse and primary human muscle cell differentiation (+3.97-fold, P < 0.001 and +3.79-fold, P < 0.001). Knockdown or overexpression of PDHB modulated the expression of genes related to muscle differentiation, namely, myogenic factor 5 (Myf5) (-46%, P < 0.01 and -27%, P < 0.05; +1.8-fold, P < 0.01), myogenic differentiation (MyoD) (-55%, P < 0.001 and -34%, P < 0.01; +2.27-fold, P < 0.001), myogenin (MyoG) (-60%, P < 0.001 and -70%, P < 0.001; +5.46-fold, P < 0.001) and myosin heavy chain (MyHC) (-70%, P < 0.001 and -69%, P < 0.001; +3.44-fold, P < 0.001) in both C2C12 cells and HSkMC. Metabolomic and transcriptomic analyses revealed that PDHB knockdown suppressed pyruvate metabolism (P < 0.001) and up-regulated ariadne RBR E3 ubiquitin protein ligase 2 (Arih2) (+7.23-fold, P < 0.001) in cellular catabolic pathways. The role of forkhead box P1 (FoxP1) (+4.18-fold, P < 0.001)-mediated Arih2 transcription was the key downstream regulator of PDHB in muscle differentiation. PDHB overexpression improved d-gal-induced muscle atrophy in mice, which was characterized by significant increases in grip strength, muscle mass and mean muscle cross-sectional area (1.19-fold to 1.5-fold, P < 0.01, P < 0.05 and P < 0.001)., Conclusions: The comprehensive results show that PDHB plays a sarcoprotective role by suppressing the FoxP1-Arih2 axis and may serve as a therapeutic target in sarcopenia., (© 2022 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Nocturnal hypoxaemia, which is common in chronic obstructive pulmonary disease (COPD) patients, is associated with skeletal muscle loss or sarcopenia, which contributes to adverse clinical outcomes. In COPD, we have defined this as prolonged intermittent hypoxia (PIH) because the duration of hypoxia in skeletal muscle occurs through the duration of sleep followed by normoxia during the day, in contrast to recurrent brief hypoxic episodes during obstructive sleep apnoea (OSA). Adaptive cellular responses to PIH are not known. Responses to PIH induced by three cycles of 8 h hypoxia followed by 16 h normoxia were compared to those during chronic hypoxia (CH) or normoxia for 72 h in murine C2C12 and human inducible pluripotent stem cell-derived differentiated myotubes. RNA sequencing followed by downstream analyses were complemented by experimental validation of responses that included both unique and shared perturbations in ribosomal and mitochondrial function during PIH and CH. A sarcopenic phenotype characterized by decreased myotube diameter and protein synthesis, and increased phosphorylation of eIF2α (Ser51) by eIF2α kinase, and of GCN-2 (general controlled non-derepressed-2), occurred during both PIH and CH. Mitochondrial oxidative dysfunction, disrupted supercomplex assembly, lower activity of Complexes I, III, IV and V, and reduced intermediary metabolite concentrations occurred during PIH and CH. Decreased mitochondrial fission occurred during CH. Physiological relevance was established in skeletal muscle of mice with COPD that had increased phosphorylation of eIF2α, lower protein synthesis and mitochondrial oxidative dysfunction. Molecular and metabolic responses with PIH suggest an adaptive exhaustion with failure to restore homeostasis during normoxia. KEY POINTS: Sarcopenia or skeletal muscle loss is one of the most frequent complications that contributes to mortality and morbidity in patients with chronic obstructive pulmonary disease (COPD). Unlike chronic hypoxia, prolonged intermittent hypoxia is a frequent, underappreciated and clinically relevant model of hypoxia in patients with COPD. We developed a novel, in vitro myotube model of prolonged intermittent hypoxia with molecular and metabolic perturbations, mitochondrial oxidative dysfunction, and consequent sarcopenic phenotype. In vivo studies in skeletal muscle from a mouse model of COPD shared responses with our myotube model, establishing the pathophysiological relevance of our studies. These data lay the foundation for translational studies in human COPD to target prolonged, nocturnal hypoxaemia to prevent sarcopenia in these patients., (© 2022 The Authors. The Journal of Physiology © 2022 The Physiological Society.)

