Myostatin (MSTN) protein, lncRNAs, and circRNAs regulate skeletal muscle growth and development. This work aims to compare the expression patterns of circRNAs and lncRNAs in the gluteus maximus tissue of wild-type (WT) and MSTN gene knockout (KO) rabbits. Within the gluteus maximus tissue of three WT and four MSTN KO rabbits, we analyzed the expression profiles of circRNAs and lncRNAs. After identifying the differently expressed RNAs, the biological pathways implicated were ascertained by performing enrichment analysis using the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO). We identified differences in the expression of 251 circRNAs (79 upregulated and 172 downregulated), 176 lncRNAs (53 upregulated and 123 downregulated), and 1178 mRNAs (408 upregulated and 770 downregulated) between WT and MSTN KO rabbits. Target genes were significantly enriched in pathways associated with protein synthesis and catabolism, such as oxidative phosphorylation, ubiquitin-mediated proteolysis, the FoxO signaling pathway, and the pentose phosphate pathway, as identified through GO and KEGG enrichment analyses. The constructed network indicates that a class of circRNAs and lncRNAs is engaged in MSTN-mediated regulation of skeletal muscle development. These findings provide valuable insights for innovative therapeutic, diagnostic, and preventive approaches to muscle disorders.

We assessed whether muscle fibers in myostatin knockout (MSTN-/-) mice are just larger or also exhibit morphological, metabolic, and functional differences from MSTN+/+ mice.

We compared single fiber contractile properties and histological fiber properties in muscles from MSTN-/- and MSTN+/+ mice.

Even though in permeabilized muscle fibers from the extensor digitorum longus and soleus muscle maximal force was higher (p < 0.001) there were no significant differences in specific power (power per unit volume), specific tension (force per cross-sectional area), maximal shortening velocity, or curvature of the force-velocity relationship between MSTN-/- and MSTN+/+ mice. In histological sections of the soleus muscle, fibers were larger (p < 0.001), but the succinate dehydrogenase staining intensity and capillary density did not differ significantly between MSTN-/- and MSTN+/+ mice, which was explicable by the larger number of capillaries around a fiber (p < 0.001). A model showed no significant differences in soleus muscle oxygenation.

The larger force-generating capacity of fibers from MSTN-/- mice is explicable by the larger fiber cross-sectional area. The data indicate that muscle fibers from MSTN-/- mice are quantitatively, but not qualitatively different from muscle fibers from MSTN+/+ mice. Myostatin inhibition may help increase muscle mass in conditions accompanied by muscle weakness without a detrimental impact on muscle quality, but systemic side effects need to be considered.

Sarcopenia is a progressive and generalized muscle wasting syndrome characterized by loss of muscle strength and mass. Although many drug candidates have been developed to treat sarcopenia, their results were unsuccessful due to adverse or off-target effects. In this study, we identified a cedrol derivative which is a bioactive sesquiterpene having substantial suppressive effects on muscle atrophy. We demonstrated that the cedrol analog regulated myostatin expression via transcriptional regulation and that the cedrol derivative regulated this expression more effectively than the original form. Cedrol derivative stimulated Ca2+ via the mouse olfactory receptor 23 (MOR23) and induced interactions between phospho-CaMKII and FoxO3a in a calcium-dependent manner. In animal models, the transcript-level expressions of myostatin and MuRF1 were lower in the extensor digitorum longus (EDL) and soleus muscles of mice fed with cedrol-derivative diet. These findings reveal that cedrol derivative suppresses sarcopenia by inhibiting myostatin and MuRF1 expressions in both in vitro and in vivo models, thus suggesting that cedrol derivatives can be potential therapeutic agents for sarcopenia.

Glucagon-like peptide-1 receptor agonists act via appetite suppression and caloric restriction. These treatments can result in significant muscle loss, likely due to evolutionary mechanisms protecting against food scarcity as muscle is a major energy utilizer. One mechanism that reduces muscle mass involves activation of type II activin receptors, ActRIIA/B, which yield profound muscle growth in humans when blocked. We previously demonstrated GDF8, also known as myostatin, and activin A are the two major ActRIIA/B ligands mediating muscle minimization. Here, we report that dual blockade can also prevent muscle loss associated with glucagon-like peptide-1 receptor agonists - and even increase muscle mass - in both obese mice and non-human primates; moreover, this muscle preservation enhances fat loss and is metabolically beneficial. These data raise the possibility that supplementing glucagon-like peptide-1 receptor agonist treatment with GDF8 and activin A blockade could greatly improve the quality of weight loss during the treatment of obesity in humans.

In the treatment and management of type 2 diabetes mellitus (T2DM), exercise therapy has received increasing attention due to its accessibility and cost-effectiveness. Regular physical exercise improves glycemic control by ameliorating insulin resistance (IR) and reducing the risk of complications. However, the distinct mechanisms underlying the efficacy of endurance training (ET) and resistance training (RT) in T2DM remain incompletely understood. This review systematically compares the molecular pathways through which ET and RT improve IR, focusing on epigenetic regulation, metabolic reprogramming, and anti-inflammatory effects. We highlight that RT enhances protein synthesis via the IGF-1/PI3K/AKT/mTOR pathway, while ET predominantly improves mitochondrial biogenesis and lipid oxidation through AMPK/SIRT1/PGC-1α signaling. Additionally, ET exerts immunomodulatory effects by suppressing pro-inflammatory cytokines (e.g., TNF-α) and elevating anti-inflammatory myokines (e.g., IL-6). These findings provide a mechanistic basis for personalized exercise prescriptions in T2DM management.

