bims-moremu Biomed News
on Molecular regulators of muscle mass
Issue of 2026–03–15
37 papers selected by
Anna Vainshtein, Craft Science Inc.
  1. OGG1 increases exercise endurance via elevated skeletal muscle FGF21.
  2. MG53 in Early Skeletal Muscle Stem Cell Activation: Implications for Aged Muscle Regeneration.
  3. Prostaglandin E2 receptor EP2 is indispensable for maintenance of skeletal muscle stem cells.
  4. Revisiting barium chloride-induced injury as a preclinical model for skeletal muscle regeneration.
  5. Deconvoluting fibre type proportions from human skeletal muscle transcriptomics and proteomics data using FibeRtypeR.
  6. Does Time Tick Faster in Cerebral Palsy? Accelerated Aging as a Framework for Skeletal Muscle Dysfunction.
  7. Muscle Movement and Metabolism: Exercise and Skeletal Muscle as Mediators of Health. A Report from the 26th Annual Harvard Nutrition Obesity Symposium, 2025.
  8. A Systematic Review and User Reference of Phenotypic and Molecular Characteristics of Dexamethasone-Mediated C2C12 Muscle Atrophy.
  9. Advanced glycation end-products accumulate preferentially in type I muscle fibers of aging adults but are unchanged by training and polyphenol supplementation.
  10. Elevated circulating GDF11 and its role in age-related sarcopenia: insights from clinical, transcriptomic, and in vitro analyses.
  11. A Novel Dysferlin-Binding Kinase CK2α Promotes Plasma Membrane Repair in Dysferlinopathy.
  12. CSRP3 promotes skeletal muscle remodeling toward aerobic metabolism and enhances exercise endurance through increasing LDHD activity.
  13. PTBP1 inhibition reprograms myogenesis to rescue impaired muscle regeneration in mdx mice through correcting E2A splicing.
  14. 0.33g mitigates muscle atrophy while 0.67g preserves muscle function and myofiber type composition in mice during spaceflight.
  15. Systemic Integrative Mechanisms and Intervention Strategies in Exercise-Induced Skeletal Muscle Damage: Evidence from Animal, Clinical, and Multi-Omics Studies.
  16. Parthenolide Attenuates Skeletal Muscle Atrophy Through Regulation of Protein Homeostasis and Inhibition of Inflammation.
  17. Exploration of the co-regulatory mechanism of calorie restriction and endurance exercise on elderly skeletal muscle and its potential intervention targets.
  18. Atmospherically relevant PM2.5 promotes age-related muscle atrophy in an age-dependent manner.
  19. Molecular biological effect of Rbm20 I538T knock-in mice on skeletal muscle.
  20. Canine Adipose MSC-Derived Exosomes Ameliorate Skeletal Muscle Injury in Mice.
  21. Burn injury dysregulates protein signaling in type 1 and type 2 muscles in rats.
  22. The role of metabolic stress, xanthine oxidase, NOX2, and redox-related signalling in regulating ACE2 protein expression in exercising human skeletal muscle.
  23. Non-canonical muscle stem cells and other lessons from regenerative vertebrates.
  24. Muscle collagen accumulation is not a universal feature of human aging: a systematic review.
  25. SORT LNPs encapsulating Cas9 mRNA achieve efficient editing in skeletal muscle in a dystrophic mouse model.
  26. Single-Cell Spatial Proteomics Uncovers Molecular Interconnectivity among Hallmarks of Aging.
  27. Eccentric treadmill training and skeletal muscle immunometabolic responses in HFD-induced insulin resistance.
  28. 3D bioprinting of alginate/gelatin hydrogels with tunable mechanical properties for skeletal muscle regeneration.
  29. Moderate Aerobic Training Causes Muscle Wasting in a DMBA-Induced Sarcoma Rat Model.
  30. The Role of Ketogenic Diet and β-Hydroxybutyrate in the Prevention of Muscle Catabolism and Sarcopenia in Aging Populations: Mechanisms, Evidence, and Clinical Perspectives.
  31. Regulatory roles of the circRNA-RBP axis in exercise-induced skeletal muscle remodeling: mechanistic controversies and translational illusions.
  32. Downregulation of Organ-Derived Activin A Attenuates Muscle Atrophy and Intramuscular Fat Infiltration in Cancer Cachexia Mice.
  33. Chronic inflammation as a driving factor for sarcopenia: an update on pathophysiology and future therapeutic targets.
  34. Humans with function-disrupting variants in the myostatin gene (MSTN) have increased skeletal muscle mass and strength, and less adiposity.
  35. Repeat-rich RNA guides repetitive genomic elements into biomolecular condensates for heterochromatin organization and muscle integrity.
  36. Ageing does not impair motor neuron adaptations: comparable motor unit responses to strength training in young and older adults.
  37. Ultrasound-guided skeletal muscle biopsy technique permits measurement of structural, functional, cellular and biochemical properties.
  1. J Biol Chem. 2026 Mar 09. pii: S0021-9258(26)00230-9. [Epub ahead of print] 111360
    OGG1 increases exercise endurance via elevated skeletal muscle FGF21.
    Bhavya Blaze, Priyanka Sharma, Bhavya Prakash Gupta, Souvik Mandal, Sai Santosh Babu Komakula, Tracy Anthony, Emmanuel Marfo, Harini Sampath.
      The base excision repair (BER) pathway maintains genomic integrity in the face of oxidative insult. It is initiated by DNA glycosylases such as 8-oxoguanine DNA glycosylase (OGG1) and is implicated in various pathologies such as cancers and neurodegenerative disease. BER proteins also modulate body weight and metabolic health. Mice lacking OGG1 are susceptible to obesity and its sequelae, while overexpression of human OGG1 (in OGG1-transgenic; Ogg1Tg mice) reverses these metabolic defects. We report here that OGG1 overexpression induces a remarkable over 3-fold increase in muscle endurance. This is accompanied by significant increases in muscle mitochondrial content and size and a selective increase in expression of the myokine, Fgf21, in skeletal muscle of Ogg1Tg mice. Together with elevated circulating FGF21 levels and peripheral markers of FGF21 action, these data demonstrate a novel role for skeletal muscle OGG1 in modulating mitochondrial health and muscle endurance via FGF21 secretion and signaling.
    Keywords:  base excision repair; exercise tolerance; fibroblast growth factor; mitochondria; myokine; skeletal muscle
    DOI:  https://doi.org/10.1016/j.jbc.2026.111360
  2. Cells. 2026 Mar 05. pii: 463. [Epub ahead of print]15(5):
    MG53 in Early Skeletal Muscle Stem Cell Activation: Implications for Aged Muscle Regeneration.
    Yanping Xu, Jethro Wang Zih-Shuo, Zhentao Zhang, Peng Chen, Usman Alizai, Keerthika Sathish, Sakai Lilian, Zhiyu Yan, Bryan A Whitson, Timothy M Pawlik, Hua Zhu.
      Skeletal muscle regeneration declines with age despite the persistence of satellite cells (muscle stem cells, MuSCs), suggesting that regenerative impairment reflects functional dysregulation rather than MuSC depletion. Increasing evidence identifies early MuSC activation during the immediate post-injury period as a stress-sensitive, rate-limiting transition that is particularly vulnerable in aged muscle. Aged MuSCs exhibit elevated stress responses and reduced membrane remodeling capacity, accompanied by weakened activation-associated transcriptional induction. In contrast, proliferative and differentiation programs remain largely intact once activation is successfully initiated. These findings underscore that impaired coordination during early activation contributes to long-term regenerative decline in aging. Within this framework, MG53 (tripartite motif-containing protein 72, TRIM72), a muscle-enriched TRIM family E3 ubiquitin ligase originally identified as a mediator of sarcolemmal membrane repair, may also function as a stress-responsive regulator that stabilizes the early activation environment. Rather than directly determining cell fate, MG53 is proposed to facilitate activation by mitigating stress-associated membrane disruption and maintaining programmatic coordination under age-related physiological constraints. Most mechanistic evidence derives from rodent models, and direct validation in human aging muscle remains limited. These observations suggest that targeting early activation, rather than simply increasing proliferation, may better preserve regenerative capacity in aging skeletal muscle.
    Keywords:  MG53/TRIM72; activation checkpoint; aging; satellite cell activation; skeletal muscle regeneration; stress
    DOI:  https://doi.org/10.3390/cells15050463
  3. Stem Cells. 2026 Mar 09. pii: sxag012. [Epub ahead of print]
    Prostaglandin E2 receptor EP2 is indispensable for maintenance of skeletal muscle stem cells.
    Yusuke Maruyama, Ken'ichiro Nogami, Norio Motohashi, Fusako Sakai-Takemura, Ahmed Elhussieny, Fumiaki Uchiumi, Yoshitsugu Aoki, Shin'ichi Takeda, Yuko Miyagoe-Suzuki.
      Muscle satellite cells are adult muscle stem cells indispensable for growth and regeneration of postnatal skeletal muscle. Notch plays a central role in maintenance of muscle satellite cells, but how Notch maintains the muscle stem cell pool is not fully understood. Previously, we reported that a prostaglandin E2 receptor, EP2, is upregulated by Notch signal and suppresses differentiation of human muscle progenitors. Here we examined the roles of EP2 in muscle satellite cells using a mouse Cre-LoxP conditional gene knockout system. Genetic inactivation of the EP2 gene (PTGER2) activated muscle satellite cells, caused their loss, and impaired muscle regeneration. These results indicate that EP2 is indispensable for maintenance of satellite cells. Ex vivo analysis using isolated myofibers showed that prostaglandin E2 (PGE2) delayed the activation of satellite cells via EP2. An extracellular signal-regulated kinase (ERK) 1/2 inhibitor blocked the activation of satellite cells on myofibers, and PGE2 attenuated the phosphorylation of ERK1/2 in muscle satellite cells. These results suggest that EP2 keeps the quiescence of satellite cells and maintains the satellite cell pool in part by inhibiting the ERK1/2 signaling pathway.
    Keywords:  EP2; ERK1/2; prostaglandin E2; quiescence; skeletal muscle stem cells
    DOI:  https://doi.org/10.1093/stmcls/sxag012
  4. Tissue Cell. 2026 Mar 04. pii: S0040-8166(26)00118-7. [Epub ahead of print]101 103426
    Revisiting barium chloride-induced injury as a preclinical model for skeletal muscle regeneration.
