bims-moremu Biomed News
on Molecular regulators of muscle mass
Issue of 2026–11–08
forty papers selected by
Anna Vainshtein, Craft Science Inc.
  1. Intermittent fasting enhances muscle regeneration via an EDA2R-NIK-myomixer axis.
  2. Evidence for spermine oxidase (SMOX) as a regulator of skeletal muscle mass throughout the lifespan.
  3. Proteostasis network dysregulation in aging skeletal muscle: Mechanisms and therapeutic targets in sarcopenia and muscle wasting.
  4. The act of balancing excitability: Novel approaches to combat skeletal muscle hyper-excitability.
  5. Constitutive Activation of Skeletal Muscle mTORC1 Drives Pro-Inflammatory Gene Expression in Skeletal Muscle of Aged Mice.
  6. Does β-hydroxy-β-methylbutyrate-associated improvement in mitochondrial respiration preserve fast-twitch muscle function in Duchenne muscular dystrophy?
  7. Revitalizing aging muscles: harnessing NAD⁺, sirtuins, and exercise to combat sarcopenia.
  8. Reprogramming muscle proteostasis in cancer cachexia: Transcriptional mechanisms and therapeutic opportunities.
  9. An integrative multi-omic analysis of skeletal muscle in response to disuse and recovery resistance training in resistance trained and untrained young adults.
  10. Exercise-induced mitochondrial remodelling: Breaking apart to rebuild.
  11. NUB1 Regulates Muscle Atrophy in Lung Cancer Cachexia via NF-κB Signaling Pathway.
  12. Plasma-membrane proteins in human skeletal muscle for targeted drug delivery: An annotated resource.
  13. Human iPSC-based skeletal muscle model of LAMA2-related congenital muscular dystrophy.
  14. S100A9 Mediates Neuroblastoma-Associated Skeletal Muscle Atrophy via O-GlcNAcylation Repression and Activate Mitophagy Activation.
  15. Sexually Dimorphic Response to Dietary Restriction-Induced Longevity and Muscle Preservation in Nothobranchius furzeri.
  16. Nr1d1 regulates ER-mitochondria interactions and calcium transfer, and muscle cell apoptosis.
  17. Cellular senescence mediates facioscapulohumeral muscular dystrophy.
  18. Local translational program at the muscle-tendon junction endows domain identity in muscle syncytia.
  19. Integrated single-cell and bulk transcriptomic analysis suggest a possible association between M1-like macrophage cuproptosis and angiogenic impairment in exercise-deficiency-associated sarcopenia.
  20. Zebrafish models for investigating skeletal muscle aging and sarcopenia.
  21. Mitochondrial Transplantation Preserves Regenerative Capacity of Denervated Skeletal Muscle by Disrupting a Ca2+ Overload-Mitophagy-Ferroptosis Circuit.
  22. Identification of Endoplasmic reticulum Homeostasis-associated diagnostic biomarkers for Sarcopenia through integrated Bioinformatics and Experimental Validation.
  23. Identification of substrates for the skeletal muscle-specific lysine methyltransferases METTL21C and METTL21E.
  24. A single liver-sparing myotropic AAV ameliorates muscular dystrophy in humanized mice by base editing.
  25. Vortex wave stimulation: A novel anabolic stimulus for ageing muscle?
  26. GLP-1 and GIP receptor agonism does not directly drive skeletal muscle atrophy or impair myogenesis in primary human myotubes.
  27. P2Y6R is associated with adipose inflammation and muscle wasting in pancreatic cancer cachexia.
  28. Aerobic exercise preconditioning enhances skeletal muscle resistance and recovery after contusion: involvement of the SIRT1/PGC-1α axis.
  29. CD90 delineates distinct muscle stem cell states of quiescence and activation.
  30. Chronic Exercise Accelerates Disease Progression in a Rat Model of Desminopathy.
  31. Steady state or not? Understanding muscle protein turnover during disuse atrophy.
  32. Branched-chain amino acids in skeletal and cardiac muscles: a review of metabolic variations and cancer's impact.
  33. Cisplatin induces skeletal muscle dysfunction, oxidative stress, and senescence-associated responses in male and female rats.
  34. Neonatal overfeeding accelerates age-related sarcopenia and metabolic disorders through lifelong gut mucosa and microbiota programming in mice.