To clarify whether direct-acting antiviral treatment improves serum myostatin levels of patients with cirrhosis caused by hepatitis C virus.

A total of 99 patients with type C liver cirrhosis were administered direct-acting antiviral treatment. The median age was 73 years, and 58 patients were women. We measured the levels of serum myostatin, decorin, follistatin, and insulin-like growth factor-1, as well as the skeletal muscle mass index at baseline. We measured the sustained virological response at 48 weeks.

Serum myostatin levels of the Child-Pugh class B or C group (n = 30) were significantly higher than those of the Child-Pugh class A group (n = 69) at baseline. The multivariate analysis indicated that the total bilirubin level and Mac-2 binding protein glycosylation isomer level were independent factors associated with serum myostatin levels. Serum myostatin levels significantly decreased, whereas the skeletal muscle mass index and insulin-like growth factor-1 level were significantly increased at 48 weeks.

Direct-acting antiviral treatment decreased serum myostatin levels and may improve sarcopenia in patients with cirrhosis.

Elucidating the molecular regulatory mechanisms underlying muscle growth and development is of profound significance in aquaculture. Yesso scallop is a cold-water bivalve of considerable economic importance, having its primary edible component of adductor muscle. In this study, comparative transcriptomics and histological analysis at different sampling times after Myostatin (MSTN) interference were performed to identify the potential candidate genes potentially involved in muscle growth and development. The comparative transcriptomics revealed that growth factors and cytokines, extracellular matrix proteins and ubiquitin-proteasome system are potentially involved in muscle hypertrophy and hyperplasia. After MSTN interference, striated adductor muscle displays significant muscle hypertrophy (51.77 % increase on day 7 and 59.83 % increase on day 21) and muscle hyperplasia (59.36 % increase on day 7 and 61.83 % increase on day 21). WGCNA identifies the key darkolivegreen module, which may play crucial roles in muscle hyperplasia and hypertrophy within the striated muscle of the scallop. Five key transcription factors (zf-CCCH, zf-C2H2, PPP1R10, LRRFIP2, and Gon4) are identified by analyzing the co-expression patterns of core genes within the module. These findings will aid in understanding the regulatory mechanisms of muscle growth in scallops and provide a basis for genetic improvement in shellfish aquaculture.

Transforming growth factor-β superfamily genes are multifunctional cytokines that play central roles in the regulation of cell proliferation, differentiation, apoptosis, adhesion, and migration. Identifying the TGF-β superfamily in crabs could provide a basis for elucidating the genetic regulatory mechanism of growth, development, sex differentiation and environmental adaptation. To understand the complexity and evolution of the TGF-β superfamily in the Chinese mitten crab Eriocheir sinensis, this study comprehensively and systematically analysed this superfamily in the genome of E. sinensis. A total of 9 TGF-β superfamily genes have been identified, including EsBMP2, EsBMP3, EsBMP7, EsBMP10, EsBMP15, EsGDF8, EsUnivin, EsINHB and EsINHBB. A wide variation in the number of motifs and CDSs was found among different subfamilies. The expression of EsBMP2 and EsBMP7 suggested that these genes may be the main genes controlling embryonic development in E. sinensis. EsBMP2, EsBMP7 and EsBMP10 are very highly expressed in the gills. The TGF-β superfamily genes presented different expression patterns during limb regeneration and molting. In addition, this gene family also responds to environmental stresses, including nanoplastic stress, cadmium stress, air exposure, and high-salinity stress, which provides a new perspective for understanding the strong tolerance and adaptability of crabs to environmental stress. To our knowledge, this study is the first genome-wide investigation of the TGF-β superfamily in crabs. This study identified the sequence structure, phylogenetic relationship, and gene expression profiles of the TGF-β superfamily genes in the Chinese mitten crab, and the above results lay a foundation for further investigation of the evolution and biological functions of this gene family.

Transposons and their derivatives make up a major proportion of the human genome, but they are not just relics of ancient genomes. They can still be expressed, potentially affecting the transcription of adjacent genes, and can sometimes even contribute to their coding sequence. Active transposons can integrate into new sites in the genome, potentially modifying the expression of nearby loci and leading to genetic disorders. In this review, we highlight work exploring the expression of transposons in skeletal muscles and transcriptional regulation by the KRAB-ZFP/KAP1/SETDB1 complex. We next focus on specific cases of transposon insertion causing phenotypic variation and distinct muscular dystrophies, as well as the implication of transposon expression in immune myopathies. Finally, we discuss the dysregulation of transposons in facioscapulohumeral dystrophy and aging.