    Shubhi Raizada, Jyotika, Sapana Kushwaha, Richa Shrivastava.
      Skeletal muscle repair and regeneration are dynamic processes that involve intricate interactions between distinct cell types, cellular mediators, and signaling networks. Although skeletal muscle has an inherent property of regeneration, it is compromised due to aging and certain disease conditions. A comprehensive understanding of the molecular processes that govern the restoration of muscle function is crucial in designing effective therapeutic strategies. Various in vivo models of muscle injury and regeneration have been established, differing primarily in terms of regeneration kinetics and their impact on muscle stem cells and vascular networks. This review aims to summarize the mechanisms, advantages, and limitations of the barium chloride (BaCl₂)-induced muscle injury model. BaCl₂ induces muscle damage via calcium-induced proteolysis and has gained widespread attention due to its ease of procurement and reproducibility in altering the muscle phenotype. The review also compiles studies utilizing the BaCl₂-induced muscle injury model for therapeutic screening and exploration into fundamental aspects of muscle biology, highlighting its use for a mechanistic understanding of skeletal muscle regeneration and the development of regenerative therapies.
    Keywords:  Barium chloride; Muscle injury; Muscle regeneration; Muscle repair; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.tice.2026.103426
  5. J Physiol. 2026 Mar 13.
    Deconvoluting fibre type proportions from human skeletal muscle transcriptomics and proteomics data using FibeRtypeR.
    Thibaux Van der Stede, Roger Moreno-Justicia, Freek Van de Casteele, Eline Lievens, Alexia Van de Loock, Jonas Vandecauter, Peter Merseburger, Jimmy Van den Eynden, Delphi Van Haver, An Staes, Lukas Moesgaard, Simon Devos, Morten Hostrup, Pieter Mestdagh, Jo Vandesompele, Ben Stocks, Atul S Deshmukh, Wim Derave.
      Muscle fibres are the dominant, multinucleated cell type in skeletal muscle. In humans, they can be classified as slow (type 1) and fast (type 2) fibres, traditionally based on distinct properties of their contractile machinery. Slow and fast fibres are characterized by shared and specific cellular complexities that are pivotal for their adaptive capacity to exercise or role in metabolic disease progression. In this era of omics research, there is a critical need to accurately infer muscle fibre type proportions from bulk tissue omics datasets because single-fibre approaches are not feasible in large-scale or retrospective studies. Here we present FibeRtypeR, an easy-to-use web application to accurately estimate fibre type proportions from bulk transcriptomics and proteomics datasets (https://muscleapps.ugent.be). FibeRtypeR exploits transcriptomics profiles of 1000 fibre-typed individual human skeletal muscle fibres and sex-specific fibre type proteomes as reference datasets and is validated against paired immunohistochemical fibre type determinations in 160 muscle biopsies. We show that FibeRtypeR can be applied to public datasets, illustrating the application potential across a wide range of biological contexts such as ageing, disease and exercise training. This new freely accessible computational tool will prove valuable to the skeletal muscle research community. KEY POINTS: Bulk muscle omics datasets lack fibre type specific information. Our new tool, FibeRtypeR, leverages in-house collected single-fibre profiles allowing for accurate fibre type inference. FibeRtypeR is methodologically robust across omics technologies and workflows. We host FibeRtypeR as an intuitive open-access Shiny app, applicable to new and publicly available transcriptomics and proteomics datasets.
    Keywords:  FibeRtypeR; Skeletal muscle; deconvolution; fibre type; proteomics; transcriptomics
    DOI:  https://doi.org/10.1113/JP290082
  6. FASEB J. 2026 Mar 31. 40(6): e71653
    Does Time Tick Faster in Cerebral Palsy? Accelerated Aging as a Framework for Skeletal Muscle Dysfunction.
    Oscar Horwath, Sebastian Edman, Sudarshan Dayanidhi, Davis Englund, Mark D Peterson, Ferdinand von Walden.
      Cerebral palsy (CP) is the most common cause of childhood-onset physical disability. It results from injury to the developing brain and is characterized by motor impairments, muscle weakness, and fatigue. CP is commonly associated with marked deficits in muscle mass and function, and many individuals experience early declines in physical performance and functional ability as they age. These features resemble changes observed in age-related muscle loss, that is, sarcopenia, raising the possibility of shared underlying mechanisms. This paper hypothesizes that skeletal muscles of individuals with CP undergo accelerated aging, driven by cellular and molecular pathways similar to those implicated in sarcopenia. To support this hypothesis, we highlight emerging evidence of phenotypic overlap between CP and aging muscle, including neuromuscular changes, impaired satellite cell function, altered niche components, chronic inflammation, and metabolic deficits such as reduced capillarization and mitochondrial dysfunction. To test this hypothesis, we propose cross-sectional and longitudinal studies targeting both baseline aging markers and the rate of aging-related changes. These studies should focus on established hallmarks of aging, such as mitochondrial dysfunction, DNA methylation, and markers of cellular senescence. If confirmed, this hypothesis could reshape our understanding of muscle pathology in CP. It may also open up the possibility of repurposing therapeutic strategies demonstrated to be effective in geriatric care for children and young adults with CP.
    Keywords:  DNA methylation; cellular senescence; fibrosis; inflammation; sarcopenia; satellite cells
    DOI:  https://doi.org/10.1096/fj.202504726R
  7. Am J Clin Nutr. 2026 Mar 09. pii: S0002-9165(26)00071-7. [Epub ahead of print] 101262
    Muscle Movement and Metabolism: Exercise and Skeletal Muscle as Mediators of Health. A Report from the 26th Annual Harvard Nutrition Obesity Symposium, 2025.
    Lauren Carollo, Elizabeth A Lawson, Takara L Stanley, Jingyu Wang, Romit Bhattacharya, David J Bishop, Owen Carmichael, Karyn A Esser, Mark A Febbraio, Roger A Fielding, Lindsay T Fourman, Bret H Goodpaster, Laurie J Goodyear, J Sawalla Guseh, Melanie S Haines, John A Hawley, Steven B Heymsfield, Malene E Lindholm, Jonathan Z Long, Michael P Snyder, Martin Whitham, Steven K Grinspoon.
      Skeletal muscle is a crucial facilitator of many of the effects of exercise on metabolic health. Intrinsic myocellular mechanisms, exercise-induced myokine secretion, and crosstalk between multiple organ systems contribute to the maintenance of energy homeostasis, cardiovascular health, strength, cognition, and quality of life. Investigating the molecular underpinnings of the skeletal muscle response to exercise from multiple perspectives, including the genetic, physiological, and environmental factors leading to metabolic dysfunction has advanced our understanding of disease risk and helped identify avenues for the prevention and treatment of metabolic disorders and chronic diseases. The National Institutes of Health-funded Boston Area Nutrition Obesity Research Center, in partnership with the Harvard Medical School Division of Nutrition, hosted their 26th Annual Symposium, "Muscle Movement and Metabolism: Exercise and Skeletal Muscle as Mediators of Health," in June of 2025. Speakers presented novel research and unique perspectives on exercise and skeletal muscle as key determinants of health. This manuscript synthesizes the symposium's major themes: 1) physiological and molecular mechanisms of exercise, 2), clinical implications of physical inactivity and reduced muscle function, and 3) individual variability and personalized medicine. By bridging mechanistic and clinical insights with principles of personalized medicine, the symposium provided key insights into the current landscape of treatments for metabolic diseases and evidence-based strategies for disease prevention.
    Keywords:  Skeletal muscle; diabetes; exercise; metabolism; obesity; sarcopenia
    DOI:  https://doi.org/10.1016/j.ajcnut.2026.101262
  8. J Cachexia Sarcopenia Muscle. 2026 Apr;17(2): e70127
    A Systematic Review and User Reference of Phenotypic and Molecular Characteristics of Dexamethasone-Mediated C2C12 Muscle Atrophy.
    Alexa J Klein, Roger A Vaughan.
       BACKGROUND: Skeletal muscle is a vital part of human physiology and is responsible for numerous essential functions. Not surprisingly, the loss of skeletal muscle mass and function is common in several pathologies including atrophy and sarcopenia, which profoundly impact quality of life of those afflicted. Thus, numerous investigations of potential therapies for mitigating or reversing such pathologies are available. Within these studies, experimental cell culture models such as the murine C2C12 myoblasts are commonly used. Over 100 publications have utilized dexamethasone-treated C2C12 myotubes to investigate various aspects of muscle atrophy. The purpose of this systematic review is to describe the experimental conditions common to these experiments, as well as phenotypical myotube presentation, and gene and protein expression of targets that regulate muscle mass, function, and metabolism.
    METHODS: A systematic review of literature was conducted until 3 January 2025 using PUBMED. Articles were included if (1) C2C12 myotubes were used, (2) the article included a dexamethasone-only group along with appropriate vehicle or true control and (3) the article assessed at least one of the related phenotypical or molecular outcomes of importance to the scope of the review.
    RESULTS: A total of 182 articles were included after screening for relevance and inclusion criteria, which were assessed for outcomes (raw data reported when available or using ratio-metric estimates of relative differences between dexamethasone treatment and control). In 24 of 26 unique experiments that utilized 10 μM dexamethasone and 37 of 39 unique experiments that utilized 100 μM dexamethasone, a decrease in myotube diameter was reported (pooled experimental average estimates from 24-h time points 69.8% ± 7.5% and 66.9% ± 14.7% for 10 and 100 μM, respectively, vs. control). All six studies that utilized 10 μM dexamethasone and all nine that treated myotubes with 100 μM dexamethasone reported reduced fusion index (pooled experimental average estimates from 24-h time points: 67.6% ± 5.3% and 68.4% ± 8.4% for 10 and 100 μM, respectively, vs. control). Dexamethasone-treated myotubes also consistently expressed increased atrophic-related molecular targets including Atrogin-1 and muscle atrophy X box 1 (MuRF1), as well as reductions in anabolic signalling (specifically, mTORC and Akt activation) and mitochondrial function.
