bims-moremu Biomed News
on Molecular regulators of muscle mass
Issue of 2025–10–26
34 papers selected by
Anna Vainshtein, Craft Science Inc.
  1. A role for the transcriptional coregulator RIP140 in the control of muscle endurance fitness.
  2. The role of sestrin2 in skeletal muscle regeneration after injury.
  3. Lamin A/C protects chromatin accessibility during mechanical loading in human skeletal muscle.
  4. Estrogen in skeletal muscle: metabolism, mechanisms, and exercise-induced changes.
  5. Pbk positively regulates myoblast differentiation and muscle regeneration via enhancing AMPK/ULK1 mediated myogenic autophagy.
  6. Dynamic time course of muscle proteome adaptation to programmed resistance training in rats.
  7. Disuse-induced muscle-type specific alterations and adiponectin pathway response in male mice.
  8. Mitochondrial dysfunction in age-related sarcopenia: mechanistic insights, diagnostic advances, and therapeutic prospects.
  9. Advancing Single-Cell Transcriptomic Analysis to Reveal Age-Related Skeletal Muscle Changes: A Systematic Review.
  10. Stromal cells unifying the pathology of acute and chronic skeletal muscle injury - clue for novel biomaterials.
  11. Spatial-proteomics reveals recombinant human laminin-111 restores adhesion-signaling to laminin-α2 deficient muscle.
  12. Health-enhancing physical activity induce beneficial skeletal muscle mitochondrial adaptations in individuals with rheumatoid arthritis.
  13. Semaglutide versus caloric restriction-induced weight loss: insights into effects on skeletal muscle mass and function.
  14. Exploring the Regulation of Tmem182 Gene Expression in the Context of Retinoid X Receptor Signaling.
  15. Effects of transient receptor potential channel activation during myogenic progression and skeletal muscle function during voluntary exercise.
  16. Spatially distinct ECM-producing fibroblasts and myonuclei orchestrate early adaptation to mechanical loading in the human muscle-tendon unit.
  17. Twice-a-day exercise increases acute MCT1 gene expression in skeletal muscle but does not change the lactate curve after 3 weeks of training in adult men.
  18. Tofogliflozin ameliorates cardiotoxin induced skeletal muscle injury and fibrosis in obesity.
  19. Multiphoton microscopy and tissue clearing for 3D characterization of the vasculature and fibrosis remodeling in rat dystrophic skeletal muscle.
  20. The role of exercise-induced short-chain fatty acids in the gut-muscle axis: implications for sarcopenia prevention and therapy.
  21. Distributed Control of Muscle Glucose Uptake: A Tribute to the Late Dr. David H. Wasserman by Revisiting a 2004 Diabetes Classic by Fueger et al.
  22. Clarifying the Role of [15O]H2O PET in Assessing Skeletal Muscle Perfusion following Post-Exercise Cooling.
  23. Role of skeletal muscle excitability in strength loss induced by submaximal isometric contractions in males with Duchenne muscular dystrophy.
  24. Enhanced therapeutic potential of a microdystrophin with an extended C-terminal domain.
  25. The Emerging Role of α-Klotho as a Therapeutic Target for Sarcopenia: Underlying Mechanisms and Clinical Prospects.
  26. Delineating transcriptomic signatures of in vitro human skeletal muscle models in comparison to in vivo references.
  27. Lysosomal damage is a therapeutic target in Duchenne muscular dystrophy.
  28. Proteomic analysis of nemaline myopathy in infants reveals distinct common dysregulated proteins and cellular pathways.
  29. TAK-242 inhibits toll-like receptor-4 signaling and attenuates cancer-associated muscle atrophy via the p38-C/EBPβ pathway.
  30. Drug Candidate BIO101 for Spinal Muscular Atrophy as Monotherapy or Combined With the Antisense Oligonucleotide ASO-10-27.
  31. The impact of second-generation androgen receptor pathway inhibitors on skeletal muscle morphology and strategies to mitigate their effects in prostate cancer patients.
  32. Sex impacts inflammatory signaling, body composition, and physical function in tumor-bearing mice receiving chemotherapy.
  33. Intermuscular adipose tissue in healthy human aging - effects of exercise training and implications to metabolic health.
  34. The Influence of Sleep Restriction and High-Intensity Interval Exercise on Plasma and Skeletal Muscle Inflammatory Markers in Young Healthy Males.
  1. JCI Insight. 2025 Oct 21. pii: e192376. [Epub ahead of print]
    A role for the transcriptional coregulator RIP140 in the control of muscle endurance fitness.
    Elizabeth Pruzinsky, Kirill Batmanov, Denis M Medeiros, Sarah M Sulon, Brian P Sullivan, Tomoya Sakamoto, Teresa C Leone, Tejvir S Khurana, Daniel P Kelly.
      Poor skeletal muscle fitness contributes to many chronic disease states including obesity, heart failure, primary muscle disorders, and age-related sarcopenia. Receptor Interacting Protein 140 (RIP140) is a striated muscle-enriched nuclear receptor coregulator known to suppress mitochondrial oxidative capacity. To investigate the role of RIP140 in skeletal muscle, striated muscle-specific RIP140-deficient (strNrip1-/-) mice were generated and characterized. strNrip1-/- mice displayed an enhanced endurance performance phenotype. RNA-sequence (RNA-seq) analysis of glycolytic fast-twitch muscle from strNrip1-/- mice identified a broad array of differentially upregulated metabolic and structural muscle genes known to be induced by endurance training, including pathways involved in mitochondrial biogenesis and respiration, fatty acid oxidation, slow muscle fiber type, and angiogenesis. In addition, muscle RIP140-deficiency induced expansive neuromuscular junction (NMJ) remodeling. Integration of RNA sequence results with CUT&RUN analysis of strNrip1-/- myotubes identified Wnt16 as a candidate effector for the NMJ biogenesis in RIP140-deficient skeletal myotubes. We conclude that RIP140 serves as a physiological "rheostat" for a broad coordinated network of metabolic and structural genes involved in skeletal muscle fitness.
    Keywords:  Metabolism; Mitochondria; Muscle biology; Skeletal muscle; Transcription
    DOI:  https://doi.org/10.1172/jci.insight.192376
  2. Korean J Physiol Pharmacol. 2025 Oct 21.
    The role of sestrin2 in skeletal muscle regeneration after injury.
    Chae Young Hwang, Sang-Min Park, Hoyeon Lee, Seung-Min Lee, Jeong Yi Choi, Su-Jin Baek, Taeyoung Kim, Yong Ryoul Yang, Ki-Sun Kwon.
      Despite advances in the understanding of muscle degeneration, the mechanisms governing muscle regeneration under stress conditions remain poorly defined. Sestrin2 (Sesn2) is a stress-inducible gene that plays a crucial role in metabolic balance, nutrient sensing, and redox homeostasis, while protecting against muscle atrophy through multiple pathways. However, its precise role in skeletal muscle differentiation and regeneration, particularly under injury conditions, remains incompletely understood. In this study, we investigated the role of Sesn2 in skeletal muscle homeostasis and regeneration using in vitro and in vivo models, complemented by transcriptome analyses. Sesn2 knockdown in C2C12 myoblasts induced senescence-like morphological changes, accompanied by upregulation of nicotinamide adenine dinucleotide phosphate oxidase 4 and transforming growth factorbeta, leading to impaired myogenic differentiation. Intriguingly, Sesn2-knockout mice developed normally under basal conditions but exhibited regenerative defects, characterized by prolonged inflammation, necrosis, and delayed muscle regeneration, following cardiotoxininduced injury. Transcriptomic analysis of Sesn2 transgenic mice further supported this conditional role, revealing that genes involved in mitochondrial function and myogenesis were preferentially upregulated under immobilized conditions compared to basal conditions. These findings underscore that the context-dependent role of Sesn2 is essential for effective muscle regeneration under injury, positioning it as a potential therapeutic target for degenerative muscle diseases.
    Keywords:  Myogenesis; Oxidative stress; Regeneration; Sestrins; Skeletal muscle
    DOI:  https://doi.org/10.4196/kjpp.25.173
  3. Cell Commun Signal. 2025 Oct 22. 23(1): 452
    Lamin A/C protects chromatin accessibility during mechanical loading in human skeletal muscle.