Sarcopenia is a syndrome characterized by the progressive and generalized loss of skeletal muscle mass and strength. This condition is associated with physical disability, decreased quality of life, and increased mortality. Therefore, reducing the prevalence of sarcopenia could significantly lower healthcare costs. Sarcopenia can be classified into primary and secondary sarcopenia. The former is related to aging and begins after the fourth decade of life; after that, there is a muscle loss of around 8% per decade until age 70 years, which subsequently increases to 15% per decade. On the other hand, secondary sarcopenia can affect all individuals and may result from various factors including physical inactivity, malnutrition, endocrine disorders, neurodegenerative diseases, inflammation, and cachexia. Understanding the multiple mechanisms involved in the onset and progression of sarcopenia allows for us to develop strategies that can prevent, treat, or at least mitigate muscle loss caused by increased protein breakdown. One potential treatment of sarcopenia is based on nutritional interventions, including adequate caloric and protein intake and specific nutrients that support muscle health. Such nutrients include natural food rich in whey protein and omega-3 fatty acids as well as nutritional supplements like branched-chain amino acids, β-hydroxy-β-methylbutyrate, and vitamin D along with food for special medical purposes. It is important to emphasize that physical exercises, especially resistance training, not only promote muscle protein synthesis on their own but also work synergistically with nutritional strategies to enhance their effectiveness.

X-linked myotubular myopathy (XLMTM) is a life-threatening congenital disorder characterized by severe respiratory and motor impairment. This disease presents significant therapeutic challenges, with various strategies being explored to address its underlying pathology. Among these approaches, gene replacement therapy has demonstrated substantial functional improvements in clinical trials. However, safety issues emerged across different therapeutic approaches, highlighting the need for further research.

This review provides a comprehensive analysis of the data gathered from natural history studies, preclinical models and clinical trials, with a particular focus on gene replacement therapy for XLMTM. The different therapeutic strategies are addressed, including their outcomes and associated safety concerns.

Despite the encouraging potential of gene therapy for XLMTM, the occurrence of safety challenges emphasizes the urgent need for a more comprehensive understanding of the disease's complex phenotype. Enhancing preclinical models to more accurately mimic the full spectrum of disease manifestations will be crucial for optimizing therapeutic strategies and reducing risks in future clinical applications.

Musculoskeletal health is strongly influenced by regulatory interactions of bone and muscle. Recent discoveries have identified a number of key mechanisms through which soluble factors released during exercise by bone exert positive effects on muscle and by muscle on bone. Although exercise can delay the negative effects of aging, these beneficial effects are diminished with aging. The limited response of aged muscle and bone tissue to exercise are accompanied by a failure in bone and muscle communication. Here, we propose that exercise induced beneficial factors must battle changes in circulating endocrine and inflammatory factors that occur with aging. Furthermore, sedentary behavior results in the release of negative factors impacting the ability of bone and muscle to respond to physical activity especially with aging. In this review we report on exercise responsive factors and evidence of modification occurring with aging.

Ageing is often accompanied by cognitive decline and an increased risk of dementia. Exercise is a powerful tool for slowing brain ageing and enhancing cognitive function, as well as alleviating depression, improving sleep, and promoting overall well-being. The connection between exercise and healthy brain ageing is particularly intriguing, with exercise-induced pathways playing key roles. This review explores the link between exercise and brain health, focusing on how skeletal muscle influences the brain through muscle-brain crosstalk. We examine the interaction between the brain with well-known myokines, including brain-derived neurotrophic factor, macrophage colony-stimulating factor, vascular endothelial growth factor and cathepsin B. Neuroinflammation accumulates in the ageing brain and leads to cognitive decline, impaired motor skills and increased susceptibility to neurodegenerative diseases. Finally, we examine the evidence on the effects of exercise on neuronal myelination in the central nervous system, a crucial factor in maintaining brain health throughout the lifespan.

Therapeutic strategies for Duchenne Muscular Dystrophy (DMD) will likely require complementary approaches. One possibility is to explore genetic modifiers that improve muscle regeneration and function. The beneficial effects of the overexpression of Jagged-1 were described in escaper golden retriever muscular dystrophy (GRMD) dogs that had a near-normal life and validated in dystrophin-deficient zebrafish (1). To clarify the underlying biology of JAG1 overexpression in dystrophic muscles, we generated a transgenic mouse (mdx5cv-JAG1) model that lacks dystrophin and overexpresses human JAG1 in striated muscles. Skeletal muscles from mdx5cv-JAG1 and mdx5cv mice were studied at one, four, and twelve-month time points. JAG1 expression in mdx5cv-JAG1 increased by three to five times compared to mdx5cv. Consequently, mdx5cv-JAG1 muscles were significantly bigger and stronger than dystrophic controls, along with an increased number of myofibers. Proteomics data show increased dysferlin in mdx5cv-JAG1 muscles and an association of Nsd1 with the phenotype. Our data supports the positive effect of JAG1 overexpression in dystrophic muscles.

Syndecan-4, a type of heparan sulfate proteoglycan, plays an important role in muscle development, regeneration, and maintenance. Although the important effects of Syndecan-4 on the regulation of myogenesis in mice, turkeys, and bovines have been consistently reported, the molecular mechanisms of Syndecan-4 in myogenesis are not well understood. In this study, the role of Syndecan-4 in regulating myogenesis was investigated in quail myoblast (QM7) cells, which constituting a quail myogenic cell line. Overexpression of Syndecan-4 inhibited myogenesis, resulting in reduced myoblast fusion and shorter myotubes than in the control group. Therefore, the cells overexpressing Syndecan-4 showed a smaller total myotube area than did the control cells. Furthermore, these cells had lesser myosin heavy chain proteins, suggesting that muscle differentiation is inhibited by Syndecan-4. To investigate the inhibitory effect of Syndecan-4 on myogenic differentiation, the mRNA expression levels in several genes known to regulate myoblast proliferation and differentiation were compared. Myogenic regulatory factors, including myogenic factor 5, myogenic differentiation 1, and myogenin, showed significantly different expressions between the groups during myogenesis. Myostatin, a negative regulator of muscle growth, showed significantly higher expression on day 4 in cells overexpressing Syndecan-4. In conclusion, Syndecan-4 could delay and inhibit muscle differentiation by regulating the expression levels of myogenic factors and muscle growth regulator in quail myocytes. This study provides valuable information regarding the role of Syndecan-4 in myogenesis, which may aid in improving the production of poultry meat.