    CONCLUSIONS: The striking consistency of these findings suggests dexamethasone treatment of C2C12 myotubes is a reliable method of mimicking many features common to skeletal muscle pathology. This review provides insight into the use and expected outcomes of the dexamethasone-mediated model of atrophy in C2C12 myotubes and may serve as a helpful reference for future experiments utilizing this model.
    Keywords:  Atrogin‐1; C2C12 myotubes; MuRF1; atrophy; dexamethasone; sarcopenia
    DOI:  https://doi.org/10.1002/jcsm.70127
  9. J Appl Physiol (1985). 2026 Mar 09.
    Advanced glycation end-products accumulate preferentially in type I muscle fibers of aging adults but are unchanged by training and polyphenol supplementation.
    Mathias Flensted-Jensen, Ann-Sofie Kleis-Olsen, Cecilie Moe Weinreich, Peter Schjerling, Flemming Dela, Christian Couppé, Rene Brüggebusch Svensson.
      Advanced glycation end-products (AGEs) accumulate with age and may contribute to skeletal muscle decline, yet their distribution within muscle compartments is unknown. Resistance training (RT) and high-intensity interval training (HIIT) improve muscle function, but their effects on muscle AGEs remain unexplored. Polyphenols have antioxidant properties, which could limit AGE formation. This study investigated AGE accumulation in different muscle compartments and whether a 12-week RT + HIIT intervention, with or without polyphenol supplementation could modify AGE levels. Forty-one healthy middle-aged and older adults (55-70 years) were randomized to receive a polyphenol-rich berry extract or placebo for 30 days, followed by 12 weeks of supervised RT + HIIT. Vastus lateralis biopsies were collected before and after the intervention and analyzed for subtypes of AGEs using immunofluorescence. AGE immunoreactivity was quantified in type I and type II fibers and in the extracellular matrix (ECM). AGE immunoreactivity was higher in type I than type II fibers (p < 0.0001) and most pronounced in the ECM (p < 0.05 vs. both fiber types). AGE signals did not differ between sexes and were unrelated to age or plasma IL-6. Neither training nor polyphenol supplementation altered AGE content in fibers or ECM. These findings provide the first evidence of fiber-type-associated localization of AGE immunoreactivity in humans. The absence of change following 12 weeks of RT and HIIT, with or without polyphenol, suggests that AGE turnover in skeletal muscle is limited in short-term interventions, highlighting the need for longer strategies to reduce AGE accumulation.
    Keywords:  Advanced Glycation End-products; Aging; Polyphenols; Resistance Training; Skeletal Muscle
    DOI:  https://doi.org/10.1152/japplphysiol.01093.2025
  10. Front Aging. 2026 ;7 1736069
    Elevated circulating GDF11 and its role in age-related sarcopenia: insights from clinical, transcriptomic, and in vitro analyses.
    Rui Chen, Xin Dai, Hong Wang, Ting Zhang, Zhao Zhang, Yaoxia Liu, Zhen Fan.
       Introduction: Growth differentiation factor 11 (GDF11), a member of the transforming growth factor-β (TGF-β) superfamily, has been implicated in aging and muscle homeostasis. However, its clinical relevance and mechanistic role in age-related sarcopenia remain incompletely defined.
    Methods: Circulating GDF11 levels were quantified in 159 participants stratified by age (<60 vs. ≥60 years) and sarcopenia status. Propensity score matching (PSM) and multivariable logistic regression analyses were applied to identify factors independently associated with sarcopenia. Mendelian randomization (MR) and mediation analyses were conducted to explore potential causal relationships and indirect pathways linking physical activity, circulating GDF11, and sarcopenia. Bioinformatic analyses integrated skeletal muscle transcriptomic datasets and protein-protein interaction (PPI) networks. Mechanistically, differentiated C2C12 myotubes were treated with recombinant GDF11 (rGDF11), followed by assessment of canonical SMAD signaling and muscle atrophy-related markers, including phosphorylated SMAD3 (immunoblotting) and the E3 ubiquitin ligases Atrogin-1 and MuRF1 at both protein (immunoblotting) and transcript (RT-qPCR) levels.
    Results: Circulating GDF11 concentrations were significantly higher in older adults than in younger individuals and were further elevated in participants with sarcopenia, both before and after PSM. Multivariable logistic regression identified circulating GDF11 as an independent risk factor for sarcopenia. MR analysis supported a causal protective effect of physical activity on sarcopenia-related traits, while mediation analysis indicated that circulating GDF11 partially mediated this association. Transcriptomic analyses demonstrated that GDF11 mRNA expression in skeletal muscle remained stable regardless of sarcopenia or exercise status, suggesting that elevated circulating GDF11 is unlikely to originate from skeletal muscle. PPI network analysis highlighted enrichment of activin receptor (ACVR)-SMAD signaling pathways. Consistent with these predictions, rGDF11 treatment activated SMAD3 phosphorylation and induced a dose-dependent upregulation of Atrogin-1 and MuRF1 at both the protein and mRNA levels in C2C12 myotubes, supporting activation of a pro-atrophic ubiquitin-proteasome program.
    Conclusion: Circulating GDF11 is elevated in individuals with sarcopenia and appears to partially mediate the protective effects of physical activity. Together with functional evidence of activation of catabolic signaling pathways, these findings support a contributory role of circulating GDF11 in age-related muscle loss.
    Keywords:  Gdf11; SMAD signaling; physical activity; sarcopenia; transcriptomics
    DOI:  https://doi.org/10.3389/fragi.2026.1736069
  11. FASEB J. 2026 Mar 31. 40(6): e71677
    A Novel Dysferlin-Binding Kinase CK2α Promotes Plasma Membrane Repair in Dysferlinopathy.
    Naoko Nakamura, Naoki Suzuki, Shin-Ichiro Kanno, Rei Yamanaka, Hiroya Ono, Rumiko Izumi, Rui Muliang, Christian Borgo, Akiyuki Ohno, Ryuhei Harada, Saki Saito, Yukino Funayama, Kensuke Ikeda, Shio Mitsuzawa, Yasuaki Watanabe, Tomomi Shijo, Tetsuya Akiyama, Toshiaki Takahashi, Makoto Kanzaki, Shion Osana, Hitoshi Warita, Yoshitsugu Aoki, Satoru Ebihara, Mauro Salvi, Ryoichi Nagatomi, Akira Yasui, Katsuya Miyake, Masashi Aoki.
      Dysferlinopathy is an adult-onset form of muscular dystrophy caused by mutations in the dysferlin gene and is inherited in an autosomal recessive manner. Dysferlin is primarily known for its role in plasma membrane repair. Although several proteins associated with dysferlin have been identified, many aspects of its signaling pathways and protein-protein interactions remain unclear. Here, we focused on the region between the third and fourth C2 domains, where frequent genetic mutations occur and functional domains are concentrated, and identified the protein kinase CK2α (formerly known as casein kinase 2) as a novel dysferlin-binding protein. CK2α was found to accumulate at membrane injury sites along with dysferlin in mouse skeletal muscle, and membrane repair was delayed in CK2α knockout cells. Furthermore, overexpression of CK2α in dysferlin-deficient mouse muscle led to improved membrane repair. Additionally, we revealed that CK2α plays a role in phosphorylating annexin A1, which is known to bind to dysferlin and is involved in plasma membrane repair. Our results indicated that CK2α controls membrane repair by participating in the phosphorylation of annexin A1. The molecular interplay among dysferlin, CK2α, and phosphorylated annexin A1 represents a novel therapeutic target for promoting membrane repair.
    Keywords:  Dysferlinopathy; annexin A1; plasma membrane repair; protein kinase CK2; skeletal muscle
    DOI:  https://doi.org/10.1096/fj.202500773RRR
  12. Metabolism. 2026 Mar 09. pii: S0026-0495(26)00087-9. [Epub ahead of print]179 156577
    CSRP3 promotes skeletal muscle remodeling toward aerobic metabolism and enhances exercise endurance through increasing LDHD activity.
    Xiuying Jiang, Zhaolu Wang, Rui Li, Yihao Liu, Boping Liu, Gongshe Yang, Jianjun Jin, Xin'e Shi.
      Exercise performance and skeletal muscle homeostasis are influenced by myofiber type composition. Cysteine and glycine-rich protein 3 (CSRP3) is highly expressed in the oxidative fiber-rich mammalian soleus muscle. However, the mechanistic basis of CSRP3's involvement in skeletal muscle development and myofiber type specification remains unclear. Here, we used various exercise training (aerobic/anaerobic) bioinformatics datasets and experimental model systems involving live mice and cell lines to determine the role of CSRP3 in driving mitochondrial metabolic reconfiguration, skeletal muscle fiber type remodeling, and improved exercise endurance. CSRP3 promotes the formation of oxidative myofibers while suppressing glycolytic myofiber differentiation. It enhances mitochondrial biogenesis, oxidative phosphorylation capacity, and elevates mitochondrial membrane potential. Conversely, AAV-mediated CSRP3 knockdown perturbs mitochondrial energy metabolism, compromises exercise performance, and reduces the proportion of oxidative myofibers. Mechanistically, CSRP3 binds to D-lactate dehydrogenase (LDHD) via a specific 33-amino acid region, promoting D-lactate metabolism in skeletal muscle. This interaction regulates mitochondrial morphology, biogenesis, oxidative phosphorylation efficiency, and TCA cycle activity, ultimately driving skeletal muscle mitochondrial energy metabolic rewiring and skeletal muscle fiber type remodeling.
    Keywords:  CSRP3; Exercise endurance; LDHD; Mitochondria; Myofiber type remodeling; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.metabol.2026.156577
  13. Nat Commun. 2026 Mar 12.
    PTBP1 inhibition reprograms myogenesis to rescue impaired muscle regeneration in mdx mice through correcting E2A splicing.
    Shusheng Fan, Xiaoyun Liu, Qian Pan, Haowei Tong, Qiaoqiao Gui, Guangyao Guo, Huitao Hong, Wanting Hu, Xiaofei Huang, Lei Zhao, Xihua Li, Qinwei Yu, Luyong Zhang, Zhenzhou Jiang.