    Saline Jabre, Emeline Cherchame, Natalia Pinzón, Eline Lemerle, Marc Bitoun, Catherine Coirault.
       BACKGROUND: Skeletal muscle nuclei (myonuclei) are subjected to high mechanical stress which plays a critical role in muscle tissue integrity and plasticity. Here we investigated the role of lamin A/C in dampening the effects of acute mechanical stretch on chromatin states and its downstream effects on gene expression.
    METHODS: We studied control and lamin A/C-deficient human myotubes both at baseline and following a mechanical stress mimicking acute muscle exercise. Chromatin accessibility and transcriptional responses were assessed using ATAC-seq (assay for transposase-accessible chromatin with sequencing) and RNA-seq, respectively.
    RESULTS: We found that stretch-induced nuclear deformations in lamin A/C-deficient myotubes but not in controls, and was associated with a widespread increase in chromatin accessibility, mainly affecting promoter regions. Concordantly, mechanical stress also increased the levels of H3K4me3 euchromatin marks and decreased heterochromatin-associated H3K27me3 in A-type lamin-deficient myotubes. Additionally, mechanical stress led to the downregulation of transcriptional pathways involved in histone deacetylation, DNA methylation, and muscle differentiation, while pathways related to cytokine activity, extracellular matrix organization, and cell adhesion were upregulated.
    CONCLUSIONS: Overall, lamin A/C deficiency amplifies the chromatin response to mechanical stress, leading to enhanced promoter accessibility and activation of stress DNA damage-related gene pathways. These findings underscore the role of lamin A/C in maintaining chromatin stability under mechanical strain.
    Keywords:  Chromatin; Lamins; Mechanical loading; Muscle cells; Nuclear mechanotransduction
    DOI:  https://doi.org/10.1186/s12964-025-02437-z
  4. J Endocrinol Invest. 2025 Oct 21.
    Estrogen in skeletal muscle: metabolism, mechanisms, and exercise-induced changes.
    Yiwei Feng, Rengfei Shi.
      With the intensification of population aging, issues such as age-related skeletal muscle loss and metabolic disorders have garnered increasing attention. As the menopausal transition progresses, circulating estrogen levels decline, making locally synthesized estrogen in peripheral tissues particularly important. In addition to the ovaries, steroidogenic enzymes are present in skeletal muscle, enabling the local synthesis of myogenic estrogen. Myogenic estrogen can regulate muscle function and metabolism in an autocrine or paracrine manner within skeletal muscle tissue. Exercise, as a safe and effective non-pharmacological intervention, has been shown to regulate estrogen levels in skeletal muscle. Exercise may promote the synthesis of myogenic estrogen by enhancing the expression of estrogen precursor substances and steroidogenic enzymes in skeletal muscle, thereby improving skeletal muscle function and metabolism. This review summarizes the structure and function of estrogen receptors in skeletal muscle, the synthesis and metabolism of myogenic estrogen, the roles and mechanisms of estrogen in skeletal muscle, and the mechanisms underlying the influence of exercise on estrogen synthesis in skeletal muscle.
    Keywords:  Aromatase; Estrogen; Exercise; Postmenopausal females; Skeletal muscle
    DOI:  https://doi.org/10.1007/s40618-025-02726-x
  5. J Transl Med. 2025 Oct 21. 23(1): 1144
    Pbk positively regulates myoblast differentiation and muscle regeneration via enhancing AMPK/ULK1 mediated myogenic autophagy.
    Dongdong Wang, Didi Shan, Dandan Zhao, Tingjun Dai, Fuchen Liu, Chuanzhu Yan.
       BACKGROUND: The activity of normal myoblasts is essential for the regeneration of skeletal muscle following injury. Nevertheless, the intrinsic mechanisms governing myoblast functions and muscle regeneration remain inadequately elucidated. PDZ binding kinase (Pbk) is a serine-threonine kinase that plays critical roles in various cellular functions and pathologies. However, its role in skeletal muscle remains largely unexplored. In this study, we have identified Pbk as a novel positive regulator of myoblast functions in vitro and muscle regeneration in vivo.
    METHODS: Herein, We analyzed the effects of Pbk on myoblast function and muscle regeneration through in vitro and in vivo experiments. In vivo, we analyzed the effects of Pbk on skeletal muscle regeneration through bioinformatic analysis combined with a mouse skeletal muscle injury model. In vitro, we analyzed the effects of Pbk knockdown or overexpression on myoblast proliferation, survival, and differentiation through lentivirus-mediated cell infection. Also, we further studied the molecular mechanisms by which Pbk affects myoblast differentiation and muscle regeneration combined with the molecular biology and biochemistry, and drug rescue approaches.
    RESULTS: In vitro experiments demonstrated that knockdown of Pbk results in impaired cell proliferation and accelerated apoptosis of myoblasts. Unlike proliferating myoblasts, Pbk is upregulated and restricted from translocating from the cytoplasm to the nucleus during myoblast differentiation. Notably, the positive effect of Pbk on myoblast differentiation and fusion is contingent upon its kinase activity. Mechanistic investigations revealed that Pbk facilitates myogenic autophagy by enhancing AMPK-mediated phosphorylation of ULK1, which ultimately contributes to myogenic differentiation and fusion. In vivo, we observed that Pbk is upregulated in embryonic myosin heavy chain (eMyHC) positive regenerative myofibers in muscle specimens from patients with Duchenne muscular dystrophy (DMD) and immune-mediated necrotizing myopathy (IMNM). Furthermore, in a murine model of skeletal muscle injury, Pbk knockdown hinders the regeneration of myofibers.
    CONCLUSIONS: Collectively, our findings suggest that Pbk plays a positive regulatory role in myoblast differentiation and muscle regeneration by modulating AMPK/ULK1-mediated autophagy signaling. This pathway may represent a novel target for the manipulation of myoblast functions and the development of myoblast-based therapies for skeletal muscle injuries.
    Keywords:  AMPK/ULK1; Autophagy; Muscle regeneration; Myoblast; Pbk
    DOI:  https://doi.org/10.1186/s12967-025-07173-z
  6. Am J Physiol Cell Physiol. 2025 Oct 21.
    Dynamic time course of muscle proteome adaptation to programmed resistance training in rats.
    Connor A Stead, Stuart J Hesketh, Aaron C Q Thomas, Mark R Viggars, Hazel Sutherland, Jonathan C Jarvis, Jatin G Burniston.
      Resistance training promotes muscle protein accretion and myofiber hypertrophy, driven by dynamic processes of protein synthesis and degradation. Muscle adaptations to on going resistance training occur over weeks but most molecular knowledge on the process of adaptation is derived from static measurements at specific time points, which do not capture the dynamics of the adaptation process. To address this, we utilised deuterium oxide labelling and peptide mass spectrometry to quantify absolute protein content (grams) and synthesis rates (grams/ day) in skeletal muscle during a timeseries experimental design. A daily programmed resistance training regimen was applied to male rat tibialis anterior via electrical stimulation of the left hind limb for 10, 20, and 30 days (5 sets of 10 repetitions daily). Muscle samples from stimulated and contralateral control limbs were analysed, quantifying 658 protein abundances and 215 protein synthesis rates. Unsupervised temporal clustering of protein responses revealed distinct phases of muscle adaptation. The early (0-10 days) response was driven by greater rates of ribosomal protein accretion and the mid (10-20 days) response by expansion of mitochondrial networks. These findings highlight that subsets of proteins exhibit distinct adaptation timelines due to variations in translation and/or degradation rates. The new understanding of temporal patterns highlighted by our dynamic proteomic data help interpret static data from studies at isolated time points and could improve the development of strategies for optimising muscle growth and functional adaptation to resistance training.
    Keywords:  Deuterium Oxide; Exercise; Protein Synthesis; Proteomics; Skeletal Muscle
    DOI:  https://doi.org/10.1152/ajpcell.00254.2025
  7. Physiol Rep. 2025 Oct;13(20): e70602
    Disuse-induced muscle-type specific alterations and adiponectin pathway response in male mice.
    Szczepanski Sébastien, Limpens Maëlle, Jenart Vincianne, Declèves Anne-Emilie, Legrand Alexandre, Tassin Alexandra.