  35. The YAP/TAZ-Tgfbr2-stiffness feedback loop governs divergent cell fates of muscle-resident mesenchymal progenitors.
  36. Wnt5a/Ca2+ signal promotes myogenic differentiation by mediating a slow and sustained influx of Ca2.
  37. Differentiated obesity treatment: Pharmacological CRF2 agonism drives fat loss, skeletal muscle hypertrophy and improved glucose metabolism in preclinical obesity.
  38. Identifying fundamental properties of neuromuscular disorder genes through genomic feature analysis.
  39. Proteomic clocks reveal organ-specific signatures of aging in mice.
  40. Cross bridges, tendons and titin: evolving roles in muscle mechanics.
  1. Cell Rep. 2026 Nov 04. pii: S2211-1247(26)01318-5. [Epub ahead of print] 118239
    Intermittent fasting enhances muscle regeneration via an EDA2R-NIK-myomixer axis.
    Dilsad H Arabaci, Melis Sucuoglu, Funda Gizem Gokoglan, Samet Agca, Aleyna Kizilyer, Zubeyde Gurel, Caroline Uslucan, Ilayda Serit, Serkan Kir.
      Skeletal muscle exhibits a remarkable regenerative capacity that relies on adult stem cells known as satellite cells (SCs), which differentiate into myogenic progenitors to drive muscle repair. How varying energy availability alters myogenesis, however, remains unknown. Here, we demonstrate that intermittent fasting (IF) in mice upregulates a myogenic gene program, including Myomixer, a muscle-specific fusogen that facilitates the merging of progenitor cells into myofibers. IF enhances the regeneration of injured muscles by expanding the SC population and promoting the proliferation and fusion of myogenic progenitors. These effects are absent in an SC-depletion model. We show that fasting-induced EDA2R-NIK signaling increases Myomixer expression and fusion in myoblasts. Notably, mice lacking EDA2R or NIK fail to respond to the myogenic effects of IF. Furthermore, our data suggest that mice with Duchenne muscular dystrophy also benefit from an IF regimen. Therefore, IF-induced regeneration holds potential for aiding recovery from muscle damage.
    Keywords:  CP: metabolism; CP: molecular biology; NF-κB signaling; intermittent fasting; muscle regeneration; muscle satellite cells; myogenic fusion; skeletal muscle
    DOI:  https://doi.org/10.1016/j.celrep.2026.118239
  2. Ageing Res Rev. 2026 Nov 03. pii: S1568-1637(26)00429-0. [Epub ahead of print]123 103437
    Evidence for spermine oxidase (SMOX) as a regulator of skeletal muscle mass throughout the lifespan.
    Cristhian F Montenegro, Kevin A Murach, Toby L Chambers.
      Age-associated loss of muscle mass and function, termed sarcopenia, increases morbidity and mortality risks concomitant with decreased physical activity. Chronic exercise training is the most effective countermeasure against sarcopenia, but physical limitations create a barrier to participation in the elderly. Investigation into alternative pharmaceutical and nutraceutical treatments to prevent sarcopenia and maintain muscle plasticity late-in-life are therefore warranted. Polyamine metabolism regulates many facets of skeletal muscle biology with the potential for targeted treatments in conditions of compromised muscle health and plasticity. Particularly, spermidine is shown to benefit muscle health in mammalian models of ageing and exercise training. Endogenous production of spermidine is partially regulated by the enzyme spermine oxidase (SMOX). SMOX catabolism cleaves spermine into spermidine to maintain a healthy polyamine pool. Anabolic signaling regulates SMOX expression suggesting a supporting role of polyamines during muscle hypertrophy. SMOX overexpression in skeletal muscle retains muscle fiber size in atrophy-inducing animal models (e.g. immobilization, fasting, denervation) potentially driven by reciprocal downregulation of p21, a marker of cellular senescence. In satellite cells, spermidine improves satellite cell function by restoring autophagy and mitophagy, potentially related to anti-ageing Yamanaka factors. Abundance of SMOX is highest in fast-twitch muscle fiber types but can respond in a fiber-type and exercise dependent manner. In humans, higher basal SMOX expression after strength training correlates to higher strength gains, but investigations of SMOX's actions in humans are lacking. Further defining the role of SMOX in animal and human models will facilitate future skeletal muscle-specific therapeutics to promote youthfulness during ageing.