Background: Chronic mTORC1 activation in skeletal muscle is linked with age-associated loss of muscle mass and strength, known as sarcopenia. Genetic activation of mTORC1 by conditionally ablating mTORC1 upstream inhibitor TSC1 in skeletal muscle accelerates sarcopenia development in adult mice. Conversely, genetic suppression of mTORC1 downstream effectors of protein synthesis delays sarcopenia in natural aging mice. mTORC1 promotes protein synthesis by activating ribosomal protein S6 kinases (S6Ks) and inhibiting eIF4E-binding proteins (4EBPs). Whole-body knockout of S6K1 or muscle-specific over-expression of a 4EBP1 mutant transgene (4EBP1mt), which is resistant to mTORC1-mediated inhibition, ameliorates muscle loss with age and preserves muscle function by enhancing mitochondria activities, despite both transgenic mice showing retarded muscle growth at a young age. Why repression of mTORC1-mediated protein synthesis can mitigate progressive muscle atrophy and dysfunction with age remains unclear., Methods: Mice with myofiber-specific knockout of TSC1 (TSC1mKO), in which mTORC1 is hyperactivated in fully differentiated myofibers, were used as a mouse model of sarcopenia. To elucidate the role of mTORC1-mediated protein synthesis in regulating muscle mass and physiology, we bred the 4EBP1mt transgene or S6k1 floxed mice into the TSC1mKO mouse background to generate 4EBP1mt-TSC1mKO or S6K1-TSC1mKO mice, respectively. Functional and molecular analyses were performed to assess their role in sarcopenia development., Results: Here, we show that 4EBP1mt-TSC1mKO, but not S6K1-TSC1mKO, preserved muscle mass (36.7% increase compared with TSC1mKO, P < 0.001) and strength (36.8% increase compared with TSC1mKO, P < 0.01) at the level of control mice. Mechanistically, 4EBP1 activation suppressed aberrant protein synthesis (two-fold reduction compared with TSC1mKO, P < 0.05) and restored autophagy flux without relieving mTORC1-mediated inhibition of ULK1, an upstream activator of autophagosome initiation. We discovered a previously unidentified phenotype of lysosomal failure in TSC1mKO mouse muscle, in which the lysosomal defect was also conserved in the naturally aged mouse muscle, whereas 4EBP1 activation enhanced lysosomal protease activities to compensate for impaired autophagy induced by mTORC1 hyperactivity. Consequently, 4EBP1 activation relieved oxidative stress to prevent toxic aggregate accumulation (0.5-fold reduction compared with TSC1mKO, P < 0.05) in muscle and restored mitochondrial homeostasis and function., Conclusions: We identify 4EBP1 as a communication hub coordinating protein synthesis and degradation to protect proteostasis, revealing therapeutic potential for activating lysosomal degradation to mitigate sarcopenia., (© 2022 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Background: Exercise is an affordable and practical strategy to alleviate several detrimental outcomes from the aging process, including sarcopenia. The elucidation of molecular mechanisms to alleviate sarcopenia is one of the most important steps towards understanding human aging. Although microRNAs (miRNAs) regulate muscle growth, regeneration and aging, the potential role of exercise-mediated miRNAs during the prevention and rehabilitation of skeletal muscle atrophy upon exercise interventions remains unclear., Methods: A miRNA profile by miRNA sequencing for gastrocnemius muscle of a 24-month-old aged male rat model mimicking the naturally aging process was established through screening the differentially expressed miRNAs (DEMs) for alleviating aging-induced skeletal muscle atrophy upon optimal exercise intervention. The screened miRNAs and hub genes, as well as biomarkers with the most significantly enriched pathways, were validated by quantitative real-time polymerase chain reaction and western blotting., Results: The sarcopenia index (SI) value and cross-sectional area (CSA) of rats from the old control (OC) group significantly decreased when compared with the youth control (YC) group (P < 0.001, P < 0.01), whereas an increased SI value and an enlarged CSA of rats from the old-aerobic exercise (OE), old-resistance exercise (OR) and old-mixed exercise (OM) groups were determined (P < 0.01, P < 0.001, P < 0.05; P < 0.01, P < 0.01, P < 0.05). Our results demonstrate that 764 known miRNAs, 201 novel miRNAs and 505 miRNA-mRNA interaction networks were identified to be related to aging-induced muscular atrophy. Among them, 13 miRNAs were differentially expressed (P < 0.05 and log 2 |fold change| > 1) between the YC group and the OC group. Compared with the OC group, 7, 2 and 11 miRNAs were differentially expressed in the OE, OR and OM groups after exercise interventions, respectively. Meanwhile, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed that the identified DEMs were