      Disuse-mediated Muscle Atrophy (DMA) causes persistent muscle weakness, limiting exercise training as a treatment. Adiponectin (ApN) emerged as a therapeutic candidate for muscle disorders. However, the effect of DMA on the ApN pathway remains poorly studied. Given ApN's metabolic effects, examining the ApN pathway response to disuse in relation with muscle type is essential. To mimic DMA while avoiding confounding factors, we combined HindLimb Unloading with Immobilization (HLUI) through a device allowing mouse displacements. The effects of disuse on DMA severity were studied in the slow-twitch Soleus and the fast-twitch Tibialis anterior (TA) muscles, together with the ApN pathway. The Soleus muscle presents a moderate atrophy of type IIa myofibers, whereas the TA muscle is more severely affected and exhibits a type I to IIa switch. HLUI increased the hybrid I/IIa myofiber proportion in both muscles, suggesting an ongoing myofiber switch that is delayed in the Soleus muscle. Concomitantly, HLUI enhances ApN plasma level, modifies oligomeric form proportions, and downregulates Adiporeceptors in the Soleus but not in the TA muscle. In conclusion, HLUI is associated with a higher ApN plasma level and disturbances in oligomeric form proportions. DMA severity, myofiber switch kinetics, and adiporeceptor regulation are muscle-type dependent.
    Keywords:  adiponectin pathway; disuse muscle atrophy; myofiber‐type
    DOI:  https://doi.org/10.14814/phy2.70602
  8. Front Cell Dev Biol. 2025 ;13 1590524
    Mitochondrial dysfunction in age-related sarcopenia: mechanistic insights, diagnostic advances, and therapeutic prospects.
    Yingtao Huang, Chenchen Wang, Haijian Cui, Guangjiang Sun, Xiaonan Qi, Xiaosheng Yao.
      Sarcopenia is a progressive age-related decline in skeletal muscle mass, strength, and function, representing a significant health burden in older adults. Diagnostic criteria have been established that integrate measures of muscle mass, strength, and physical performance [e.g., European Working Group on Sarcopenia in Older People 2010 (EWGSOP1) and 2019 (EWGSOP2) criteria]. Mechanistically, sarcopenia is driven by hormonal changes, chronic inflammation, cellular senescence, and, importantly, mitochondrial dysfunction. Age-related declines in sex hormones and activation of myostatin impair muscle regeneration and metabolism, while chronic low-grade inflammation disrupts protein synthesis and accelerates proteolysis via the ubiquitin-proteasome system (UPS) and autophagy-lysosome pathway (ALP). The accumulation of senescent cells and their secretory phenotype further exacerbates muscle degeneration and functional decline. Mitochondrial dysfunction plays a central role, characterized by impaired biogenesis, excessive reactive oxygen species (ROS) production, compromised autophagy/mitophagy, and accumulation of mitochondrial DNA (mtDNA) mutations. These defects collectively disrupt muscle energy homeostasis, promoting atrophy. The AMPK/SIRT1/PGC-1α and mTORC1 signaling pathways, along with PINK1/Parkin-mediated and receptor-dependent mitophagy, are essential for regulating mitochondrial biogenesis, protein synthesis, and mitochondrial quality control. Current and emerging therapeutic approaches include resistance and endurance exercise, nutritional and pharmacological agents targeting mitochondrial health, and hormonal modulation. Innovative treatments such as senolytics, exerkines, and gene therapies show promise but require further validation. Future advances in mechanistic understanding, diagnostics, and therapeutic strategies offer hope for mitigating sarcopenia and improving the quality of life in aging populations.
    Keywords:  aging; chronic inflammation; mitochondrial dysfunction; muscle atrophy; sarcopenia; therapeutic strategies
    DOI:  https://doi.org/10.3389/fcell.2025.1590524
  9. Aging Dis. 2025 Oct 14.
    Advancing Single-Cell Transcriptomic Analysis to Reveal Age-Related Skeletal Muscle Changes: A Systematic Review.
    Chaoran Liu, Hei Yuet Wong, Ranyang Tao, Baoqi Li, Pui Yan Wong, Chun Ho Tam, Ning Zhang, Ling Qin, Jiankun Xu, Gustavo Duque, Christoph Brochhausen, Wing Hoi Cheung, Ronald Man Yeung Wong.
      Population aging has become a widespread health problem that leads to huge socioeconomic burden. Skeletal muscle as an important component of motor system, gradually degenerates with age. Age-related muscle disorders, such as sarcopenia is associated with higher risks of falls, fracture, disability, and mortality in old people. As there is still no Food and Drug Administration (FDA) approved drug to treat sarcopenia, conducting research of in-depth mechanisms is warranted to develop novel treatments. The cutting-edge techniques single-cell and single-nuclei RNA sequencing can help to address this issue by discovering age-related changes of muscle at the single-cell level. This review aims to systematically explore current evidence of age-related muscle changes during normal aging, regeneration, and after treatments at the single-cell level. 29 studies were eligible and included in the current review according to the PRISMA guideline. The muscle cell composition was altered with age, such as diminished muscle stem cells (MuSCs), vascular cells, Schwann cells, and increased myocytes as well as some types of immune cells. Inflammation levels, collagen and extracellular matrix (ECM) signaling, protein catabolism, TGFβ signaling, apoptosis, and autophagy of MuSCs, myocytes, fibro-adipogenic progenitor cells, vascular cells, or immune cells were regulated with age. Delayed muscle regeneration of aged muscle was relied on disorders of cell-specific immune response, myogenesis, angiogenesis, and ECM remodeling. Three treatments involved in this review could reverse age-related dysfunction of muscle cells to some extent. Further research targeting age-related changes of muscle at the single-cell level is an important tool in assisting development of more effective treatments for sarcopenia.
    DOI:  https://doi.org/10.14336/AD.2025.0701
  10. Front Bioeng Biotechnol. 2025 ;13 1684310
    Stromal cells unifying the pathology of acute and chronic skeletal muscle injury - clue for novel biomaterials.
    Xianglong Liu.
      
    Keywords:  biomaterials; degeneration; regeneration; skeletal muscle; stromal cells
    DOI:  https://doi.org/10.3389/fbioe.2025.1684310
  11. JCI Insight. 2025 Oct 16. pii: e194581. [Epub ahead of print]
    Spatial-proteomics reveals recombinant human laminin-111 restores adhesion-signaling to laminin-α2 deficient muscle.
    Hailey J Hermann, Ryan D Wuebbles, Marisela Dagda, Axel Munoz, Lauren L Parker, Paula C C Guzman, Lola T Byrne, Steven A Moore, Dean J Burkin.
      Laminin-α2-related Congenital Muscular Dystrophy (LAMA2-CMD) is a severe neuromuscular disorder caused by mutations in the LAMA2 gene, leading to loss of heterotrimers laminin-211/221, key components of the skeletal muscle extracellular matrix. Their absence disrupts adhesion between the cytoskeleton and extracellular matrix, resulting in progressive muscle wasting. Laminin-211/221 interacts with adhesion complexes such as the dystrophin/Utrophin glycoprotein complex and the α7β1-integrin. However, the regulatory mechanisms of these laminin-binding complexes and the broader role of laminin's influence on the formation of the macromolecular network in skeletal muscle remain unclear. We previously demonstrated that mouse laminin-111 delivered in the dyW⁻/⁻ mouse model of LAMA2-CMD prevented disease progression, improved strength, and extended survival. We hypothesize that laminin-111, the embryonic laminin isoform, restores key adhesion-signaling networks. Using spatial-proteomics on patient and mouse muscle, we identified loss of essential signaling components: heat shock proteins 27 and 70, c-Jun N-terminal kinase, and glucose transporter 1 in laminin-α2 deficient muscle. Treatment with recombinant human laminin-111 (rhLAM-111) restored protein localization, reduced ROS, and promoted glycolytic, pro-survival signaling. These findings highlight laminin's role in maintaining muscle homeostasis and metabolism and support the therapeutic potential of rhLAM-111 for treating LAMA2-CMD by restoring adhesion and intracellular signaling in dystrophic muscle.
    Keywords:  Cell biology; Extracellular matrix; Genetic diseases; Muscle biology; Proteomics
    DOI:  https://doi.org/10.1172/jci.insight.194581
  12. Clin Rheumatol. 2025 Oct 20.
    Health-enhancing physical activity induce beneficial skeletal muscle mitochondrial adaptations in individuals with rheumatoid arthritis.