      Duchenne muscular dystrophy, caused by mutations in the DMD gene encoding dystrophin, is a severe progressive muscle-wasting disorder characterized by impaired muscle regeneration. We reveal the alternative splicing of transcription factor E2-alpha (encoding transcription factors E12 and E47) plays a pivotal role in myogenic progression. E47 is highly expressed in proliferating myoblasts and promotes proliferation, whereas E12 is upregulated during differentiation and drives myogenic commitment. Mechanistically, we identify the nuclear splicing factor polypyrimidine tract binding protein 1 as a key regulator of transcription factor E2-alpha mutually exclusive alternative splicing. Polypyrimidine tract binding protein 1 levels decline during normal myoblast differentiation, facilitating the switch from E47 to E12. However, in Duchenne muscular dystrophy patients and mdx mice, polypyrimidine tract binding protein 1 remains aberrantly elevated, resulting in dysregulated E47/E12 ratios (increased E47 and decreased E12), which disrupts myogenic differentiation and impairs muscle regeneration. Therapeutically, polypyrimidine tract binding protein 1 knockdown restores myoblast differentiation, enhances muscle repair, and improves muscle function in mdx mice. Furthermore, we demonstrate that dergrasyn, a deubiquitinase inhibitor, induces polypyrimidine tract binding protein 1 degradation, restores myogenic differentiation, and ameliorates dystrophic pathology. Our findings identify polypyrimidine tract binding protein 1 as a potential therapeutic target for Duchenne muscular dystrophy and highlight modulation of transcription factor E2-alpha splicing as a promising strategy to restore muscle regeneration.
    DOI:  https://doi.org/10.1038/s41467-026-70669-9
  14. Sci Adv. 2026 Mar 13. 12(11): eaed2258
    0.33g mitigates muscle atrophy while 0.67g preserves muscle function and myofiber type composition in mice during spaceflight.
    Ryosuke Tsuji, Ryo Fujita, Takuto Hayashi, Shunya Sadaki, Tatsuya Matsumoto, Yuri Inoue, Yuka Murakami, Michito Hamada, Masafumi Muratani, Hiroe Kobayashi, Akane Yumoto, Maki Okada, Daisuke Kamimura, Risa Okada, Takafumi Suzuki, Ryo Kurosawa, Akihito Otsuki, Seizo Koshiba, Martha Hotz Vitaterna, Charles A Fuller, Marie Mortreux, Dong-Min Sung, Jason Ciola, Seward B Rutkove, Jennifer Coulombe, Takashi Kudo, Masayuki Yamamoto, Mary L Bouxsein, Dai Shiba, Satoru Takahashi.
      As human space exploration advances, understanding how different gravity levels affect skeletal muscle is critical for long-term health. Among the major organ systems, skeletal muscle is particularly sensitive to gravitational unloading, yet the gravity threshold required to maintain homeostasis remains unclear. Using the Multiple Artificial-gravity Research System aboard the International Space Station, mice were exposed to graded gravity levels, microgravity, 0.33g, 0.67g, and 1g, and their muscles were analyzed postflight. In the gravity-sensitive soleus, the cross-sectional area was preserved at 0.33g, while the slow-to-fast myofiber transition was partially suppressed at 0.33g and fully prevented at 0.67g. Functional measures, including forelimb grip strength and electrical impedance myography, indicated that 0.67g was sufficient to maintain muscle performance. Plasma metabolomics identified 11 metabolites with gravity-dependent changes, suggesting potential biomarkers for monitoring physiological adaptation. Collectively, these results identify 0.67g as a critical threshold for mitigating spaceflight-induced muscle atrophy and myofiber type transitions.
    DOI:  https://doi.org/10.1126/sciadv.aed2258
  15. Int J Mol Sci. 2026 Mar 06. pii: 2451. [Epub ahead of print]27(5):
    Systemic Integrative Mechanisms and Intervention Strategies in Exercise-Induced Skeletal Muscle Damage: Evidence from Animal, Clinical, and Multi-Omics Studies.
    Tianhang Peng, Zike Zhang, Ju Wei, Ni Ding, Wanyuan Liang, Xiuqi Tang.
      Exercise-induced muscle damage (EIMD) has classically been attributed to localized mechanical disruption following eccentric contractions. Emerging evidence, however, indicates that EIMD represents a systems-level failure of stress integration within skeletal muscle rather than a purely mechanical lesion. Mechanical loading initiates disturbances in intracellular Ca2+ homeostasis, which interact with metabolic stress, redox imbalance, and immune activation to form self-reinforcing feedback loops. When compensatory capacity is exceeded, transient injury may shift toward maladaptive remodeling marked by mitochondrial dysfunction, ferroptosis, chronic inflammation, and impaired regeneration. Recent studies identify reactive oxygen species accumulation, iron-dependent lipid peroxidation, dysregulated energy sensing, and aberrant immune polarization as key molecular tipping points governing injury reversibility. Beyond their regenerative role, satellite cells act as integrators of metabolic history and epigenetic memory, linking repetitive injury to reduced muscle adaptability, age-related sarcopenia, and heightened metabolic disease risk. Here, we synthesize evidence from animal models, clinical studies, and multi-omics analyses to establish a systems biology framework for EIMD. We delineate the spatiotemporal interactions among mechanical, metabolic, oxidative, immune, and regenerative modules; identify regulatory nodes that determine adaptive repair versus pathological outcomes; and critically evaluate current nutritional, physical, pharmacological, and regenerative interventions from a mechanism-oriented perspective. Finally, we discuss how multi-omics, digital monitoring, and individualized rehabilitation may enable precision management of EIMD and advance understanding of muscle stress resilience and adaptive limits.
    Keywords:  exercise-induced muscle damage; ferroptosis; multi-omics integration; oxidative stress; satellite cells; stress integration
    DOI:  https://doi.org/10.3390/ijms27052451
  16. FASEB J. 2026 Mar 31. 40(6): e71660
    Parthenolide Attenuates Skeletal Muscle Atrophy Through Regulation of Protein Homeostasis and Inhibition of Inflammation.
    Yu Bai, Weiqing Li, Yahong Lu, Hehuan Lai, Lin Ye, Kechi Li, Chendi Wang, Yi Ding, Wenhao Li, Yitao Chen, Keping Gan, Zhenzhong Chen, Dengwei He.
      Skeletal muscle atrophy is a complex condition associated with various diseases, including chronic inflammation, and significantly impairs quality of life. Parthenolide, a bioactive compound derived from Tanacetum parthenium (feverfew), is well known for its anti-inflammatory properties, but its potential therapeutic effects on muscle atrophy remain underexplored. In this study, we evaluated the protective effects of parthenolide against muscle atrophy in both in vitro and in vivo models. Using TNF-α-treated C2C12 myotubes and a lipopolysaccharide (LPS)-induced muscle atrophy in mice, we assessed the impact of parthenolide through histology, functional assays, and molecular analyses. Our results demonstrated that parthenolide promoted myoblast differentiation and alleviated TNF-α-induced myotube atrophy by restoring myosin heavy chain (MyHC) expression and inhibiting muscle-specific ubiquitin ligases MuRF1 and MAFbx. Mechanistically, parthenolide regulates protein homeostasis by activating the Akt-mTOR pathway, inhibiting FoxO transcription factors, and suppressing inflammation via NF-κB inhibition. In vivo, parthenolide effectively reduced LPS-induced muscle mass loss, muscle fiber atrophy, and grip strength decline, with improvements linked to the downregulation of atrophy markers and the preservation of MyHC levels in muscle tissue. These findings indicate that parthenolide mitigates skeletal muscle atrophy through dual regulation of protein homeostasis and inflammation, highlighting its potential as a novel therapeutic agent for muscle-wasting disorders such as sarcopenia.
    Keywords:  Akt–mTOR pathway; NF‐κB; inflammation; muscle atrophy; natural compounds; parthenolide; protein homeostasis
    DOI:  https://doi.org/10.1096/fj.202504024RR
  17. Exp Gerontol. 2026 Mar 05. pii: S0531-5565(26)00061-6. [Epub ahead of print]217 113083
    Exploration of the co-regulatory mechanism of calorie restriction and endurance exercise on elderly skeletal muscle and its potential intervention targets.
    Donghui Zhu, Xiuxiu Chen.
      This study aims to explore the shared transcriptomic features of caloric restriction (CR) and endurance exercise in skeletal muscle among older adults. As age increases, muscle atrophy gradually becomes a common issue of functional decline in the elderly. Utilizing bioinformatics analysis, this research identified 101 overlapping differentially expressed genes (DEGs) involved in both CR and endurance exercise. These genes are primarily enriched in key biological pathways related to longevity, Apelin signaling, AMPK signaling, FoxO signaling, and cGMP-PKG signaling pathways. Additionally, we identified 10 key genes (such as LPL, PPARGC1A, and IGF1), 4 transcription factors (FOXC1, POU2F2, GATA2, and STAT3), and 4 microRNAs (miR-155-5p, miR-124-3p, miR-1-3p, and miR-16-5p) interacting with these genes. Drug-gene interaction analysis identified carotuximab as a compound with potential relevance for future investigation in the context of muscle aging. These findings provide new insights into the molecular mechanisms underlying muscle functional decline in the elderly and propose potential targets and drugs for intervention development.
    DOI:  https://doi.org/10.1016/j.exger.2026.113083
  18. Exp Gerontol. 2026 Mar 10. pii: S0531-5565(26)00069-0. [Epub ahead of print]217 113091
    Atmospherically relevant PM2.5 promotes age-related muscle atrophy in an age-dependent manner.
    Zilin Wang, Wenduo Liu, Sang Hyun Kim.
       BACKGROUND: Maintaining the quality and function of skeletal muscle in the older adult has become a key topic in successful aging. However, the impact of environmental factors on skeletal muscle aging is often overlooked.
    METHODS: This study used male mice aged 1, 6, and 15 months, which were each exposed to PM2.5 (50 μg/m3, 2 h/day) for 5 days, and the skeletal muscles of each age group were analyzed one month after the end of the treatment to verify the age-specific effects of PM2.5 on the skeletal muscle system.