    Keywords:  Ageing; Polyamine metabolism; Skeletal muscle; Spermine oxidase
    DOI:  https://doi.org/10.1016/j.arr.2026.103437
  3. Exp Gerontol. 2026 Oct 31. pii: S0531-5565(26)00353-0. [Epub ahead of print] 113373
    Proteostasis network dysregulation in aging skeletal muscle: Mechanisms and therapeutic targets in sarcopenia and muscle wasting.
    Syeda Kubra, Farhad Badshah, Gholamreza Abdi.
      Aging is a universal biological process signified by a time-dependent decline in physiological activity, driven by molecular and cellular damage, leading to greater susceptibility to diseases and fatal outcomes. Impaired proteostasis is a key aspect of cellular aging in which the cells become less efficient at folding, repairing, and recycling proteins, consequently inducing accumulation of damaged and aggregation-prone proteins. The onset of muscle loss is driven by a reduction in protein synthesis, heightened activation of proteolytic pathways, and elevated ER stress factors, collectively contributing to functional decline and increased vulnerability with aging. Muscle atrophy, whether age-related or driven by chronic illness, represents a major role in defective health, impacting both quality of life and survival. This review explores the intricate and multidimensional nature of proteostasis network regulating protein quality control across skeletal muscles. We examined how the malfunction of components within proteostasis networks during aging contributes to the induction, progression, and chronicity of common age-related muscle wasting. Experimental and clinical studies exploring potential therapeutic strategies for better proteostasis in muscle wasting have been discussed. In this review, we emphasized the increasing demand for effective therapeutic interventions that can slow down or mitigate age-related deterioration in muscle physiology and sustain mobility and quality of life in the elderly. We analyzed the roles of ubiquitin proteasome system, autophagy lysosomal pathway, and unfolded protein response in muscle wasting, highlighting protein loss from synthesis-degradation imbalance as a major driver of muscle atrophy under catabolic conditions. This review outlines key findings with emerging insights to help drive the development of targeted therapies against muscle wasting. Looking ahead, emerging approaches such as PROTACs, extracellular vesicle-based therapies, and artificial intelligence-driven predictive models hold promise for advancing precision interventions in muscle wasting research.
    Keywords:  Aging; Autophagy lysosome pathway; Muscle wasting; Proteostasis; Sarcopenia; Therapeutics; Ubiquitin proteasome system; Unfolded protein response
    DOI:  https://doi.org/10.1016/j.exger.2026.113373
  4. J Physiol. 2026 Oct 31.
    The act of balancing excitability: Novel approaches to combat skeletal muscle hyper-excitability.
    Jeppe Blichfeldt Winther.
      
    Keywords:  excitability; myotonia; skeletal muscle
    DOI:  https://doi.org/10.1113/JP292785
  5. Aging Cell. 2026 Nov;pii: e70805. [Epub ahead of print]25(11):
    Constitutive Activation of Skeletal Muscle mTORC1 Drives Pro-Inflammatory Gene Expression in Skeletal Muscle of Aged Mice.
    Erik D Marchant, Hanna Kalenta, Jacquelyn May, Zhao Lai, Adam B Salmon, Blake B Rasmussen.
      mTORC1 activity is increased in muscle with aging and is implicated as a potential driver of age-related declines in muscle health. While pharmacological inhibition of mTORC1 improves lifespan and healthspan, it remains unclear whether chronic activation of mTORC1 is sufficient to accelerate aging in skeletal muscle. We aimed to address this question using an inducible model of muscle-specific knockout of Depdc5, which encodes the protein DEP domain containing 5 (DEPDC5), a negative regulator of mTORC1. In 27-month-old mice, Depdc5 knockout induced a robust upregulation of inflammatory and immune-related genes, accompanied by alterations in metabolic and angiogenic pathways. Additionally, Depdc5 knockout mice exhibited an increase in TNF-α protein expression. However, these transcriptional and protein changes were not associated with an altered macrophage phenotype or with changes in muscle capillary density. Dietary rapamycin partially reversed mTORC1 signaling and some of the transcriptional changes, including those related to angiogenesis, but did not suppress inflammation-related transcripts or protein expression. These findings demonstrate that constitutive activation of mTORC1 is sufficient to drive pro-inflammatory changes in aged skeletal muscle, adding to the inflammation that already occurs with aging.