Myostatin (MSTN) is a protein that plays a crucial role in regulating skeletal muscle development. Despite the known benefits of MSTN mutant cattle for increasing beef production, their potential impact on CH4 emissions has not been quantified. The study comparing wild-type (WT) cattle to MSTN-knockout (MSTN-KO) cattle revealed that CH4 production was lower. Macrogenomic analysis revealed a significant decrease in rumen archaea, with reduced Richness indices (P = 0.036). The MSTN-KO cattle also showed altered archaea distribution and composition at different taxonomic levels. LEfSe results showed changes in 21 methanogenic archaea clades, with obligately hydrogen (H2)-dependent methylotrophs Candidatus Methanoplasma termitum species belonging to Methanomassiliicoccales order demonstrating the most significant decrease. Rumen metabolites revealed a decrease in the ratio of acetate to propionate, indicating a shift in rumen fermentation pattern towards propionate fermentation. Additionally, the changing trend of methanogenic archaea is consistent with the evolution of methanogens, and this is correlated with the higher levels of linoleic acid in the rumen of MSTN-KO cattle. Linoleic acid affects the utilization of H2 by methanogenic archaea, leading to a reduction in obligately H2-dependent methylotrophs. Our study suggests that MSTN-KO cattle have potential as an economically and ecologically benign breed for reducing methane emissions.

Physical activity plays a fundamental role in human health and disease. Exercise has been shown to improve a wide variety of disease states, and the scientific community is committed to understanding the precise molecular mechanisms that underlie the exquisite benefits. This review provides an overview of molecular responses to acute exercise and chronic training, particularly energy mobilization and generation, structural adaptation, inflammation, and immune regulation. Furthermore, it offers a detailed discussion of known molecular signals and systemic regulators activated during various forms of exercise and their role in orchestrating health benefits. Critically, the increasing use of multiomic technologies is explored with an emphasis on how multiomic and multitissue studies contribute to a more profound understanding of exercise biology. These data inform anticipated future advancement in the field and highlight the prospect of integrating exercise with pharmacology for personalized disease prevention and treatment.

Myostatin, a potent negative regulator of skeletal muscle mass, has garnered significant attention as a therapeutic target for muscle dystrophies. Despite extensive research and promising preclinical results, clinical trials targeting myostatin inhibition in muscle dystrophies have failed to yield substantial improvements in muscle function or fitness in patients. This review details the mechanisms behind myostatin's function and the various inhibitors that have been tested preclinically and clinically. It also examines the challenges encountered in clinical translation, including issues with drug specificity, differences in serum myostatin concentrations between animal models and humans, and the necessity of neural input for functional improvements. Additionally, we explore promising avenues of research beyond muscle dystrophies, particularly in the treatment of metabolic syndromes and orthopedic disorders. Insights from these alternative applications suggest that myostatin inhibition may hold the potential for addressing a broader range of pathologies, providing new directions for therapeutic development.

Sarcopenia is a syndrome commonly found in older people. The aim of this study was to evaluate the effects of whole-body vibration training (WBVT) and resistance training (RT) on body composition, muscle strength, physical performance and blood biomarkers in older people with sarcopenia. We conducted a 12-week, 3-times-weekly assessor-blinded, randomized controlled trial of 27 older people with sarcopenia aged ≥ 65 years. Subjects were randomized into WBVT group (n = 14) and RT group (n = 13). The primary outcome was knee extension strength (KES). Secondary outcomes were body composition [body weight, body mass index (BMI), percentage of body fat (PBF), and appendicular skeletal muscle mass index (ASMI)], muscle strength [handgrip strength (HS)], physical performance [gait speed (GS), 5-time chair stand test (5CST), and short physical performance battery (SPPB)], blood biomarkers (inflammatory factors, hormones, growth factors, and muscle injury biomarker), and quality of life questionnaire [medical outcomes study short-form 36 (SF-36)]. After 12-week intervention, in the WBVT group, we observed significant improvements in body composition (weight, BMI, PBF and ASMI), muscle strength (KES), physical performance (GS, SPPB and 5CST), blood biomarkers [insulin-like growth factor 1 (IGF-1), growth hormone, follistatin (FST) and creatine kinase (CK)] and quality of life. In the RT group, we observed significant improvements in body composition (weight, BMI and PBF), muscle strength (KES), physical performance (GS and SPPB), blood biomarkers (growth hormone, FST and CK) and quality of life. Between-group comparisons were only significant for KES (P = 0.007) and the role-physical (RP) dimension of the SF-36 (P = 0.007). WBVT and RT both improved the physical condition of older people with sarcopenia. RT excelled in muscle strength, but WBVT offered an alternative for those with restrictions. WBVT's low risk and flexibility suited diverse conditions, providing a new rehabilitation option for patients with sarcopenia.