primarily related to apoptosis, autophagy and the NF-κB/MuRF1 signalling pathways (P < 0.05). Meanwhile, four DEMs (miR-7a-1-3p, miR-135a-5p, miR-151-5p and miR-196b-5p), six hub genes (Ar, Igf1, Hif1a, Bdnf, Fak and Nras) and several biomarkers (LC3, Beclin1, p62, Bax, Bcl-2 and NF-κB/MuRF1) with the most significantly enriched pathways were confirmed, which may play a key role in muscular atrophy during the aging process., Conclusions: These findings are closely correlated with the progression of sarcopenia and could act as potential biomarkers for the diagnosis and interventional monitoring of aging-induced skeletal muscle atrophy., (© 2022 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Sarcopenia is a senile disease with high morbidity, serious complications and limited clinical treatments. Menopause increases the risk of sarcopenia in females, while the exact pathogenesis remains unclear. To systematically investigate the development of hormone-related sarcopenia, we established a model of sarcopenia by ovariectomy and recorded successive characteristic changes. Furthermore, we performed the transcriptome RNA sequencing and bioinformatics analysis on this model to explore the underlying mechanism. In our study, we identified an integrated model combining obesity, osteoporosis and sarcopenia. Functional enrichment analyses showed that most of the significantly enriched pathways were down-regulated and closely correlated with endocrine and metabolism, muscle dysfunction, cognitive impairment and multiple important signaling pathways. We finally selected eight candidate genes to verify their expression levels. These findings confirmed the importance of estrogen in the maintenance of skeletal muscle function and homeostasis, and provided potential targets for further study on hormone-related sarcopenia., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Shu, Huang, Zhang, Ling, Hua and Xiong.)

Background: Sarcopenia is common in patients with Parkinson's disease (PD), showing mitochondrial oxidative stress in skeletal muscle. The aggregation of α-synuclein (α-Syn) to induce oxidative stress is a key pathogenic process of PD; nevertheless, we know little about its potential role in regulating peripheral nerves and the function of the muscles they innervate., Methods: To investigate the role of α-Syn aggregation on neuromuscular system, we used the Thy1 promoter to overexpress human α-Syn transgenic mice (mThy1-hSNCA). hα-Syn expression was evaluated by western blot, and its localization was determined by confocal microscopy. The impact of α-Syn aggregation on the structure and function of skeletal muscle mitochondria and neuromuscular junctions (NMJs), as well as muscle mass and function were characterized by flow cytometry, transmission electron microscopy, Seahorse XF24 metabolic assay, and AAV9 in vivo injection. We assessed the regenerative effect of mitochondrial-targeted superoxide dismutase (Mito-TEMPO) after skeletal muscle injury in mThy1-hSNCA mice., Results: Overexpressed hα-Syn protein localized in motor neuron axons and NMJs in muscle and formed aggregates. α-Syn aggregation increased the number of abnormal mitochondrial in the intramuscular axons and NMJs by over 60% (P < 0.01), which inhibited the release of acetylcholine (ACh) from presynaptic vesicles in NMJs (P < 0.05). The expression of genes associated with NMJ activity, neurotransmission and regulation of reactive oxygen species (ROS) metabolic process were significantly decreased in mThy1-hSNCA mice, resulting in ROS production elevated by ~220% (P < 0.05), thereby exacerbating oxidative stress. Such process altered mitochondrial spatial relationships to sarcomeric structures, decreased Z-line spacing by 36% (P < 0.05) and increased myofibre apoptosis by ~10% (P < 0.05). Overexpression of α-Syn altered the metabolic profile of muscle satellite cells (MuSCs), including basal respiratory capacity (~170% reduction) and glycolytic capacity (~150% reduction) (P < 0.05) and decreased cell migration and fusion during muscle regeneration (~60% and ~40%, respectively) (P < 0.05). We demonstrated that Mito-TEMPO treatment could restore the oxidative stress status (the complex I/V protein and enzyme activities increased ~200% and ~150%, respectively), which caused by α-Syn aggregation, and improve the ability of muscle regeneration after injury. In addition, the NMJ receptor fragmentation and ACh secretion were also improved., Conclusions: These results reveal that the α-synuclein aggregation plays an important role in regulating acetylcholine release from neuromuscular junctions and induces intramuscular mitochondrial oxidative stress, which can provide new insights into the aetiology of muscle atrophy in patients with Parkinson's disease., (© 2022 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)