    Emily Shorter, Elena Ossipova, Estela Santos Alves, Helena Idborg, Jone Vanluyten, Eva Kosek, Liu Zhengye, Birgitta Nordgren, Cecilia Fridén, Ferdinand von Walden, Christer Malm, Per-Johan Jakobsson, Christina H Opava, Marina Korotkova, Ingrid E Lundberg, Johanna T Lanner.
       OBJECTIVE: Rheumatoid arthritis (RA) is a common chronic systemic inflammatory disease that causes musculoskeletal impairments and fatigue. Physical activity is recommended for individuals with RA, and health-enhancing physical activity (HEPA) has been shown to improve health perception and physical fitness in this group. However, the molecular adaptations of skeletal muscle in response to an exercise intervention are still unexplored in individuals with RA. This study aimed to assess the skeletal muscle response to a 2-year HEPA intervention in individuals with RA.
    METHODS: Thirteen individuals with RA (65 ± 2 years old, 13 ± 2 years disease duration) participated. The 2-year HEPA intervention involved 150 min of weekly moderately intense aerobic activity and twice-weekly circuit training. Practical and theoretical physiotherapist support was available the first year, but not the second year. Skeletal muscle biopsies, functional assessments, and mass spectrometry-based proteomics analysis were conducted.
    RESULTS: Compliance was high the first year but dropped significantly the second year. Functional improvements in strength, endurance, and lower extremity muscle function (TST) were observed after year 1. Proteomics analysis revealed significant enrichment of mitochondrial proteins including COX8A, citrate synthase, M2OM, NDUFA6, NDUFS2, and VDAC3 after year 1, indicating positive muscle adaptations. However, these changes regressed to baseline levels by year 2.
    CONCLUSION: HEPA can induce beneficial mitochondrial adaptations in skeletal muscle of individuals with RA. However, insufficient compliance and progression in HEPA exercise load led to a reversal of these adaptations. Continuous support and motivation are crucial for maintaining and progressing exercise levels and muscle health in individuals with RA. Key points • Health-enhancing physical activity (HEPA) can induce beneficial mitochondrial adaptations in the skeletal muscle proteome of individuals with RA. • Positive effects on mitochondrial protein levels aligned with the participants compliance to the HEPA intervention. • Results emphasizes that sustaining and progressing exercise regimen is crucial to maintain beneficial adaptations for individuals with RA.
    Keywords:  Exercise adaptation; Health-enhancing physical activity; Mitochondria; Muscle biopsy; Rheumatoid arthritis; Skeletal muscle
    DOI:  https://doi.org/10.1007/s10067-025-07734-z
  13. J Physiol. 2025 Oct 25.
    Semaglutide versus caloric restriction-induced weight loss: insights into effects on skeletal muscle mass and function.
    Harsh Shah, Julio E Ayala.
      
    Keywords:  caloric restriction; semaglutide; skeletal muscle
    DOI:  https://doi.org/10.1113/JP290060
  14. J Dev Biol. 2025 Sep 24. pii: 34. [Epub ahead of print]13(4):
    Exploring the Regulation of Tmem182 Gene Expression in the Context of Retinoid X Receptor Signaling.
    Saadia Khilji, Munerah Hamed, Jihong Chen, Qiao Li.
      We have previously established that bexarotene, a clinically approved agonist of retinoid X receptor (RXR), promotes the differentiation and fusion of skeletal myoblasts. We have also analyzed the genomic programs underlying rexinoid-enhanced myogenic differentiation to identify novel regulatory pathways. As such, we observed a significant upregulation of a transcript encoding a predicted transmembrane protein, Tmem182, during C2C12 myoblast differentiation. Despite the documentation of Tmem182 expression in skeletal muscles, its regulation had yet to be explored. Here, we show that Tmem182 gene expression is markedly augmented in early myoblast differentiation and further enhanced by RXR signaling. In addition, Tmem182 expression is specific to muscle tissues and related to muscle master regulator MyoD. We found that MyoD and histone acetyltransferase p300 are bound to the Tmem182 promoter, and Tmem182 expression is p300-dependent. Thus, our data display a putative epigenetic signature associated with p300 and histone acetylation in rexinoid-responsive locus activation and transcription of myogenic targets.
    Keywords:  Tmem182; myogenic regulation; nuclear receptor signaling
    DOI:  https://doi.org/10.3390/jdb13040034
  15. Biosci Biotechnol Biochem. 2025 Oct 22. pii: zbaf149. [Epub ahead of print]
    Effects of transient receptor potential channel activation during myogenic progression and skeletal muscle function during voluntary exercise.
    Hiroyuki Yamamoto, Kota Kojima, Shuto Kasai, Yusuke Takimoto, Aya Kato, Kaichi Yamamoto, Yuna Moriya, Ayaka Koida, Umon Agata.
      Capsaicin and menthol, agonists of transient receptor potential (TRP) channels, are known to influence energy metabolism. However, their roles in skeletal muscle function are unclear. Therefore, this study aimed to investigate the effects of capsaicin and menthol on skeletal muscle differentiation and muscle quality. In vitro, capsaicin and menthol increased myosin heavy chain (MYH)4 expression, while menthol upregulated MYH1. Both compounds reduced MYH2 and MYH7 levels. Additionally, capsaicin enhanced uncoupling protein (UCP)3 expression, and menthol increased UCP2, UCP3, and M-type creatine kinase. In vivo, topical application during voluntary running did not affect body or muscle mass, but capsaicin reduced fat mass and increased locomotor activity. Menthol enhanced light-phase activity. Both treatments elevated MYH4, UCP2, and UCP3 in muscle, and suppressed myostatin expression. These findings suggest capsaicin and menthol modulate skeletal muscle phenotype and metabolism through both direct cellular effects and increased physical activity.
    Keywords:  capsaicin; menthol; muscle differentiation; myosin heavy chain; uncoupling protein
    DOI:  https://doi.org/10.1093/bbb/zbaf149
  16. Am J Physiol Cell Physiol. 2025 Oct 21.
    Spatially distinct ECM-producing fibroblasts and myonuclei orchestrate early adaptation to mechanical loading in the human muscle-tendon unit.
    Ask Møbjerg, Danielle Steffen, Peter Schjerling, Jens Rithamer Jakobsen, Anja Jokipii-Utzon, Mykhailo Y Batiuk, Konstantin Khodosevich, Michael Rindom Krogsgaard, Valerio Izzi, Abigail L Mackey, Michael Kjaer, Ching-Yan Chloé Yeung.
      Mechanical loading drives structural and functional improvements in muscle and tendon, protecting against injury at their interface - the myotendinous junction (MTJ) - and within the tendon matrix. However, the early cellular and molecular events that initiate these adaptations in humans remain poorly understood. To investigate this, we applied single nucleus RNA sequencing and in situ hybridization to map the acute transcriptional response of the human muscle-tendon unit to a single bout of eccentric resistance exercise, with a focus on extracellular matrix (ECM) regulation. We identified four transcriptionally distinct fibroblast subtypes expressing key ECM components, including COL1A1 and DCN. Three of these subtypes were localized to tendon and responded to exercise: two were spatially restricted to the collagen fascicles or the MTJ, while the third, enriched in the interfascicular matrix (IFM), exhibited the strongest response. This IFM population, marked by PDGFRA, upregulated PRG4 and VCAN, ECM genes linked to tissue lubrication and resilience. In parallel, exercise induced dynamic ECM regulation in myonuclei, particularly in a distinct subset of type II myonuclei at the MTJ that expanded in number and robustly upregulated COL22A1, a collagen essential for MTJ integrity. Together, these findings uncover a spatially organized, cell type-specific program of ECM remodeling in response to mechanical load, offering new insight into the early molecular events of human muscle-tendon adaptation.
    Keywords:  exercise; extracellular matrix; fibroblast; myotendinous junction; tendon
    DOI:  https://doi.org/10.1152/ajpcell.00700.2025
  17. Braz J Med Biol Res. 2025 ;pii: S0100-879X2025000100673. [Epub ahead of print]58 e14500
    Twice-a-day exercise increases acute MCT1 gene expression in skeletal muscle but does not change the lactate curve after 3 weeks of training in adult men.
    A P Arcoverde-Mello, V A Andrade-Souza, S K Learsi, F Tomazini, T Ataide-Silva, J Kuang, R Bertuzzi, C G Leandro, D J Bishop, A E Lima-Silva, T Ghiarone, K A S Silva.