The molecular mechanisms involved in bone metabolism abnormalities in individuals with type 2 diabetes mellitus (T2DM) are a prominent area of investigation within the life sciences field. Myostatin (MSTN), a member of the TGF-β superfamily, serves as a critical negative regulator of skeletal muscle growth and bone metabolism. Current research on the exercise-mediated regulation of MSTN expression predominantly focuses on its role in skeletal muscle. However, due to the intricate and multifaceted mechanical and biochemical interactions between muscle and bone, the precise mechanisms by which exercise modulates MSTN to enhance bone metabolic disorders in T2DM necessitate additional exploration. The objective of this review is to systematically synthesize and evaluate the role of MSTN in the development of bone metabolism disorders associated with T2DM and elucidate the underlying mechanisms influenced by exercise interventions, aiming to offer novel insights and theoretical recommendations for enhancing bone health through physical activity.

Relevant articles in Chinese and English up to July 2024 were selected using specific search terms and databases (PubMed, CNKI, Web of Science); 147 studies were finally included after evaluation, and the reference lists were checked for other relevant research.

Myostatin's heightened expression in the bone and skeletal muscle of individuals with T2DM can impede various pathways, such as PI3K/AKT/mTOR and Wnt/β-catenin, hindering osteoblast differentiation and bone mineralization. Additionally, it can stimulate osteoclast differentiation and bone resorption capacity by facilitating Smad2-dependent NFATc1 nuclear translocation and PI3K/AKT/AP-1-mediated pro-inflammatory factor expression pathways, thereby contributing to bone metabolism disorders. Physical exercise plays a crucial role in ameliorating bone metabolism abnormalities in individuals with T2DM. Exercise can activate pathways like Wnt/GSK-3β/β-catenin, thereby suppressing myostatin and downstream Smads, CCL20/CCR6, and Nox4 target gene expression, fostering bone formation, inhibiting bone resorption, and enhancing bone metabolism in T2DM.

In the context of T2DM, MSTN has been shown to exacerbate bone metabolic disorders by inhibiting the differentiation of osteoblasts and the process of bone mineralization while simultaneously promoting the differentiation and activity of osteoclasts. Exercise interventions have demonstrated efficacy in downregulating MSTN expression, disrupting its downstream signaling pathways, and enhancing bone metabolism.

Prior studies suggested that canonical Activin Receptor II (ActRII) and BMP receptor (BMPR) ligands can have opposing, distinct effects on skeletal muscle depending in part on differential downstream SMAD activation. It was therefore of interest to test ActRII ligands versus BMP ligands in settings of muscle differentiation and in vivo.

In human skeletal muscle cells, both ActRII ligands and BMP ligands inhibited myogenic differentiation: ActRII ligands in a SMAD2/3-dependent manner, and BMP ligands via SMAD1/5. Surprisingly, a neutralizing ActRIIA/B antibody mitigated the negative effects of both classes of ligands, indicating that some BMPs act at least partially through the ActRII receptors in skeletal muscle. Gene expression analysis showed that both ActRII and BMP ligands repress muscle differentiation genes in human myoblasts and myotubes. In mice, hepatic BMP9 over-expression induced liver toxicity, caused multi-organ wasting, and promoted a pro-atrophy gene signature despite elevated SMAD1/5 signaling in skeletal muscle. Local overexpression of BMP7 or BMP9, achieved by intramuscular AAV delivery, induced heterotopic ossification. Elevated SMAD1/5 signaling with increased expression of BMP target genes was also observed in sarcopenic muscles of old rats.

The canonical ActRII ligand-SMAD2/3 and BMP ligand-SMAD1/5 axes can both block human myoblast differentiation. Our observations further demonstrate the osteoinductive function of BMP ligands while pointing to a potential relevancy of blocking the BMP-SMAD1/5 axis in the setting of therapeutic anti-ActRIIA/B inhibition.

Ferroptosis is a programmed cell death, and its mechanism involves multiple metabolic pathways, such as iron and lipid metabolism, and redox homeostasis. Exerkines are important mediators that optimize cellular homeostasis and maintain physiological health during exercise stimulation. This article comprehensively examines the mechanisms and regulatory networks for governing ferroptosis and summarizes the impact of exercise and exerkines on ferroptosis under varying load intensities and disease contexts. Notably, despite its significant efficacy and minimal side effects, the therapeutic and prognostic potential of exercise in ferroptosis-related diseases remains largely unexplored. This article, by summarizing recent progresses in the regulation of exerkines-mediated ferroptosis, could further uncover the preventive or alleviative mechanisms of some diseases upon exercise interventions, which will be beneficial to design exercise interventional strategies for alleviating disease progression through the regulation of ferroptosis.