    Keywords:  aging; geroscience; inflammaging; inflammation; mTOR; nutrient sensing
    DOI:  https://doi.org/10.1111/acel.70805
  6. J Physiol. 2026 Nov 01.
    Does β-hydroxy-β-methylbutyrate-associated improvement in mitochondrial respiration preserve fast-twitch muscle function in Duchenne muscular dystrophy?
    Israel Lopes de Lima.
      
    Keywords:  Duchenne muscular dystrophy; mitochondria; skeletal muscle; β‐hydroxy‐β‐methylbutyrate
    DOI:  https://doi.org/10.1113/JP292720
  7. J Bioenerg Biomembr. 2026 Nov 03. pii: 61. [Epub ahead of print]58(1):
    Revitalizing aging muscles: harnessing NAD⁺, sirtuins, and exercise to combat sarcopenia.
    Yan Wang, Guimei Zhang.
      Aging is associated with systemic metabolic dysfunction that contributes to geriatric syndromes such as sarcopenia-the progressive loss of skeletal muscle mass and function. Evidence from preclinical models suggests that age-associated depletion of nicotinamide adenine dinucleotide (NAD⁺) may contribute to this decline by limiting the activity of sirtuin deacetylases (SIRT1-7). These enzymes act as metabolic sensors regulating mitochondrial biogenesis, oxidative capacity, DNA repair and pathways related to muscle atrophy. Physical exercise enhances NAD⁺ salvage through upregulation of nicotinamide phosphoribosyltransferase (NAMPT). Pharmacological approaches including NAD⁺ precursor supplementation (nicotinamide riboside or nicotinamide mononucleotide) and inhibition of NAD⁺-consuming enzymes have shown benefits in preclinical models. However, clinical translation remains inconsistent. Recent meta-analyses have found no significant effect of these precursors on muscle mass or strength in adults aged over 60 years. Moreover, experimental evidence indicates that even profound NAD⁺ depletion in adult mouse skeletal muscle does not necessarily compromise function or accelerate aging. We conclude that pharmacological NAD⁺ restoration alone is currently insufficient to reverse sarcopenia in humans. A synergistic approach combining exercise with targeted NAD⁺ support, together with emerging strategies involving precursor transporters, trigonelline and hypothalamic NAD⁺-sirtuin circuits, represents a testable avenue that requires rigorous, stratified clinical evaluation.
    Keywords:  Aging; Exercise; NAD⁺ metabolism; Sarcopenia; Sirtuins; Skeletal muscle; Translational gap
    DOI:  https://doi.org/10.1007/s10863-026-10140-y
  8. Cancer Lett. 2026 Nov 03. pii: S0304-3835(26)00708-1. [Epub ahead of print]664 218944
    Reprogramming muscle proteostasis in cancer cachexia: Transcriptional mechanisms and therapeutic opportunities.
    Bowen Xu, Aishwarya Jaiswal, Silin Liu, Ashok Kumar, Meiricris Tomaz da Silva.
      Cancer cachexia is a multifactorial syndrome characterized by progressive skeletal muscle wasting that impairs quality of life, limits responses to anticancer therapies, and increases mortality. Although excessive protein degradation has traditionally been viewed as a primary driver of muscle loss, cachectic muscle undergoes broader disruptions in proteostasis involving protein turnover, organelle quality control, stress adaptation, metabolism, and regenerative capacity. Accumulating evidence suggests that diverse tumor- and host-derived signals converge on interconnected transcriptional networks that coordinate these processes. Rather than functioning independently, transcription factors integrate inflammatory, metabolic, hormonal, and cellular-stress signals to orchestrate catabolic, stress-responsive, anabolic, and regenerative programs, with effects that vary with disease stage and cellular context. Importantly, these transcriptional responses are not uniformly pathological but can represent causal, adaptive, or compensatory programs. Epigenetic, post-transcriptional, and post-translational mechanisms add further regulatory layers that shape the activation and magnitude of these transcriptional programs. Emerging single-cell and multi-omic approaches have further revealed myofiber- and cell-specific regulatory networks that contribute to the heterogeneous response of skeletal muscle to tumor growth. In this review, we propose that transcriptional reprogramming represents a central integrative mechanism through which diverse catabolic signals remodel skeletal muscle proteostasis, and we examine how network-level regulation contributes to muscle adaptation and wasting in cancer cachexia. Defining which regulatory programs are causal, maladaptive, adaptive, or compensatory may reveal more precise biomarkers and therapeutic targets for preserving skeletal muscle mass and function in patients with cancer cachexia.