      We have previously demonstrated that different modalities of endurance exercise combined with lower muscle glycogen content elicit several physiological and molecular benefits in men. In this study, we hypothesized that these exercise strategies modulate monocarboxylate transporters (MCTs) and plasma lactate. We investigated MCT1 and MCT4 gene expression after two forms of exercise (i.e., once daily and twice-a-day) under low carbohydrate (CHO) availability (Acute - Study 1) and whether three weeks under once daily or twice-a-day training differentially affected plasma lactate during exercise (Chronic - Study 2). In Study 1, five participants performed a high-intensity interval exercise (HIIE) 2 h (twice-a-day) or 15 h (once daily) after exercise and diet manipulations to reduce endogenous CHO stores or without previous CHO manipulation (Control). Muscle biopsies were collected before, right after, and 3 h after HIIE. In Study 2, plasma lactate was measured during a graded exercise test before and after three weeks of once-daily (n=7) or twice-a-day training (n=7). MCT1 gene expression increased from before to after and 3-h post-HIIE only in the twice-a-day exercise (P<0.05). MCT4 gene expression was unaltered in all conditions (P>0.05). The plasma lactate curve shifted to the right in both training approaches, without differences in lactate slope reduction between once-daily (-0.49±0.58 mmol·L-1·min-1) and twice-a-day (-0.46±0.73 mmol·L-1·min-1) exercise. In conclusion, twice-a-day training increased acute MCT1 gene expression but did not result in chronic changes in plasma lactate response during exercise.
    DOI:  https://doi.org/10.1590/1414-431X2025e14500
  18. Sci Rep. 2025 Oct 22. 15(1): 32633
    Tofogliflozin ameliorates cardiotoxin induced skeletal muscle injury and fibrosis in obesity.
    Muhammad Bilal, Nguyen Quynh Phuong, Tomonobu Kado, Jianhui Liu, Le Duc Anh, Sana Khalid, Muhammad Rahil Aslam, Memoona, Ayumi Nishimura, Yoshiko Igarashi, Yoshiyuki Watanabe, Waseem Abbas, Maki Yokoyama, Yasuhiro Onogi, Kenichi Hirabayashi, Seiji Yamamoto, Kunimasa Yagi, Marsel Lino, Isao Usui, Masaru Kato, Shiho Fujisaka, Allah Nawaz, Kazuyuki Tobe.
      Obesity impairs muscle function through effects on lipid metabolism, systemic inflammation, and insulin resistance, leading to muscle loss and reduced regeneration. Tofogliflozin (Tofo), a sodium-glucose cotransporter 2 inhibitor (SGLT2i), exclusively inhibits SGLT2 and is used to treat hyperglycemia in patients with diabetes. The mechanism by which Tofo promotes myogenic potential in an injury model remains elusive. This study investigated Tofo's role in skeletal muscle repair in diet-induced obesity. C57BL/6 J male mice were fed a high-fat diet (HFD) with or without Tofo for 12 weeks. Cardiotoxin (CTX) was used to induce acute injury. We showed that Tofo administration during HFD alleviates obesity-induced disruption in glucose metabolism and upregulates Pax7 and MyoG expression in skeletal muscle, thereby promoting myogenesis following acute injury. Tofo activates fibro-adipogenic progenitors (FAPs) in skeletal muscle, leading to upregulated follistatin (Fst) expression and boosting the recovery process after acute injury. Mechanistically, Tofo prevented the obesity-induced decline in AMPK phosphorylation, rescued the impairment of lipid metabolism, and improved skeletal muscle function, which led to increased exercise tolerance, activation of FAPs, facilitation of skeletal muscle repair, and reduction of fibrosis.
    Keywords:  Cardiotoxin-induced injury; Exercise tolerance; Fibro-adipogenic progenitors (FAPs); Follistatin; Skeletal muscle
    DOI:  https://doi.org/10.1038/s41598-025-12734-9
  19. Sci Rep. 2025 Oct 21. 15(1): 36686
    Multiphoton microscopy and tissue clearing for 3D characterization of the vasculature and fibrosis remodeling in rat dystrophic skeletal muscle.
    Ibrahim Hassani, Mireille Ledevin, Chantal Thorin, Tony Fiore, Marie-Anne Colle, Karl Rouger, Laurence Dubreil.
      Duchenne muscular dystrophy (DMD) is characterized by progressive muscle fiber degeneration and replacement by fibrous and adipose tissues, alongside significant vascular abnormalities. Traditional two-dimensional (2D) histological assessments provide limited insight into the complex three-dimensional (3D) spatial organization and structural disorganization within dystrophic muscle. Here, we present a novel 3D approach combining multiphoton microscopy (second harmonic generation [SHG] and two-photon excited fluorescence [TPEF]) with tissue-clearing methods to comprehensively characterize microvascular and connective tissue remodeling in dystrophic skeletal muscle. We established a dedicated 3D image analysis workflow utilizing deep-learning-based segmentation techniques to quantify key parameters in both vascular and fibrotic compartments in healthy and dystrophic rat muscle samples. Our findings reveal a profound spatial reorganization of the vascular network in dystrophic muscle, marked by its embedding within an expanded connective tissue and a significant reduction in physical interactions with muscle fibers. This advanced imaging and analysis pipeline provides detailed insights into the extent of vascular and fibrotic remodeling in dystrophic muscle, and represents a powerful tool for monitoring disease progression and evaluating the efficacy of therapeutic interventions.
    Keywords:  Clearing; Fibrosis; Image analysis; Multiphoton microscopy; Muscular dystrophy; Vasculature
    DOI:  https://doi.org/10.1038/s41598-025-20335-9
  20. Front Microbiol. 2025 ;16 1665551
    The role of exercise-induced short-chain fatty acids in the gut-muscle axis: implications for sarcopenia prevention and therapy.
    Junyi Fang, Weiyi Yan, Xuao Sun, Jun Chen.
      Sarcopenia is an age-related syndrome characterized by a progressive loss of skeletal muscle mass and function, with its prevalence increasing annually and severely compromising the quality of life in older adults. The pathogenesis of sarcopenia is complex and closely associated with gut microbiota dysbiosis. Emerging evidence suggests that short-chain fatty acids (SCFAs), the main metabolites produced by the gut microbiota, act as key mediators linking gut microbes to skeletal muscle health, a relationship referred to as the gut-muscle axis. SCFAs not only regulate muscle protein metabolism and inflammatory responses but also improve skeletal muscle insulin sensitivity and mitochondrial function, thereby playing a crucial role in maintaining muscle health. Notably, exercise has been shown to increase the abundance of SCFA-producing bacteria in the gut of older adults, thereby elevating circulating SCFA levels. This review summarizes the effects of different exercise modalities on SCFA-producing gut microbiota and circulating SCFA levels in older adults. Furthermore, it discusses the potential mechanisms through which exercise-induced SCFAs contribute to the prevention and management of age-related sarcopenia, thereby providing new insights and scientific references for exercise-based strategies to prevent and treat this condition.
    Keywords:  exercise; gut microbiota; gut-muscle axis; sarcopenia; short-chain fatty acids
    DOI:  https://doi.org/10.3389/fmicb.2025.1665551
  21. Diabetes. 2025 Nov 01. 74(11): 1889-1891
    Distributed Control of Muscle Glucose Uptake: A Tribute to the Late Dr. David H. Wasserman by Revisiting a 2004 Diabetes Classic by Fueger et al.
    Julio E Ayala.
      The control of muscle glucose uptake (MGU) is distributed across delivery, transport, and phosphorylation of glucose. These steps have been defined as control points of MGU in vivo due to the application of isotopic tracer techniques to transgenic mouse models. Using these techniques in a classic study published in Diabetes, Fueger et al. demonstrated that overexpression in skeletal muscle of hexokinase II (HKII), the enzyme responsible for intracellular glucose phosphorylation, enhanced MGU in insulin-sensitive but not in insulin-resistant mice. Conversely, HKII overexpression enhanced MGU in insulin-resistant mice in response to exercise. Since exercise reduces barriers of glucose delivery and transport, this suggested that these two processes contribute to the dysregulation of MGU in insulin-resistant states. These fundamental findings have spurred subsequent studies highlighting the contribution of glucose delivery and transport to the regulation of MGU in health and disease.