    RESULTS: Total body weight and lean body weight were significantly affected by age and PM2.5 exposure. However, fat levels were not affected by PM2.5 exposure. PM2.5 exposure promoted the development of age-related muscle atrophy by inducing oxidative stress and increased expression of Myostatin in skeletal muscle of older adults. On the other hand, the damaging effect of PM2.5 exposure on skeletal muscle mitochondria was age-related. Young and older adult mice showed extensive mitochondrial damage after PM2.5 exposure. In particular, older adults showed a marked increase in mitochondrial fission and mitophagy after PM2.5 exposure.
    CONCLUSIONS: The effects of PM2.5 exposure on the skeletal muscle system are age-specific, with distinct damaging effects during growth and aging, whereas skeletal muscles in middle-aged mice are resistant to PM2.5-induced damage.
    Keywords:  Age groups; Air pollution; Atrophy; Mitochondrial damage; Mitophagy
    DOI:  https://doi.org/10.1016/j.exger.2026.113091
  19. Leg Med (Tokyo). 2026 Mar 04. pii: S1344-6223(26)00057-X. [Epub ahead of print]82 102829
    Molecular biological effect of Rbm20 I538T knock-in mice on skeletal muscle.
    Aya Miura, Takuma Yamamoto, Minori Nishiguchi, Hajime Nishio.
       INTRODUCTION: RBM20 regulates pre-mRNA splicing, and its mutations cause dilated cardiomyopathy by disrupting cardiac RNA splicing, particularly of the TTN gene. While RBM20 is known to affect TTN splicing in the heart, its role in skeletal muscle remains unclear. This study investigated the effects of an RBM20 variant using an Rbm20 I538T knock-in mouse model, performing pathological and RNA-seq analyses to assess its impact on skeletal muscle.
    METHODS: We used Rbm20 I538T knock-in mouse and performed pathological and RNA-seq analyses to evaluate the effect of the variant on skeletal muscle.
    RESULTS AND DISCUSSION: Histopathological examination revealed no skeletal muscle abnormalities in any genotype. Although potential splicing effects on Ttn and Ldb3 were considered, no abnormal splicing was detected. Differentially expressed gene analysis showed no differences among genotypes. Therefore, we conclude that the Rbm20 I538T variant does not affect the splicing of skeletal structural proteins or lead to a skeletal muscle phenotype.
    Keywords:  Alternative splicing; Knock-in mice; RBM20; RNA recognition motif; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.legalmed.2026.102829
  20. Animals (Basel). 2026 Mar 09. pii: 855. [Epub ahead of print]16(5):
    Canine Adipose MSC-Derived Exosomes Ameliorate Skeletal Muscle Injury in Mice.
    Jiaxuan Gao, Yujue Li, Yougang Zhong.
      Severe skeletal muscle injury in dogs can result in muscle atrophy, fibrotic remodeling, and fat accumulation, leading to skeletal muscle dysfunction and impaired quality of life. However, there is currently no effective treatment available. This study aims to investigate the potential of canine adipose mesenchymal stem cell-derived exosomes (cADMSC-Exos) as a novel acellular therapy for the repair of muscle atrophy and injury. cADMSCs and their derived exosomes were isolated and characterized. A dexamethasone-induced C2C12 myotube atrophy model was established to evaluate the effects of cADMSC-Exos on muscle atrophy by assessing myotube morphology and the expression of atrophy-related factors. Subsequently, a glycerol-induced mouse muscle injury model was constructed. Through histological analysis and Western blot, the efficacy and safety of cADMSC-Exos in vivo were systematically evaluated. Results indicated that cADMSC-Exos demonstrated significant anti-atrophic activity in both two models, ameliorating skeletal muscle atrophy and the upregulation of muscle RING finger 1 (MuRF1) and muscle atrophy F-box (Atrogin-1) (p < 0.05), consistent with morphological alterations. Moreover, cADMSC-Exos markedly alleviated fibrosis and fatty infiltration in injured muscle tissue (p < 0.0001). Overall, these findings indicate that cADMSC-Exos promote muscle repair and attenuate pathological remodeling by modulating the local microenvironment and protein expression, highlighting their potential as a therapeutic strategy for muscular disorders.
    Keywords:  canine adipose-derived mesenchymal stem cells; exosomes; fibrosis; lipid infiltration; muscle atrophy; regenerative therapy; skeletal muscle injury; veterinary medicine
    DOI:  https://doi.org/10.3390/ani16050855
  21. Burns. 2026 Mar 03. pii: S0305-4179(26)00100-2. [Epub ahead of print]52(4): 107948
    Burn injury dysregulates protein signaling in type 1 and type 2 muscles in rats.
    Dorien Dombrecht, Ulrike Van Daele, Birgit Van Asbroeck, David R Schieffelers, Pieter-Jan Guns, Eric van Breda.
       BACKGROUND: Skeletal muscle wasting is one of the systemic hallmarks of severe burn injuries. The underlying mechanisms of muscle wasting post-burn, and in particular the differences between muscle fiber types, are not well understood. This study aimed to investigate the protein signaling pathways involved in skeletal muscle atrophy following severe burn injury.
    METHODS: 11 rats were submitted to sham injury and 11 rats to a severe burn (40% total body surface area burn) using the Walker-Mason burn model. Muscle samples from predominantly type II m. extensor digitorum longus (EDL) and predominantly type I m. soleus (SOL) were collected 40 days post-burn. Body and muscle weights, immunohistochemistry and Western blotting were used to assess anthropometric differences and the expression of key proteins involved in protein imbalance causing muscle wasting.
    RESULTS: Rats with severe burn injury showed less body weight gain (39.73 ± 10.97 g vs 77.12 ± 4.83 g; p < 0.01) and lower muscle wet weights of both SOL (123.1 ± 3.63 mg vs 102.7 ± 3.67 mg; p < 0.001) and EDL (127.9 ± 2.95 mg vs 110.3 ± 2.80 mg; p < 0.001) compared to sham-treated rats. Immunohistochemical analysis revealed no significant differences in fiber type distribution between the groups. Western blot analysis showed altered expression of proteins involved in protein synthesis and proteolysis pathways, with differences between SOL and EDL muscles. In SOL, severe burns induce inhibition of anabolic pAkt (p < 0.0001) and eEF2 signaling (p < 0.05), while in EDL increased levels of pAkt (p < 0.01) were found. Catabolic E3 ligases MURF1,2,3 and Atrogin-1 show higher activation in SOL after severe burn injury (p < 0.0001; both) but not in EDL, where decreases were found (p < 0.0001; p < 0.001; respectively). Analysis of myokines post-burn in SOL show lower expression of Decorin (p < 0.0001) and higher of myostatin (p < 0.0001), but in EDL both myostatin and irisin expressions were lower (p < 0.001; p < 0.05; respectively).
    CONCLUSIONS: Severe burn injury resulted in skeletal muscle wasting, as evidenced by decreased body weight gain in growing rats and reduced muscle weights. Protein signaling pathways related to protein synthesis and proteolysis are dysregulated in muscles of burned rats, with significant differences between slow- and fast-twitch muscles. Further research is needed to understand the long-term effects of postburn metabolism on skeletal muscle protein balance and develop targeted therapies to prevent muscle wasting in burn survivors.
    Keywords:  Burns; Muscle atrophy; Myokines; Signaling pathways; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.burns.2026.107948
  22. Free Radic Biol Med. 2026 Mar 07. pii: S0891-5849(26)00189-9. [Epub ahead of print]249 103-116
    The role of metabolic stress, xanthine oxidase, NOX2, and redox-related signalling in regulating ACE2 protein expression in exercising human skeletal muscle.
    Giovanni Garcia-Perez, Eduardo Garcia-Gonzalez, Victor Galvan-Alvarez, Miriam Martinez-Canton, Elisabetta De Nigris, Alfredo Santana, Jose A L Calbet, Marcos Martin-Rincon, Angel Gallego-Selles.
      The renin-angiotensin system (RAS) modulates skeletal muscle vascular and metabolic function depending on the balance between the "classical" angiotensin-converting enzyme (ACE1)/angiotensin II/angiotensin II type 1 receptor (AT1R) axis and the counter-regulatory angiotensin-converting enzyme 2 (ACE2)/angiotensin 1-7/Mas Receptor (MasR) and angiotensin II type 2 receptor (AT2R) pathways. Although ACE2 has been implicated in reactive oxygen species (ROS)-related responses, no direct mechanistic evidence in human skeletal muscle has been reported. This study aimed to determine whether the protein expression of ACE2 and other components of the RAS are modulated by intense exercise and redox-sensitive signalling mechanisms in human skeletal muscle. We hypothesised that exhaustive exercise would increase ACE2 expression, and that this effect would be amplified by severe acute hypoxia and post-exercise ischaemia via redox-signalling mechanisms. Eleven active men performed incremental exercise to exhaustion in normoxia (PIO2: 143 mmHg) and severe acute hypoxia (PIO2: 73 mmHg). At exhaustion, the circulation of one leg was occluded (300 mmHg) for 60 s. Muscle biopsies (vastus lateralis) were taken before and after exercise (at 10 and 60 s). ACE2 protein expression was increased at exhaustion, independently of inspired O2, and remained elevated during the 60 s post-exercise ischaemia, while it returned to baseline in the leg that recovered with free circulation. Transmembrane protease, serine 2 (TMPRSS2) protein expression increased at exhaustion and rose further with ischaemia. AT2R protein expression decreased modestly, whereas MasR, ACE1 and AT1R remained unchanged. Phospho-p47phox Ser359 (a proxy for NADPH oxidase 2 (NOX2) activation) and xanthine oxidase (XO) protein expression increased by exercise and even further by ischaemia. ACE2 correlated positively with TMPRSS2 protein expression and with redox-sensitive signalling and antioxidant enzyme expression. In another experiment, Zynamite® PX (a polyphenol mixture containing mangiferin and quercetin, known to inhibit NOX2 and XO in vitro) was administered every 8 h for 48 h before incremental exercise to exhaustion. Zynamite® PX prevented NOX2 activation and the increase of XO protein expression induced by exercise, thereby blunting the upregulation in ACE2 observed in the non-supplemented group. Our data reveal that ACE2 is a fast, exercise-responsive enzyme that elevates its expression in human skeletal muscle during intense exercise via a redox-linked mechanism, a response inhibited by antioxidant polyphenol supplementation.