Exercise can improve health via skeletal muscle remodeling. Elucidating the underlying mechanism may lead to new therapeutics for aging-related loss of skeletal muscle mass. Here, we show that endurance exercise suppresses expression of YT521-B homology domain family (Ythdf1) in skeletal muscle, which recognizes the N6-methyladenosine (m6A). Ythdf1 deletion phenocopies endurance exercise-induced muscle hypertrophy in mice increases muscle mitochondria content and type I fiber specification. At the molecular level, Ythdf1 recognizes and promotes the translation of m6A-modified Mstn mRNA, which encodes a muscle growth inhibitor, Myostatin. Loss of Ythdf1 leads to hyperactivation of skeletal muscle stem cells (MuSCs), also called satellite cells (SCs), enhancing muscle growth and injury-induced regeneration. Our data reveal Ythdf1 as a key regulator of skeletal muscle homeostasis, provide insights into the mechanism by which endurance exercise promotes skeletal muscle remodeling and highlight potential strategies to prevent aging-related muscle degeneration.

Skeletal muscle plays a pivotal role in physical activity, protein storage and energy utilization. Skeletal muscle wasting due to immobilization, aging, muscular dystrophy and cancer cachexia has negative impacts on the quality of life. The deletion of myostatin, a growth and differentiation factor-8 (GDF-8) augments muscle mass through hyperplasia and hypertrophy of muscle fibers. The present study examines the impact of myostatin deletion using CRISPR/Cas9 editing on the myogenic differentiation (MD) of C2C12 muscle stem cells. A total of five myostatin loci were targeted using guided RNAs that had been previously cloned into a vector. The clones were transfected in C2C12 cells via electroporation. The cell viability and MD of myostatin-edited clones (Mstn-/-) were compared with C2C12 (Mstn+/+) using a series of assays, including MTT, sulforhodamine B, immunocytochemistry, morphometric analysis and RT-qPCR. The clones sequenced showed evidence of nucleotides deletion in Mstn-/- cells. Mstn-/- cells demonstrated a normal physiological performance and lack of cytotoxicity. Myostatin depletion promoted the myogenic commitment as evidenced by upregulated MyoD and myogenin expression. The number of MyoD-positive cells was increased in the differentiated Mstn-/- clones. The Mstn-/- editing upregulates both mTOR and MyH expression, as well as increasing the size of myotubes. The differentiation of Mstn-/- cells upregulates ActRIIb; in contrast, it downregulates decorin expression. The data provide evidence of successful CRISPR/Cas9-mediated myostatin deletion. In addition, targeting myostatin could be a beneficial therapeutic strategy to promote MD and to restore muscle loss. In conclusion, the data suggest that myostatin editing using CRISPR/Cas9 could be a potential therapeutic manipulation to improve the regenerative capacity of muscle stem cells before in vivo application.

To investigate the effects of photoperiods on the growth and muscle quality indicators of grass carp (Ctenopharyngodon idella), 225 fish (109.65 ± 3.62 g) were randomly assigned into five different photoperiod groups (0L:24D, 8L:16D, 12L:12D, 16L:8D, and 24L:0D). The experiment spanned a 75-day period, after which sampling and analysis were performed. Compared with the 0L:24D and 8L:16D groups, the 12L:12D and 16L:8D groups significantly promoted the growth of grass carp (p < 0.05). The texture parameters of the muscle in the 0L:24D and 16L:8D groups were significantly greater than those in the 12L:12D group (p < 0.05). The crude protein content was significantly higher in the 12L:12D and 16L:8D groups (p < 0.05). The amino acid content and muscle fiber characteristics, as well as the mRNA levels of myostatin (mstn), myogenic factor 5 (myf5), type I collagen α1 (col1α1), and α2 (col1α2), along with the hydroxyproline and collagen contents, were all significantly influenced by the photoperiod (p < 0.05). The lysine (Lys), aspartic acid (Asp), and alanine (Ala) contents in the muscle and muscle fiber density of grass carp reached the highest levels under the 16L:8D treatment (p < 0.05). Collectively, these results indicate that a 16L:8D photoperiod is optimal for enhancing both the growth and muscle quality indicators of grass carp. The findings of this study offer valuable scientific references for the precise regulation of grass carp quality when using a photoperiod, and they are anticipated to foster the further development and optimization of strategies for improving grass carp quality.

Adult stem cells maintain homeostasis and enable regeneration of most tissues. Quiescence, proliferation, and differentiation of stem cells and their progenitors are tightly regulated processes governed by dynamic transcriptional, epigenetic, and metabolic programs. Previously thought to merely reflect a cell's energy state, metabolism is now recognized for its critical regulatory functions, controlling not only energy and biomass production but also the cell's transcriptome and epigenome. In this review, we explore how metabolic pathways, metabolites, and transcriptional and epigenetic regulators are functionally interlinked in adult and aging skeletal muscle stem cells.

Muscle stem cells (MuSCs) are essential for the regenerative capabilities of skeletal muscles. MuSCs are maintained in a quiescent state, but, when activated, can undergo proliferation and differentiation into myocytes, which fuse and mature to generate muscle fibers. The maintenance of MuSC quiescence and MuSC activation are processes that are tightly regulated by autophagy, a conserved degradation system that removes unessential or dysfunctional cellular components via lysosomes. Both the upregulation and downregulation of autophagy have been linked to impaired muscle regeneration, causing myopathies such as cancer cachexia, sarcopenia and Duchenne muscular dystrophy. In this Review, we highlight the importance of autophagy in regulating MuSC activity during muscle regeneration. Additionally, we summarize recent studies that link the transcriptional dysregulation of autophagy to muscle atrophy, emphasizing the dominant roles that transcription factors play in myogenic programs. Deciphering and understanding the roles of these transcription factors in the regulation of autophagy during myogenesis could advance the development of regenerative medicine.