    DOI:  https://doi.org/10.2337/dbi25-0022
  22. Med Sci Sports Exerc. 2025 Oct 22.
    Clarifying the Role of [15O]H2O PET in Assessing Skeletal Muscle Perfusion following Post-Exercise Cooling.
    Chris Mawhinney, Kari Kalliokoski, Warren Gregson, Ilkka Heinonen.
      
    DOI:  https://doi.org/10.1249/MSS.0000000000003881
  23. Neuromuscul Disord. 2025 Sep 25. pii: S0960-8966(25)00944-7. [Epub ahead of print]56-57 106217
    Role of skeletal muscle excitability in strength loss induced by submaximal isometric contractions in males with Duchenne muscular dystrophy.
    Mo Chen, Teresa J Kimberley, Molly M Stark, Angus Lindsay, Dawn A Lowe, Joyce P Trost.
      The role of muscle excitability in the underlying mechanism of contraction-induced strength loss and the recovery processes in those with Duchenne muscular dystrophy is unknown. Strength loss of wrist extensor muscles was induced by an intermittent, submaximal, isometric contraction exercise protocol in males with (n = 10) and without Duchenne muscular dystrophy (n = 10). Muscle strength was measured by torque from isometric maximum voluntary contractions. Muscle excitability was measured by compound muscle action potential evoked by transcutaneous magnetic stimulation. Central component of electromyogram was measured by integral electromyogram during isometric maximum voluntary contractions. Significant reductions in muscle excitability were observed in both groups along with reduced maximum voluntary contractions torque after exercise. Muscle excitability was positively correlated with maximum voluntary contractions torque and did not show between-group differences before or immediately after exercise. However, this correlation showed significant between-group differences during recovery. Results indicate that in males with Duchenne muscular dystrophy, muscle strength loss was accompanied by reduced muscle excitability. Importantly, the difference in excitability-torque correlation between groups during recovery suggests that DMD muscle function was affected by the ability to recover from strength loss more than during the contraction-induced strength loss.
    Keywords:  Duchenne muscular dystrophy; Electromyography; Exercise; Muscle excitability; Strength loss
    DOI:  https://doi.org/10.1016/j.nmd.2025.106217
  24. Mol Ther Methods Clin Dev. 2025 Sep 11. 33(3): 101519
    Enhanced therapeutic potential of a microdystrophin with an extended C-terminal domain.
    Steven J Foltz, Randolph Qian, Jason Yang, Kirk Elliott, Benjamin P Heithoff, Hannah Jasick, Jared B Smith, Subha Karumuthil-Melethil, Chunping Qiao, Ye Liu, Olivier Danos.
      Gene replacement therapy is becoming a therapeutic option for patients with Duchenne muscular dystrophy. Truncated dystrophins that can be expressed from adeno-associated viral (AAV) vectors have been designed and shown to retain many, though not all, functional features of the full-length protein. These "microdystrophins" differ by their combination of hinges and spectrin-like repeats and the inclusion of functional domains. Several microdystrophins have advanced to the clinic, and although all have been shown to restore muscle force in preclinical models, they may differ in the efficiency of providing muscle resilience and resistance to contraction-induced stress. Here, we examine whether the inclusion of a highly evolutionarily conserved domain found at the C-Terminus of dystrophin may improve the therapeutic activity of microdystrophin. We find that adding this portion of the C-Terminal domain results in a microdystrophin that is maintained at higher levels in the transduced muscles, recruits the dystrophin-associated protein complex more effectively to the sarcolemma, provides improved histopathological benefit, and increases muscle force and resistance to damage in mice lacking dystrophin. These findings indicate that incorporation of the dystrophin C-Terminus is an enhancement for microdystrophin design and may improve functional benefit.
    Keywords:  AAV; Duchenne muscular dystrophy; Microdystrophin; gene therapy; skeletal muscle
    DOI:  https://doi.org/10.1016/j.omtm.2025.101519
  25. Compr Physiol. 2025 Oct;15(5): e70060
    The Emerging Role of α-Klotho as a Therapeutic Target for Sarcopenia: Underlying Mechanisms and Clinical Prospects.
    Chen-Chen Sun, Yu-Jie Chen, Jiang-Ling Xiao, Zhe Zhao, Chang-Fa Tang.
      Sarcopenia is a syndrome characterized by progressive decline in skeletal muscle mass, strength, and physical performance. It has become a common pathological manifestation of aging, physical inactivity, and multiple chronic diseases. The α-Klotho protein, a well-established anti-aging factor, exists in both membrane-bound and soluble forms. Soluble α-Klotho (s-α-Klotho) circulates systemically and performs a wide range of physiological functions. Studies indicate that α-Klotho is closely associated with multiple age-related disorders, including diabetes, osteoporosis, chronic kidney disease, and neurodegenerative diseases such as Alzheimer's and Parkinson's. Notably, recent studies have revealed reduced expression of α-Klotho in sarcopenia, implicating it in the disease pathogenesis through the regulation of multiple signaling pathways. Given its anti-aging properties, α-Klotho has emerged as a promising therapeutic target for sarcopenia. This review summarizes current evidence supporting the role of α-Klotho in sarcopenia, with a focus on its mechanisms of action in determining skeletal muscle cell fate. Furthermore, it evaluates the potential of various α-Klotho-targeted interventions to ameliorate sarcopenia and discusses challenges and future directions in this evolving field.
    Keywords:  mechanism; sarcopenia; therapeutic target; α‐Klotho
    DOI:  https://doi.org/10.1002/cph4.70060
  26. Stem Cell Reports. 2025 Oct 23. pii: S2213-6711(25)00288-7. [Epub ahead of print] 102684
    Delineating transcriptomic signatures of in vitro human skeletal muscle models in comparison to in vivo references.
    Margaux Van Puyvelde, Eslam Essam Mohammed, Ángela Moreno Anguita, Jarne Bonroy, Sandra Jansen, Atilgan Yilmaz.
      A pivotal question at the heart of stem cell research is how faithful cellular models recapitulate human tissues. Skeletal muscle, the largest organ in the human body, has been modeled by various in vitro systems. Here, we sought to delineate the state-of-the-art of muscle models by performing a large-scale analysis of transcriptome datasets, covering over 400 samples across 39 studies, including bulk and single-cell RNA sequencing of 2D and 3D models and their in vivo counterparts. By comparing these models to in vivo muscle, we highlighted failed upregulation of myogenic factors and retention of epigenetic memory from the in vitro source material. We featured differences in lipid metabolism and depletion of multiple fibroblast growth factor (FGF) ligands in the in vitro models. Finally, we revealed model-dependent variation in myogenic progenitors. Our analyses highlight targetable processes to improve the models while paving the way for similar studies on other cell types.
    Keywords:  bulk RNA sequencing; in vitro models; single cell RNA sequencing; skeletal muscle; skeletal muscle differentiation; skeletal muscle transdifferentiation; transcriptomics
    DOI:  https://doi.org/10.1016/j.stemcr.2025.102684
  27. Sci Adv. 2025 Oct 24. 11(43): eadv6805
    Lysosomal damage is a therapeutic target in Duchenne muscular dystrophy.
    Abbass Jaber, Laura Palmieri, Rania Bakour, Nathalie Bourg, Ai Vu Hong, Elise Lachiver, Carinne Roudaut, Jérôme Poupiot, Sonia Albini, Daniel Stockholm, Laetitia Van Wittenberghe, Adeline Miranda, Guillaume Tanniou, Nathalie Danièle, Inès Barthélémy, Stephane Blot, Mai Thao Bui, Bornale Das, Edoardo Malfatti, Teresinha Evangelista, Isabelle Richard, David Israeli.
      Duchenne muscular dystrophy (DMD), a muscle degenerative disease affecting young boys, arises from the loss of dystrophin. Current gene therapy approaches aim to restore a shortened form of dystrophin (microdystrophin) via adeno-associated vector delivery. While recent clinical studies show promise, therapeutic efficacy remains incomplete, emphasizing the need for improved approaches. Here, we identified lysosomal perturbations in myofibers of patients with DMD and animal models, an overlooked mechanism of cellular damage in muscular dystrophies. These were notably marked by the up-regulation and recruitment of Galectin-3, a biomarker of lysosomal membrane permeabilization, to lysosomes, alongside alterations in lysosome number, morphology, and function. Microdystrophin therapy in Dmdmdx mice fails to fully correct these damages. However, combining it with trehalose, a lysosome-protective disaccharide, substantially improves the outcome, enhancing muscle function, myopathology, and transcriptome. These findings highlight lysosomal damage as an important pathomechanism in DMD and suggest that combining trehalose with gene therapy could enhance therapeutic efficacy.