    Keywords:  Ischaemia; NOX2; Redox signalling; Renin–angiotensin system; Skeletal muscle; Xanthine oxidase
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.03.011
  23. NPJ Regen Med. 2026 Mar 10.
    Non-canonical muscle stem cells and other lessons from regenerative vertebrates.
    Vijayishwer Singh Jamwal, Wouter Masselink, Karen Crawford, Prayag Murawala.
      In this perspective, we explore the developmental mechanisms of muscle stem cells in multiple non-mammalian vertebrate species, and we compare these phenomena to those in mammals. Particularly, we discuss two recently described populations of noncanonical muscle progenitors in regenerative vertebrates: one in zebrafish and one in axolotl. We discuss the capabilities of these two populations during muscle development and regeneration, including the implications for muscle repair in mammals.
    DOI:  https://doi.org/10.1038/s41536-026-00468-9
  24. Am J Physiol Cell Physiol. 2026 Mar 11.
    Muscle collagen accumulation is not a universal feature of human aging: a systematic review.
    Allyson M Schweitzer, Max J Abercrombie, Justin M Losciale, Cameron J Mitchell.
      The extracellular matrix is critical to skeletal muscle structure and function, with collagen its largest component. Fibrosis, excessive collagen accumulation, disrupts muscle function. While animal studies consistently report age-related intramuscular collagen accumulation, human findings are inconsistent. This systematic review evaluated primary, peer-reviewed studies to assess if collagen accumulation is a universal feature of human aging. The review was registered on PROSPERO (CRD42024569964). Following PRISMA guidelines, five databases (MEDLINE [Ovid], Web of Science, SCOPUS, CINAHL, SPORTDiscus) were searched in January 2026 for studies comparing intramuscular collagen/extracellular matrix content in healthy young and older (> 60 years) adults. Eligible studies used histological or hydroxyproline techniques to quantify collagen/extracellular matrix content. Study screening, review, data extraction, and risk of bias were performed independently by two reviewers. Results were synthesized narratively. Nine studies (including 122 young and 119 older adults) were included. Four reported no age-related differences, four showed age-related intramuscular collagen accumulation, and one found equivocal results when distinguishing perimysial from endomysial collagen. Considerable heterogeneity was observed in collagen quantification methods and control of mediators including hypertension, diabetes, aerobic fitness and physical activity. Studies with rigorous control generally found no age-related differences, whereas those with limited control generally reported age-related collagen accumulation. Collagen accumulation is not an inevitable feature of human chronological aging. Observed differences may instead reflect comorbidities or lifestyle factors associated with aging; thus, through these mediators, muscle collagen accumulation may be elevated in older populations. Future studies should control mediators and investigate mechanisms regulating collagen in skeletal muscle.
    Keywords:  Aging; Collagen; Extracellular matrix; Fibrosis; Skeletal muscle
    DOI:  https://doi.org/10.1152/ajpcell.00789.2025
  25. Mol Ther. 2026 Mar 11. pii: S1525-0016(26)00195-4. [Epub ahead of print]
    SORT LNPs encapsulating Cas9 mRNA achieve efficient editing in skeletal muscle in a dystrophic mouse model.
    Sukanya Iyer, Katelyn Daman, Yehui Sun, Amanda Tutto, Sarah E Holbrook, Anya T Joynt, Jing Yan, Prajakta Ambegaokar, Dongsheng Guo, Pengpeng Liu, Jennifer Stauffer, Stacy A Maitland, Sang M Lee, Yufen Xiao, Hsi-Chien Huang, Lihua J Zhu, Thomas L Gallagher, Gregory A Cox, Allison M Keeler, Daniel J Siegwart, Charles P Emerson, Scot A Wolfe.
      Limb Girdle Muscular Dystrophy (LGMD) is the fourth most common type of muscular dystrophy. Gene editing holds promise for treating neuromuscular disorders such as LGMD, but clinical translation remains challenging due to lack of complementary delivery tools for skeletal muscle. Lipid nanoparticles (LNPs) offer a promising platform for transient delivery of gene editing reagents as mRNA or ribonucleoprotein complexes (RNPs) to skeletal muscle but editing efficiencies remain modest. While lipid compositions have been optimized to improve delivery to muscle, the impact of cargo type on editing efficiency, biodistribution and immune response has not been evaluated. Here we demonstrate that selective organ targeting (SORT) LNPs encapsulating optimized Cas9 cargo facilitate efficient, local delivery to skeletal muscle. Using a LGMDR7 mouse model harboring a mutation in TCAP as a proof-of-concept target, we show that LNP cargo type impacts LNP size, delivery to neighboring muscle groups and editing efficiency. RNP and mRNA LNPs also provoked distinct innate and adaptive immune responses upon repeated dosing. The optimized SORT LNP platform resulted in 40% restoration of Telethonin expression in treated muscle. Overall, these findings offer valuable insights for the continued development of LNP-based gene editing reagents to facilitate disease-modifying interventions for neuromuscular diseases.
    DOI:  https://doi.org/10.1016/j.ymthe.2026.03.010
  26. bioRxiv. 2026 Feb 28. pii: 2026.02.26.708335. [Epub ahead of print]
    Single-Cell Spatial Proteomics Uncovers Molecular Interconnectivity among Hallmarks of Aging.
    Seungmin Yoo, Christopher Young, Liying Li, Lingraj Vannur, Junming Zhuang, Fan Zheng, Meiying Wu, Julie K Andersen, Chuankai Zhou.
      Aging is accompanied by conserved hallmarks including genomic instability, epigenetic alterations, loss of proteostasis, and mitochondrial dysfunction, but how these processes emerge and become mechanistically linked remains unclear. Here we leverage a proteome-wide, single-cell, subcellular atlas of protein expression, localization, and aggregation across yeast replicative aging to map hallmark-linked remodeling in its spatial context. We identify hundreds of previously unappreciated molecular changes that underlie major hallmarks of aging and show that hallmark phenotypes frequently manifest as compartment-specific erosion of spatial confinement, relocalization, and aggregation. 91.6% human orthologs of these hallmark-linked yeast proteins also change during human aging. Integrating these spatial phenotypes reveals many molecular connections linking different hallmarks. Temporal analysis suggests that disorganization of nucleolar ribosome biogenesis, proteostasis decline, and mitochondrial dysfunction precede other hallmarks. Together, our findings substantially deepen the molecular underpinnings of aging hallmarks and provide a framework for linking them into a hierarchical sequence of cellular failures.
    DOI:  https://doi.org/10.64898/2026.02.26.708335
  27. Front Immunol. 2026 ;17 1757925
    Eccentric treadmill training and skeletal muscle immunometabolic responses in HFD-induced insulin resistance.
    Wei Luo, Yuanyuan Wang, Siyi He, Shijin Zhao, Yue Zhou, Lei Ai.
       Introduction: In recent years, repeated eccentric exercise has gained increasing attention as a potentially superior intervention for ameliorating insulin resistance (IR). However, the underlying mechanisms responsible for these effects remain incompletely understood. This study aims to investigate the effects and underlying mechanisms of moderate-intensity eccentric treadmill training on skeletal muscle IR.
    Methods: A mouse model of IR was established using a high-fat diet (HFD) for 12 weeks, followed by an 8-week eccentric treadmill training. In vitro, RAW264.7 macrophages under high-glucose conditions were treated with the AKT agonist SC79 or inhibitor MK2206. Comprehensive assessments included protein localization and expression (immunofluorescence, Western blot), macrophage polarization status (flow cytometry), inflammatory infiltration (H&E staining), cytokine profiles (ELISA), and cellular viability (CCK-8).
    Results: HFD-induced IR led to elevated pro-inflammatory factors and reduced GLUT4, F4/80 & phospho-AKT (Ser473) co-localization, IL-10, and Arg-1 levels, all of which were significantly reversed by eccentric training. In vitro, high glucose reduced the phospho-AKT (Ser473)/AKT ratio, while SC79 suppressed an M1-like pro- inflammatory phenotype, as indicated by decreased iNOS and F4/80&CD86 double-positive rates and increased Arg-1 and F4/80&CD206 double-positive rates. These effects were abolished by MK2206.
    Conclusion: Moderate-intensity eccentric treadmill training ameliorates HFD-induced skeletal muscle IR, likely driven by AKT-mediated reduction in pro-inflammatory M1 macrophage polarization.
    Keywords:  AKT signal; eccentric exercise; insulin resistance; macrophages; skeletal muscle
    DOI:  https://doi.org/10.3389/fimmu.2026.1757925
  28. Biomater Adv. 2026 Mar 05. pii: S2772-9508(26)00108-1. [Epub ahead of print]184 214810
    3D bioprinting of alginate/gelatin hydrogels with tunable mechanical properties for skeletal muscle regeneration.
    Kapil D Patel, Mark R Shannon, Adam W Perriman.
      Mechanically tunable double-network (DN) hydrogels are emerging as versatile biomaterials for soft tissue engineering, yet achieving precise control over their architecture and mechanics remains challenging. Here, we develop soft ionically crosslinked double-network hydrogels composed of sodium alginate (Alg) and gelatin (Gel) for three-dimensional (3D) skeletal muscle tissue engineering. Calcium ion (Ca2+) crosslinking of the Alg generated entrapped Gel microphases, producing mechanically reinforced hydrogels with interconnected microporous structures. Three compositions of Alg/Gel (Alg:Gel = 1:0, 1:0.25, and 1:0.50 w/w) were fabricated, in which increasing Gel content significantly modulated hydrogel properties. The compressive modulus increased from 14.8 kPa to 23.7 kPa, while the Alg:Gel (1:0.25) formulation exhibited the highest tensile strength of 194 kPa. The storage (G') and loss (G") moduli also increase with gelatin incorporation and exhibit maxima of 43.5 kPa (G'), and 9.6 kPa (G") for Alg/Gel (1:0.50). Developed Alg/Gel hydrogels were explored as bioinks for 3D bioprinting, enabling fabrication of mechanically stable 3D complex structures with high shape fidelity. C2C12 myoblasts encapsulated in 3D bioprinted Alg/Gel hydrogels exhibited robust metabolic activity, cell viability (>90%), and enhanced proliferation. Furthermore, the Alg/Gel hydrogels supported enhanced expression of MyoD, MyoG, myosin heavy chain (MYH), driving efficient myogenic differentiation and formation of multinucleated myotubes. Together, the tunable mechanics, microporosity, viscoelastic relaxation, and gelatin-mediated bioactivity position Alg/Gel double-network hydrogels as a promising bioink platform for 3D bioprinted skeletal muscle regeneration.