Sarcopenia, a common condition observed in the elderly, presenting a significant public health challenge due to its high prevalence, insidious onset and diverse systemic effects. Despite ongoing research, the precise etiology of sarcopenia remains elusive. Aging-related processes, which included inflammation, oxidative stress, compromised mitochondrial function and apoptosis, have been implicated in its development. Notably, effective pharmacological treatments for sarcopenia are currently lacking, highlighting the necessity for a deeper understanding of its pathogenesis and causative factors to enable proactive interventions. This article is aimed to provide an extensive overview of the pathogenesis of sarcopenia, along with a summary of current treatment and prevention strategies.

Embryonic muscle fiber formation determines post-birth muscle fiber totals. The previous research shows SYISL knockout significantly increases muscle fiber numbers and mass in mice, but the mechanism remains unclear. This study confirms that the SYISL gene, maternal gut microbiota, and their interaction significantly affect the number of muscle fibers in mouse embryos through distinct mechanisms, as SYISL knockout alters maternal gut microbiota composition and boosts butyrate levels in embryonic serum. Both fecal microbiota transplantation and butyrate feeding significantly increase muscle fiber numbers in offspring, with butyrate inhibiting histone deacetylases and increasing histone acetylation in embryonic muscle. Combined analysis of RNA-seq between wild-type and SYISL knockout mice with ChIP-seq for H3K9ac and H3K27ac reveals that SYISL and maternal microbiota interaction regulates myogenesis via the butyrate-HDAC-H3K9ac/H3K27ac pathway. Furthermore, scRNA-seq analysis shows that SYISL knockout alone significantly increases the number and proportion of myogenic cells and their dynamics, independently of regulating histone acetylation levels. Cell communication analysis suggests that this may be due to the downregulation of signaling pathways such as MSTN and TGFβ. Overall, multiple pathways are highlighted through which SYISL influences embryonic muscle development, offering valuable insights for treating muscle diseases and improving livestock production.

Objective: Volumetric muscle loss (VML) leads to permanent muscle mass and functional impairments. While mesenchymal stromal cells (MSCs) and their secreted factors can aid muscle regeneration, MSCs exhibit limited persistence in injured tissue post-transplantation. Human placental-derived stem cells (hPDSCs), sharing surface markers with MSCs, demonstrate superior regenerative potential due to their fetal origin. Previously, a biosponge (BS) scaffold was shown to augment muscle regeneration post-VML. This study aims to coapply BS therapy and hPDSCs to further enhance muscle recovery following VML. Approach: A VML defect was created by removing ∼20% of the tibialis anterior muscle mass in male Lewis rats. Injured muscles were either left untreated or treated with BS or BS-encapsulated hPDSCs cultured under normoxic or hypoxic conditions. On day 28 postinjury, peak isometric torque was measured, and the muscle was harvested for analysis. Results: BS encapsulated hPDSCs subjected to hypoxic preconditioning persisted in larger quantities and enhanced muscle mass at day 28 postinjury. BS encapsulated hPDSCs cultured under normoxic or hypoxic conditions increased small myofibers (<500 µm2) percentage, MyoD protein expression, and both pro- and anti-inflammatory macrophage marker expression. BS encapsulated hPDSCs also reduced fibrosis and BS remodeling rate. Innovation: This study is the first to examine the therapeutic effects of hPDSCs in a rat VML model. A BS carrier and hypoxic preconditioning were investigated to mitigate low cell survival postimplantation. Conclusion: hPDSCs augment the regenerative effect of BS. Combining hPDSCs and BS emerges as a promising strategy worthy of further investigation.

Background/Objectives: Carbohydrate and protein restriction are associated with sarcopenia and osteopenia, but the underlying mechanisms remain unclear. We aimed to determine whether mild protein restriction affects muscle and bone function in wild-type (WT) and homozygous carbohydrate response element binding protein (Chrebp) knockout (KO) mice. Methods: Eighteen-week-old male wild-type and homozygous carbohydrate response element binding protein (Chrebp) knockout (KO) mice were fed a control diet (20% protein) or a low-protein diet (15% protein) for 12 weeks. We estimated the muscle weight and limb grip strength as well as the bone mineral density, bone structure, and bone morphometry. Results: Chrebp deletion and a low-protein diet additively decreased body weight (WT control-KO low-protein: mean difference with 95% CI, 8.7 [6.3, 11.0], p < 0.0001) and epidydimal fat weight (1.0 [0.7, 1.2], p < 0.0001). Chrebp deletion and a low-protein diet additively decreased tibialis anterior muscle weight (0.03 [0.01, 0.05], p = 0.002) and limb grip strength (63.9 [37.4, 90.5], p < 0.0001) due to a decrease in insulin/insulin-like growth factor 1 mRNA and an increase in myostatin mRNA. In contrast, Chrebp deletion increased bone mineral density (BMD) (WT control-KO control: -6.1 [-1.0, -2.3], p = 0.0009), stiffness (-21.4 [-38.8, -4.1], p = 0.011), cancellous bone BV/TV (-6.517 [-10.99, -2.040], p = 0.003), and the number of trabeculae (-1.1 [-1.8, -0.5], p = 0.0008). However, in KO mice, protein restriction additively decreased BMD (KO control-KO low-protein: 8.1 [4.3, 11.9], p < 0.0001), bone stiffness (38.0 [21.3, 54.7], p < 0.0001), cancellous bone BV/TV (7.7 [3.3, 12.2], p = 0.006), and the number of trabeculae (1.2 [0.6, 1.9], p = 0.0004). The effects of mild protein restriction on bone formation parameters (osteoid volume (WT control-WT low-protein: -1.7 [-2.7, -0.7], p = 0.001) and the osteoid surface (-11.2 [-20.8, -1.5], p = 0.02) were observed only in wild-type (WT) mice. The levels of bone resorption markers, such as the number of osteoclasts on the surface, the number of osteoclasts, and surface erosion, did not differ between the groups. Conclusions: Both Chrebp deletion and protein restriction led to a decrease in muscle and bone function; therefore, an adequate intake of carbohydrates and proteins is important for maintaining muscle and bone mass and function. Further studies will be needed to elucidate the mechanisms by which ChREBP deletion and a low-protein diet cause osteosarcopenia.