    DOI:  https://doi.org/10.1126/sciadv.adv6805
  28. Front Neurol. 2025 ;16 1661747
    Proteomic analysis of nemaline myopathy in infants reveals distinct common dysregulated proteins and cellular pathways.
    Carola Hedberg-Oldfors, Ali Zeki Bedir, Kittichate Visuttijai, Eva Michael, Anders Oldfors.
       Background: Nemaline myopathy is a rare congenital muscle disorder characterized by the presence of nemaline rods, protein aggregates, in muscle fibers. Pathogenic variants in several genes, most commonly NEB and ACTA1, which encode thin filament proteins of the sarcomere, have been implicated in its etiology. Currently, there is no cure for nemaline myopathy, underscoring the need to identify disease-modifying targets for therapeutic development.
    Methods: In this study, we employed quantitative nanoscale liquid chromatography-tandem mass spectrometry (LC-MS3) with labeled protein analysis on muscle tissue from five normal controls and seven infants diagnosed with nemaline myopathy due to NEB or ACTA1 pathogenic variants.
    Results: We identified and quantified 4,846 proteins across all samples, with 183 proteins showing significant dysregulation. Protein-protein interaction analysis revealed nine upregulated, muscle-specific proteins: NRAP, FBXO40, TRIM63, TRIM54, ALPK3, XIRP1, ANKRD2, LMOD2, and CSRP3. Further pathway analysis indicated upregulation of protein synthesis and proteasomal degradation processes, alongside downregulation of glycolysis. Notably, the dysregulated proteins and pathways were consistent across both genetic subtypes, suggesting shared molecular mechanisms underlying the disease.
    Conclusion: This proteomic profiling study has identified key dysregulated proteins and pathways in infantile nemaline myopathy. These findings advance our understanding of the disease's molecular basis and highlight candidate targets for future therapeutic intervention.
    Keywords:  dysregulated proteins; glycolysis; nemaline myopathy; pathology; protein degradation; proteinsynthesis; proteomics
    DOI:  https://doi.org/10.3389/fneur.2025.1661747
  29. J Mol Histol. 2025 Oct 22. 56(6): 347
    TAK-242 inhibits toll-like receptor-4 signaling and attenuates cancer-associated muscle atrophy via the p38-C/EBPβ pathway.
    Yongfei You, Zhouzhou Su, Haozheng Wang, Shanshan Liu, Jiayi Wang, Feng Qiu, Zhiqun Jiang, Jianxin Wang, Yong Li, Guohua Zhang.
       BACKGROUND AND AIMS: Cancer cachexia is a paraneoplastic syndrome characterized by progressive muscle atrophy, which negatively impacts treatment efficacy, quality of life, and survival in individuals with cancer. Despite extensive research, no effective medical intervention has completely reversed cachexia, primarily due to an incomplete understanding of its pathogenesis. Toll-like receptor 4 (TLR4) plays an important role in inflammation and metabolic regulation. In this study, the role of TLR4 in muscle catabolism was investigated, with a focus on its regulation of the p38 mitogen-activated protein kinase (MAPK)-mediated activation of C/enhancer-binding protein beta (C/EBPβ) pathway.
    METHODS: TLR4 expression was silenced in C2C12 myotubes using specific small interfering RNAs (siRNAs). Conditioned medium derived from various cancer cell types was applied to C2C12 myotubes to simulate the tumor microenvironment. The pharmacological TLR4 inhibitor TAK-242 was administrated to C2C12 myotubes and C26 tumor-bearing mice to evaluate its effects on muscle atrophy. Western blot analysis and immunofluorescence microscopy were performed on C2C12 myotubes, while muscle tissues from C26 tumor-bearing mice, a model of cancer cachexia, were analyzed using western blot and histological examination.
    RESULTS: Exposure to conditioned medium from cachexia-associated cancer cell lines induced p38 MAPK-C/EBPβ in C2C12 myotubes, leading to upregulation of Ubr2 and Atrogin-1, myosin heavy chain degradation, and myotube atrophy. Silencing or inhibition of TLR4 using siRNA or TAK-242 prevented these catabolic effects in vitro. In C26 tumor-bearing mice, TAK-242 administration significantly attenuated cancer-associated muscle atrophy.
    CONCLUSIONS: TLR4 plays a critical role in cancer-associated muscle atrophy through the p38β MAPK-C/EBPβ signaling pathway in both in vitro and in vivo models. Pharmacological inhibition of TLR4 with TAK-242 effectively attenuated muscle atrophy, highlighting its potential therapeutic value.
    Keywords:  Cancer cachexia; Muscle wasting; TAK242; TLR4; p38 MAPK
    DOI:  https://doi.org/10.1007/s10735-025-10587-0
  30. J Cachexia Sarcopenia Muscle. 2025 Oct;16(5): e70104
    Drug Candidate BIO101 for Spinal Muscular Atrophy as Monotherapy or Combined With the Antisense Oligonucleotide ASO-10-27.
    Cynthia Bézier, Steve Cottin, Parvin Nazari Hashemi, Mirella El Khoury, Zoé Clerc, Christine Balducci, Delphine Sapaly, Laure Weill, René Lafont, Stanislas Veillet, Pierre J Dilda, Frédéric Charbonnier, Mathilde Latil, Olivier Biondi.
       BACKGROUND: Spinal muscular atrophy (SMA) is a neuromuscular disease caused by loss of survival of motor neuron (SMN) protein inducing progressive muscle weakness and atrophy due to motor neurons degeneration. Despite benefits of SMN restoration therapies in patients, motor defects are still persistent. We investigated the potential of BIO101, a new drug candidate promoting muscle growth by activating the protective arm of the renin-angiotensin system through the MAS receptor, as monotherapy or in combination with the SMN-based therapy ASO-10-27 (Nusinersen).
    METHODS: BIO101 was administrated daily on severe or mild Taiwanese SMA mouse models or diluted in culture medium of SMA patient-derived myoblasts. The BIO101 effects were evaluated on severe SMA mouse model in vivo (growth, survival and motor function), ex vivo (motor neuron, neuromuscular junction maturation, skeletal muscle phenotype) and on muscle SMN expression, while motor function effects were evaluated on mild SMA mouse model. The in vitro effects on proliferation, differentiation, metabolism and SMN expression of SMA patient-derived myoblasts were analysed. Effects of the combination of BIO101 with ASO-10-27 were evaluated on severe SMA mouse model, in vivo and on tissular intracellular AKT signalling and SMN expression.
    RESULTS: In severe SMA mice, BIO101 alone protected lateral motor neurons (+20%, p < 0.05), limited muscular atrophy (+30%, p < 0.01), accelerated maturation of muscular fibres (+70% for fast-twitch muscles) and neuromuscular junctions (+50% of perforated clustering, p < 0.05) with more prominent effects on fast-twitch muscles. Those adaptations led to an improvement of muscular function, significant at 7, 9 and 10 days post-natal (+2-fold for crossed squares and time of suspension, p < 0.01), which was also observed in mild SMA mice at 8 and 9 months of age (p < 0.01). Interestingly, BIO101 treatment also improved SMA patient-derived myoblast differentiation (+20% myotube diameter and nuclei/myotube, p < 0.05) and anaerobic performances (ECAR, + 10%; p ≤ 0.05) without any impact on the proliferative state and aerobic capacities through MAS receptor activation. All BIO101 effects were independent of SMN protein expression. When combined with the ASO-10-27, BIO101 enhanced even more muscle resistance to fatigue (> 3-fold over 27 days for time of suspension, p < 0.05) when compared with severe SMA mice treated with ASO-10-27 alone, without effects on survival through the activation of AKT intracellular pathway and independently of SMN protein expression.
    CONCLUSIONS: We showed that BIO101 constitutes an efficient SMN-independent therapy to improve muscle performance in SMA, which could open new therapeutic avenues for patients in combination with SMN-based therapies, or as monotherapy for less severe forms.