    Keywords:  3D bioprinting; Double-network; Hydrogel; Skeletal muscle; Tissue engineering
    DOI:  https://doi.org/10.1016/j.bioadv.2026.214810
  29. Int J Mol Sci. 2026 Mar 04. pii: 2381. [Epub ahead of print]27(5):
    Moderate Aerobic Training Causes Muscle Wasting in a DMBA-Induced Sarcoma Rat Model.
    Rafael Ribeiro Correia, Allice Santos Cruz Veras, Maria Eduarda Almeida Tavares, Victor Rogério Garcia Batista, Sarah Santiloni Cury, Jakeline Santos Oliveira, Geysson Javier Fernandez, Brittany R Counts, Omnia U Gaafer, Sara Ota, Mateus Machado Frigo, Rebeca Vieira E Magalhães Rodrigues, Larissa Victorino Sampaio, Antonio Hernandes Chaves-Neto, Robson Francisco Carvalho, Teresa A Zimmers, Giovana Rampazzo Teixeira.
      Cancer cachexia, characterized by severe body weight loss, negatively affects patient quality of life and survival. Although moderate exercise benefits healthy and chronically ill individuals, and the effect of exercise in cachexia generally appears beneficial, conflicting results have been reported in cancer-associated cachexia. This study examined the effects of moderate aerobic exercise in a rat cancer model, focusing on molecular crosstalk among tumors, serum, and skeletal muscle. Male Sprague-Dawley rats were divided into Non-Cancer, Cancer, and Cancer + Exercise (Ex) groups. Cancer was induced with an intraperitoneal injection of 7,12-dimethylbenz[a]anthracene (DMBA), and the Cancer + Ex group completed an eight-week treadmill regimen. Tibialis anterior muscle, serum, and tumor tissues were analyzed by RNA sequencing. DMBA injection produced sarcoma-like tumors, reduced body weight, elevated inflammatory mediators, and activated muscle atrophy genes (Fbxo32). Exercise led to progressive intolerance, further weight loss, lower muscle mass, and larger tumors. Transcriptomic profiling revealed exacerbated cachexia signatures and suppressed energy metabolism genes in exercised cancer rats. Bioinformatic analysis of serum proteins and tissue transcriptomes identified enhanced chemokine-receptor signaling, including pro-tumorigenic (CXCL6_CXCR2) and pro-cachexia (CCL19_CXCR3, CCL5_CCR3, CXCL11_CXCR3) interactions. These findings suggest that in a pro-inflammatory cancer context, late-onset moderate exercise may worsen cachexia and stimulate tumor progression. Thus, exercise protocols should be cautiously tailored in cancer settings.
    Keywords:  aerobic exercise; cancer cachexia; muscle wasting; transcriptomics; tumor
    DOI:  https://doi.org/10.3390/ijms27052381
  30. Nutrients. 2026 Feb 26. pii: 761. [Epub ahead of print]18(5):
    The Role of Ketogenic Diet and β-Hydroxybutyrate in the Prevention of Muscle Catabolism and Sarcopenia in Aging Populations: Mechanisms, Evidence, and Clinical Perspectives.
    Claudia Venturini, Giulia Matacchione, Lucia Mancinelli, Sara Caccese, Michele Alfieri, Fabrizia Lattanzio, Fabiola Olivieri, Roberto Antonicelli.
      Sarcopenia, characterized by the progressive loss of skeletal muscle mass, strength, and function, represents a growing public health challenge in aging populations. Emerging mechanistic evidence suggests that ketogenic diets (KDs) and elevated circulating β-hydroxybutyrate (βOHB) levels may offer selective and context-dependent nutritional strategies to support muscle health during aging. This review summarizes current evidence on the effects of ketogenic diets and ketone body metabolism on muscle mass and function, with a focus on underlying molecular mechanisms and clinical relevance in older adults. βOHB acts not only as an alternative energy substrate but also as a signaling molecule, notably through histone deacetylase inhibition and modulation of inflammatory pathways. Nutritional ketosis in humans typically results in circulating βOHB concentrations of approximately 0.5-3.0 mM, which may be sufficient to engage some of these signaling pathways, although the extent of these effects in human tissues remains incompletely defined. Preclinical studies indicate that long-term ketogenic diets preserve muscle mass, strength, and mitochondrial function in aging models. Limited clinical evidence, largely derived from populations with sarcopenic obesity or metabolic comorbidities, suggests that protein-adequate ketogenic diets, when implemented as an adjunct to physical exercise, may help preserve fat-free mass and improve functional outcomes, while exogenous ketones show potential to augment post-exercise anabolic signaling. Overall, the integration of mechanistic and preliminary clinical data provides a supplementary and exploratory framework suggesting that ketogenic diets may represent a promising adjunctive strategy for sarcopenia prevention, although well-designed long-term randomized controlled trials are required to define their efficacy, safety, and optimal clinical application.
    Keywords:  aging; ketogenic diet; muscle mass; sarcopenia; β-hydroxybutyrate
    DOI:  https://doi.org/10.3390/nu18050761
  31. Front Genet. 2026 ;17 1772541
    Regulatory roles of the circRNA-RBP axis in exercise-induced skeletal muscle remodeling: mechanistic controversies and translational illusions.
    Junjie Liu, Yupeng Yang, Heming Chen, Mingming Liu, Zhujun Mao, Mi Zheng.
      Metabolic health and physical performance rely upon skeletal muscle adaptation that is a result of exercise. Recent advancements in high-throughput sequencing and functional genomics have successfully identified a vast landscape of exercise-responsive circRNAs, providing critical insights into the molecular complexity of muscle adaptation. While these studies have established a foundational framework for understanding the circRNA-RBP axis, there are serious issues related to current research. There are serious issues related to current research: an insufficient level of endogenous circRNA to produce substantial ceRNA effects, unconfirmed circRNA scaffolding due to overactivity of RBPs, poor conservation of so-called exercise-related circRNAs evolutionarily, and the over-interpretation of specific effects. The article focuses on basic concerns of the ceRNA model quantitative limitations, and specificity debate of the scaffolding model, current model and technical gaps, etc. and suggests an experimental framework transitioning from "narrative models" to "physiologically credible mechanisms," offering references for future rigorous research and elucidating the authentic role of the circRNA-RBP axis.
    Keywords:  RNA-binding proteins; circRNA; competing endogenous RNA; exercise adaptation; exosomes; experimental rigor; muscle plasticity; skeletal muscle remodeling
    DOI:  https://doi.org/10.3389/fgene.2026.1772541
  32. J Cachexia Sarcopenia Muscle. 2026 Apr;17(2): e70237
    Downregulation of Organ-Derived Activin A Attenuates Muscle Atrophy and Intramuscular Fat Infiltration in Cancer Cachexia Mice.
    Cui Wang, Lin Gao, Rui Xue, Jia Su, Honghui Li, Wei Yang, Yan Tang, Zhihang Su, Shasha Min, Changyong Tang, Yuqi Zhu, Bo Mu, John R Speakman, Xina Xie, Zesong Li.
       BACKGROUND: Cancer cachexia is a multifactorial wasting syndrome marked by profound skeletal muscle loss. Tumours can release high levels of Activin A (ActA), which activates the ubiquitin-proteasome pathway (UPP) and drives muscle wasting. Systemic blockade of the ActA pathway is associated with inflammatory adverse effects, and tumour-restricted targeting alone often fails to reverse cachexia. We asked whether ActA produced by host (nontumour) organs contributes to circulating ActA and muscle wasting.
    METHODS: We profiled ActA across tissues and in serum in Lewis lung carcinoma (LLC) cancer cachexia mice to generate an organ-wide expression map. Functional studies were then performed using adeno-associated-virus (AAV)-knockdown in the heart (cTnT/hTCF21 promoters) and kidney (CMV promoter), followed by cachexia induction. Body weight (BW), food intake, skeletal muscle mass, muscle function and muscle histomorphology were assessed. Mitochondrial ultrastructure and lipid metabolic pathways in muscle and adipose tissue were also examined.
    RESULTS: LLC cachexia mice exhibited significant reductions in body weight (-6.0%, p < 0.05), food intake (-9.9%, p < 0.05), quadriceps mass (-15.3%, p < 0.05) and grip strength (-13.0%, p < 0.0001) compared with non-tumour-bearing (NTB) mice (n = 6-12/group). ActA expression was markedly increased in the host organs, particularly in the kidney (2.8-fold vs. NTB, p < 0.001) and heart (2.7-fold vs. NTB, p < 0.05) (n = 10/group). Compared with the sh-NC, organ-targeted ActA knockdown restored body weight (+6.1%, p < 0.05) and food intake (+8.4%, p < 0.05), increased quadriceps mass (+17.2%, p < 0.05) and grip strength (+10.7%, p < 0.01), reduced intramuscular fat infiltration and attenuated UPP signalling (n = 8-16/group). These effects were accompanied by increased expression of the mitochondrial fatty-acid oxidation regulator carnitine palmitoyltransferase 1B (CPT1B) (+42.3% of mRNA level; +30.9% of protein level; both p < 0.05) and CPT2 (+57.7% of mRNA level, p < 0.05), improved mitochondrial ultrastructure and partial restoration of adipose mass.
    CONCLUSIONS: Simultaneous downregulation of Activin A in the kidney and heart attenuates skeletal muscle atrophy and intramuscular adipogenesis, improves muscle mass and function and mitigates adipose tissue mass loss in cancer cachexia mice. These findings identify heart- and kidney-derived Activin A as a key driver of cachexia, which acts through a combinatorial effect rather than an isolated contribution from either one alone, highlighting its potential as a therapeutic target.
    Keywords:  Activin A; cancer cachexia; heart and kidney; intramuscular fat infiltration; muscle atrophy
    DOI:  https://doi.org/10.1002/jcsm.70237
  33. Front Pharmacol. 2026 ;17 1733798
    Chronic inflammation as a driving factor for sarcopenia: an update on pathophysiology and future therapeutic targets.