Myokine is a general term for hormones, peptides, and other substances secreted by skeletal muscle. Myokine has attracted much attention in recent years as a key substance for understanding the mechanism of "exercise and health". Skeletal muscle accounts for about 40% of the total human weight and is now recognized as an endocrine organ that produces myokines, which have physiological activity. Representative myokines include IL-6, myostatin, irisin, brain-derived neurotropic factor, fibroblast growth factor-21, and decorin. On the other hand, sarcopenia, defined by quantitative and qualitative loss of skeletal muscle, is a condition that has received much attention in recent years because of its close correlation with prognosis. In patients with chronic liver disease (CLD), sarcopenia is a common complication. Mechanisms underlying sarcopenia in CLD patients have been reported to involve protein-energy malnutrition, which is characteristic of patients with cirrhosis, signaling involved in protein synthesis and degradation, myokines such as myostatin and decorin, the ubiquitin-proteasome pathway, sex hormones such as testosterone, dysbiosis, and insulin resistance, etc., in addition to aging. Each of these pathological conditions is thought to be intricately related to each other, leading to sarcopenia. This review will summarize the relationship between CLD and myokines.

A muscle hormone controls the mammalian reproductive system.

Myostatin is a paracrine myokine that regulates muscle mass in a variety of species, including humans. In this work, we report a functional role for myostatin as an endocrine hormone that directly promotes pituitary follicle-stimulating hormone (FSH) synthesis and thereby ovarian function in mice. Previously, this FSH-stimulating role was attributed to other members of the transforming growth factor-β family, the activins. Our results both challenge activin's eponymous role in FSH synthesis and establish an unexpected endocrine axis between skeletal muscle and the pituitary gland. Our data also suggest that efforts to antagonize myostatin to increase muscle mass may have unintended consequences on fertility.

Sarcopenia is defined as a muscle-wasting syndrome that occurs with accelerated aging, while cachexia is a severe wasting syndrome associated with conditions such as cancer and immunodeficiency disorders, which cannot be fully addressed through conventional nutritional supplementation. Sarcopenia can be considered a component of cachexia, with the bidirectional interplay between adipose tissue and skeletal muscle potentially serving as a molecular mechanism for both conditions. However, the underlying mechanisms differ. Recognizing the interplay and distinctions between these disorders is essential for advancing both basic and translational research in this area, enhancing diagnostic accuracy and ultimately achieving effective therapeutic solutions for affected patients. This review discusses the muscle microenvironment's changes contributing to these conditions, recent therapeutic approaches like lifestyle modifications, small molecules, and nutritional interventions, and emerging strategies such as gene editing, stem cell therapy, and gut microbiome modulation. We also address the challenges and opportunities of multimodal interventions, aiming to provide insights into the pathogenesis and molecular mechanisms of sarcopenia and cachexia, ultimately aiding in innovative strategy development and improved treatments.

To establish if osteosarcopenia is related to postoperative complications, prognosis, and recurrence of colorectal cancer (CRC) after curative surgery.

The clinical data of 594 patients who underwent curative resection for CRC between January, 2013 and December, 2018 were analyzed retrospectively to examine the relationship between clinicopathological data and osteosarcopenia. The following definitions were used: sarcopenia, low skeletal muscle mass index; osteopenia, low bone mineral density on computed tomography at the level of the 11th thoracic vertebra; and osteosarcopenia, sarcopenia with osteopenia.

Osteosarcopenia was identified in 98 patients (16.5%) and found to be a significant risk factor for postoperative complications (odds ratio 2.53; p = 0.011). The 5-year overall survival (OS) and recurrence-free survival (RFS) rates of the patients with osteosarcopenia were significantly lower than those of the patients without osteosarcopenia (OS: 72.5% and 93.9%, respectively, p < 0.0001; RFS: 70.8% and 92.4%, respectively, p < 0.0001). Multivariate analysis identified osteosarcopenia as an independent prognostic factor associated with OS (hazard ratio 3.31; p < 0.0001) and RFS (hazard ratio 3.67; p < 0.0001).

Osteosarcopenia may serve as a predictor of postoperative complications and prognosis after curative surgery for CRC.