    Keywords:  20‐hydroxyecdysone; combinatorial therapy; motor performance; motor units; mouse models; spinal muscular atrophy
    DOI:  https://doi.org/10.1002/jcsm.70104
  31. Front Rehabil Sci. 2025 ;6 1655422
    The impact of second-generation androgen receptor pathway inhibitors on skeletal muscle morphology and strategies to mitigate their effects in prostate cancer patients.
    Sarah Edwards, Tea Lulic-Kuryllo, Anupam Batra.
      The standard of care for metastatic castrate sensitive prostate cancer (mCSPC) involves the use of doublet therapies, which prolong survival and delay disease progression. Doublet therapies include the addition of second-generation androgen receptor pathway inhibitors (ARPIs) to androgen deprivation therapy (ADT). ADT monotherapy has been associated with adverse effects on skeletal muscle morphology, muscle strength, and physical function. Our findings suggest that the addition of ARPIs to ADT may further exacerbate these adverse effects. This review provides an overview of the current evidence to initiate exercise during treatment as an intervention to mitigate these adverse effects. Despite growing research in exercise oncology, research on the effects of exercise in men with mCSPC treated with doublet therapy is lacking. Much of the current supporting evidence is based on men with metastatic castrate resistant prostate cancer. Nonetheless, this review examines the available research on the efficacy and benefits of participating in a regimented exercise program in men with metastatic prostate cancer. We highlight the emerging evidence that exercising during treatment has the potential to protect against the adverse effects of doublet therapy. Future research to uncover the effects of different doublet therapies on muscle health in mCSPC is needed. Moreover, an improved understanding of the optimal training dose and timing that would elicit the most optimal benefits on muscle health in men with mCSPC is required.
    Keywords:  exercise; metastatic castrate sensitive; metastatic prostate cancer; muscle morphology and function; muscle strength; physical function
    DOI:  https://doi.org/10.3389/fresc.2025.1655422
  32. Am J Physiol Cell Physiol. 2025 Oct 24.
    Sex impacts inflammatory signaling, body composition, and physical function in tumor-bearing mice receiving chemotherapy.
    Jessica L Halle, Quan Zhang, Dryden R Baumfalk, Melissa J Puppa, Junaith S Mohamed, Evan S Glazer, Ashley J Smuder, Stephen E Alway, James A Carson.
      Cancer-induced inflammation has been widely investigated as a driver of cachexia, and sex can affect the inflammatory response to cancer. We have an incomplete understanding of how anti-cancer treatments and sex impact the relationship between inflammatory responses and changes to body composition and physical function during cancer treatment. We investigated the effect of FOLFOX chemotherapy (5-fluorouracil, leucovorin, oxaliplatin) on circulating inflammatory cytokines, body composition, and physical function in CT26 tumor-bearing male and female mice. BALB/c mice were injected with CT26 tumor cells, and after the tumor was palpable, underwent three cycles of FOLFOX. FOLFOX reduced tumor mass in both sexes. CT26 induced plasma IL-6, LIF, and TNF-α in males and females. FOLFOX attenuated the CT26-induced IL-6 and LIF levels in males, but in females FOLFOX alone induced IL-6 and TNF-α, and did not attenuate their CT26 induction. In CT26 males, but not females, total lean and hindlimb mass were negatively associated with IL-6, and FOLFOX disrupted this association. The CT26-induced muscle p-STAT3 was inversely associated with muscle mass in males only and disrupted by FOLFOX. Circulating inflammatory cytokines were associated with body composition changes and functional deficits in CT26 males, but FOLFOX and female sex altered this relationship. Our results provide evidence that the female response to circulating inflammatory cytokines in the CT26 tumor environment, following FOLFOX chemotherapy, differs from that of males, and the physiological ramifications of this regulation warrant further investigation.
    Keywords:  FOLFOX; Interleukin-6 (IL-6); colorectal cancer; leukemia inhibitory factor (LIF); signal transducer and activator of transcription 3 (STAT3)
    DOI:  https://doi.org/10.1152/ajpcell.00643.2025
  33. J Appl Physiol (1985). 2025 Oct 20.
    Intermuscular adipose tissue in healthy human aging - effects of exercise training and implications to metabolic health.
    Andrew M Alexander, Lucy M Fitzgibbons, Hawley E Kunz, Zinnarky K Ortiz Correa, K Sreekumaran Nair, John Port, Ian R Lanza.
      Intermuscular adipose tissue (IMAT) is an anatomically distinct depot that is associated with metabolic dysfunction and aging. IMAT decreases with exercise in older adults with obesity, but less is known about how exercise influences IMAT in healthy, non-obese older adults in relation to insulin sensitivity. The purpose of this study was to determine if lower leg IMAT accumulates in healthy older adults in the absence of obesity, diabetes, or frailty and its relationship to insulin sensitivity. We also determined the influence of exercise training on lower leg IMAT. 29 young (25.0 ± 3.7 years) and 22 older (70.0 ± 4.0 years) adults underwent MRI-based measurements of lower leg IMAT and insulin sensitivity measurements by hyperinsulinemic euglycemic clamp before and after 12 weeks of exercise training. IMAT was higher in older compared to young adults (521 ± 217 mm3 vs 278 ± 131 mm3; p<0.0001). The glucose infusion rate (GIR) during hyperinsulinemia was similar in young and older adults (13.5 ± 2.9 mg/kg FFM/min vs 14.1 ± 4.2 mg/kg FFM/min; p=0.38), but negatively associated with IMAT (r=-0.43; p=0.002), particularly in older adults (r=-0.55; p=0.01). Exercise training reduced IMAT in young (p=0.04) but not older adults. GIR increased in response to exercise but dissociated from changes in IMAT. These data demonstrate that lower leg IMAT accumulated even in healthy aging, and although IMAT may have metabolic implications, the metabolic improvements with exercise training appear to be independent of lower leg IMAT in this population of older adults.
    Keywords:  Aging; exercise; glucose; intermuscular adipose; muscle
    DOI:  https://doi.org/10.1152/japplphysiol.00719.2025
  34. Med Sci Sports Exerc. 2025 Oct 22.
    The Influence of Sleep Restriction and High-Intensity Interval Exercise on Plasma and Skeletal Muscle Inflammatory Markers in Young Healthy Males.
    Nicholas J Saner, Esther Garcia-Dominguez, Matthew J-C Lee, Andrew Garnham, Jonathan D Bartlett, David J Bishop.
       PURPOSE: Inadequate sleep has been linked to the development of cardiometabolic disease, with increases in inflammation suggested as a possible underlying mechanism. Exercise has anti-inflammatory properties and may ameliorate some of the detrimental inflammatory effects associated with sleep loss. The present study aimed to investigate the effect of sleep restriction, with or without high-intensity interval exercise (HIIE), on plasma and skeletal muscle markers of inflammation.
    METHODS: Twenty-four healthy, young males underwent a five-night sleep intervention period. Participants were allocated to one of three groups; Normal Sleep (NS, n=8) (8 h time in bed each night (TIB)), Sleep Restriction (SR, n=8) (4 h TIB), or Sleep Restriction and Exercise (SR+EX, n=8, 4 h TIB, with three sessions of HIIE). Skeletal muscle and plasma samples were collected pre- and post-intervention and assessed for inflammatory markers.
    RESULTS: Plasma inflammatory cytokines (IL-6, TNF-α, and IFN-γ) did not change from pre- to post-intervention in any group (P > 0.05). Skeletal muscle protein content of NFAT1 increased in the SR group only (mean difference ± SD: 0.39 ± 0.45 A.U.; 95% CI: 0.10 to 0.67 A.U.; P=0.010). However, no further changes in inflammatory-related skeletal muscle mRNA content (NF-KB (p50), NF-KB (p65), SOD1) or protein content (p-STAT1, p-JNK, p-ERK 1/2) were observed in any group (P > 0.05).
    CONCLUSIONS: Five nights of sleep restriction, with or without HIIE, resulted in minimal changes to plasma and skeletal muscle inflammatory markers. Additional timepoints and broader inflammatory assessments may better elucidate the relationship between sleep loss and inflammation.
    Keywords:  CARDIOMETABOLIC HEALTH; CYTOKINES; EXERCISE; IMMUNE RESPONSE; OXIDATIVE STRESS; SLEEP DEPRIVATION; SLEEP LOSS
    DOI:  https://doi.org/10.1249/MSS.0000000000003879
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