    Zihan Liang, Lin Zhang.
      Sarcopenia is a syndrome characterized by an age-related progressive decline in skeletal muscle mass, strength, and function. It represents a significant public health concern because of its adverse impact on the quality of life and prognosis of older adults. Chronic low-grade inflammation contributes to the pathophysiology of sarcopenia through multiple pathways, including cellular senescence, immunosenescence, oxidative stress, mitochondrial dysfunction, hormonal alterations, and gut microbiota dysbiosis. To elucidate the role of chronic inflammation in the development of sarcopenia, we systematically searched PubMed and Web of Science databases using combinations of keywords such as "sarcopenia," "chronic inflammation," "inflammaging," "cytokines" and "muscle atrophy," which specifically addressed mechanistic pathways linking inflammation to muscle loss and emerging therapeutic targets. Moreover, obesity, a chronic inflammatory condition, is associated with sarcopenia, leading to sarcopenic obesity, which further exacerbates muscle loss and functional impairment. In terms of interventions, exercise, nutritional supplementation, and combined approaches have demonstrated efficacy in improving muscle mass and function, as well as conferring demonstrable anti-inflammatory benefits. In addition to conventional hormonal therapies, pharmacological strategies, particularly anti-inflammatory agents and treatments targeting inflammatory pathways, show considerable therapeutic promise. This review systematically examines the central role of chronic inflammation in the development and progression of sarcopenia, as well as its underlying mechanistic basis. It also elaborates on the roles of key inflammatory cytokines, such as C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), in regulating muscle protein metabolic balance and their potential utility as biomarkers. A deeper understanding of the relationship between inflammation and sarcopenia will not only help elucidate its complex pathogenesis but also offer critical directions for the future development of early diagnostic tools and targeted anti-inflammatory interventions.
    Keywords:  aging; inflammation; inflammatory cytokines; sarcopenia; treatment
    DOI:  https://doi.org/10.3389/fphar.2026.1733798
  34. Nat Commun. 2026 Mar 13.
    Humans with function-disrupting variants in the myostatin gene (MSTN) have increased skeletal muscle mass and strength, and less adiposity.
    Regeneron Genetics Center
      Myostatin negatively regulates skeletal muscle size in multiple species, and therefore, myostatin blockade has been therapeutically explored to promote muscle growth in humans, including to counter the muscle loss seen in obese humans using GLP1R agonists. In this study, we present results from a large multi-cohort genetic association analysis, using data from 1.1 million individuals to examine the effects of function-disrupting mutations in the myostatin gene (MSTN) on traits relevant to body composition and cardiometabolic health. Carriers of function-disrupting variants display decreased adiposity, an increase in lean mass, and increased grip strength and creatinine levels. We further characterize the effects of these variants on body composition using whole-body MRI data from UK Biobank, leveraging deep learning models to perform automated image segmentation for 77,572 individuals. Among mutation carriers increased muscle mass is observed across multiple muscle groups, with heterozygote carriers of loss-of-function-like mutations exhibiting increases in excess of 10%. Our findings demonstrate that lifelong reduction in myostatin function enhances muscle size and strength in humans while decreasing body adiposity, providing insights into the potential benefits and safety of long-term therapeutic blockade of myostatin signaling.
    DOI:  https://doi.org/10.1038/s41467-026-70422-2
  35. Nucleic Acids Res. 2026 Feb 24. pii: gkag168. [Epub ahead of print]54(5):
    Repeat-rich RNA guides repetitive genomic elements into biomolecular condensates for heterochromatin organization and muscle integrity.
    Jinmi Choi, Sangha Park, Nahee Kim, Soonho Kwon, Jinyoung Park, Somin Lee, Hongmin Lee, Keonjin Kang, Taewan Kim, Jaehoon Sul, Dong-Gyu Jo, Hong-Duk Youn, Eun-Jung Cho.
      Biomolecular condensation is a pivotal mechanism in chromatin organization and nuclear compartmentalization. However, the molecular mechanism that drives heterochromatin organization and selectively partitions heterochromatin components in muscle cells remains unclear. Furthermore, its pathological implications remain unexplored. Here, we demonstrate that ChRO1, a muscle-specific RNA enriched with simple dinucleotide repeats, is associated with static heterochromatin foci containing similar repetitive elements in mouse muscle cells. Through its CU-repeat-rich region, ChRO1 promotes heterochromatin clustering and facilitates the selective partitioning of heterochromatin proteins, as shown in vitro and in C2C12 cells. Consequently, chromatin interaction stabilized at ChRO1-bound regions, reinforcing TAD boundaries and promoting inactive chromatin states. The enhanced intra- and interchromosomal interactions secure the heterochromatinization of non-muscle genes, highlighting ChRO1's role in chromatin organization. Disruption of ChRO1 or perturbation of condensate organization induces chromocenter disintegration and muscle atrophic phenotypes, underscoring the importance of these processes in maintaining muscle integrity. Notably, ChRO1 mitigates chromocenter disintegration and atrophic phenotypes in chemically induced atrophy models, emphasizing its protective role. These findings reveal a novel repeat-rich RNA-based mechanism of repetitive DNA condensation that safeguards heterochromatin organization and muscle integrity, providing mechanistic insight and therapeutic implications for muscle-related disorders.
    DOI:  https://doi.org/10.1093/nar/gkag168
  36. J Physiol. 2026 Mar 13.
    Ageing does not impair motor neuron adaptations: comparable motor unit responses to strength training in young and older adults.
    Andrea Casolo, Stefanie Del Vecchio, Benjamin I Goodlich, Bastian Schrader, Stefano Nuccio, Edoardo Lecce, Ilenia Bazzucchi, Luca Angius, Francesco Felici, Joachim Schrader, Dario Farina, Alessandro Del Vecchio.
      Ageing induces structural and functional changes in the neuromuscular systems that impair voluntary force production, compromising daily function and wellbeing. We examined whether older adults preserve the capacity for motor unit adaptations to a short-term strength training intervention previously shown to enhance neural drive to muscle in young adults. Twenty‑three older adults were assigned to a training group (INT, n = 13, 71 ± 4 years of age) or a control group (CON, n = 10, 69 ± 2 years of age) and completed pre- and postintervention assessments of ankle dorsiflexor maximal voluntary force (MVF). Motor unit behaviour was analysed from high‑density surface EMG recorded from tibialis anterior during submaximal trapezoidal contractions. The INT group performed a 4 week supervised isometric strength training programme, whereas the CON group maintained habitual activity. High‑density surface EMG signals were decomposed into individual motor units, tracked longitudinally across sessions. Training increased MVF by 17.6% and enhanced motor unit discharge rate at recruitment (+8.2%, P = 0.031) and constant force (+11.3%, P < 0.001), without changes in recruitment or derecruitment thresholds. Estimates of persistent inward currents (delta frequency) increased (+1.0 pulses per second) and were positively correlated with changes in discharge rate, which, in turn, were correlated with gains in MVF (rrm = 0.54-0.57, P < 0.05). This pattern suggests that enhanced intrinsic excitability and synaptic input to motor neurons contributed to improvements in strength. These results demonstrate that, despite age-related motor unit remodelling, the ageing nervous system remains responsive to targeted strength training, preserving the capacity for meaningful neural adaptations. KEY POINTS: We assessed whether a short-term intensive strength training intervention, previously shown to increase spinal motor output to the muscle significantly in young adults, would also be effective in older adults. High-density surface EMG was used to identify and longitudinally track the same motor units before and after a 4 week isometric strength training intervention. We found significant strength gains in older adults, with the increase in muscle force output being positively associated with higher motor unit discharge rate and persistent inward currents, indicating that neural drive enhancement was a key contributor to the observed improvements in force. Despite age-related motor neuron remodelling, the older nervous system remains highly responsive to strength training, exhibiting qualitatively similar but attenuated motor unit adaptations compared with young adults.
    Keywords:  ageing; high‐density surface EMG; motor neuron; motor unit; strength training
    DOI:  https://doi.org/10.1113/JP290541
  37. Sci Rep. 2026 Mar 10.
    Ultrasound-guided skeletal muscle biopsy technique permits measurement of structural, functional, cellular and biochemical properties.
    Addison Barber, Amber Willbanks, Guadalupe Meza, Jeremie L A Ferey, Gretchen A Meyer, Sudarshan Dayanidhi, W David Arnold, Richard L Lieber, Ishan Roy.
      Human muscle biopsies are often required to study or diagnose diseases. However, traditional approaches are challenging due to limited sample size, quality, or participant discomfort. Fine-gauge needle biopsies (≥ 14-gauge), present an alternative but may yield insufficient tissue for comprehensive analysis. Ultrasound guidance, coupled with vacuum-assisted, single needle-insertion multiple sampling addresses these challenges. In 19 healthy participants (mean age: 30.1 ± 10 years, 42% male), 2-3 samples were collected from a single needle insertion into the vastus lateralis (VL) and tibialis anterior (TA). Summed VL and TA sample masses averaged 148 ± 38 mg and 166 ± 64 mg, with dimensions of 15.83 ± 8 × 2.9 ± 0.6mm2 (VL) and 15.07 ± 7 × 3.1 ± 0.9mm2 (TA). VL had a mean fiber cross-sectional area of 4,347 ± 1,931µm2, with 221 ± 86 fibers quantified. Samples were of sufficient size and quality for thorough analyses from a single biopsy procedure, including mitochondrial respirometry, RT-PCR, collagen content, and biomechanical function. Fibers produced typical isometric stress values of 187 kPa with a passive modulus of 239 kPa (peak) and 79 kPa (stress-relaxed). The procedure was well tolerated, with an average immediate pain rating of 1.5 ± 1 (range:0-4, scale: 0-10) and 24-hour follow-up rating of 1.7 ± 1 (range:0-4). This report describes an approach that yields high-quality muscle samples suitable for histological and biochemical analyses while minimizing discomfort.
    Keywords:  Diagnostic methods; Human muscle biopsy; Muscle imaging; Translational medicine
    DOI:  https://doi.org/10.1038/s41598-026-42776-6
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