    Keywords:  Cancer cachexia; FOXO; Muscle atrophy; NF-κB; Proteostasis; STAT3; Skeletal muscle; Transcriptional regulation
    DOI:  https://doi.org/10.1016/j.canlet.2026.218944
  9. Skelet Muscle. 2026 Aug 05. pii: 40. [Epub ahead of print]16(1):
    An integrative multi-omic analysis of skeletal muscle in response to disuse and recovery resistance training in resistance trained and untrained young adults.
    J Max Michel, Joshua S Godwin, Zachary A Graham, Jacob A Siedlik, Melissa D Boersma, Martino V Franchi, Harsimran S Baweja, C Brooks Mobley, Andreas N Kavazis, David C Hughes, Marcas M Bamman, Michael D Roberts, Christopher G Vann.
      We previously reported that resistance trained (T) and untrained (UT) individuals exhibit similar targeted molecular responses in skeletal muscle following two weeks of leg immobilization and eight weeks of subsequent recovery resistance training (RT). The present analysis examined the skeletal muscle transcriptome, microRNA (miR)-ome, and proteome responses in a subset of these participants (N = 8 T and N = 8 UT). Vastus lateralis biopsies were obtained at baseline (PRE), after the 2-wk immobilization protocol (DIS), and after 8-wk of recovery RT (REC-RT). Tissue RNA and protein were subjected to RNA- and miR-sequencing and proteomics, respectively. Analyses included: (i) group and time differential expression (DE) and pathway enrichment for each independent -ome; (ii) multi-omics integration to reveal modules across the -omes; and (iii) leave one out cross-validated linear regression modeling (LOOCV) to reveal key features predictive of atrophy and hypertrophy. Most differentially expressed (DE) RNAs or differentially abundant (DA) proteins were time-driven rather than training status-driven. In all participants, the transcriptome was most responsive to disuse (PRE-to-DIS: 2047 DE mRNAs; 3 DE miRs; 10 DA proteins) while the transcriptome and proteome were both responsive to recovery RT (DIS-to-REC-RT: 446 DE mRNAs; 0 DE miR; 415 DA proteins). Pathways analyses revealed proteostasis and DNA repair with disuse atrophy, whereas striated muscle contraction, transcriptional regulation, and rRNA expression were enriched with recovery RT. Integrative analyses identified SLIT-ROBO signaling as a potentially novel axis in disuse atrophy, driven predominantly by transcriptomic changes, whereas enrichment of striated muscle contraction pathways in recovery RT was supported by coordinated mRNA and protein regulation. Via LOOCV, the 10 top predictors of disuse atrophy were RNAs (8 protein coding) primarily related to mitochondrial function and protein trafficking, while 9 of the top 10 predictors of recovery RT hypertrophy were RNAs (8 protein coding) related to membrane dynamics, ECM/cytoskeletal organization, and translation initiation. This integrative multi-omic approach reiterates that disuse atrophy and recovery RT-induced hypertrophy elicit similar molecular responses in T and UT individuals, highlighting distinct molecular signatures governing skeletal muscle atrophy and recovery hypertrophy independent of training status.
    Keywords:  Atrophy; Disuse; Hypertrophy; Integrative networks; Proteomics; RNA-seq; miRNA
    DOI:  https://doi.org/10.1186/s13395-026-00440-7
  10. J Physiol. 2026 Nov 05.
    Exercise-induced mitochondrial remodelling: Breaking apart to rebuild.
    Lucas Esposito Dos Santos, Andressa Crystine da Silva Sobrinho, Guilherme da Silva Rodrigues, Bianca Rocha Nicoletti.
      
    Keywords:  exercise; mitochondrial dynamics; mitochondrial fission; mitochondrial fusion; skeletal muscle; systems biology
    DOI:  https://doi.org/10.1113/JP292575
  11. Adv Sci (Weinh). 2026 Oct 31. pii: e78492. [Epub ahead of print]
    NUB1 Regulates Muscle Atrophy in Lung Cancer Cachexia via NF-κB Signaling Pathway.
    Yuqi Han, Yaru Xia, Weiquan Li, Jiaming Wu, Tiexi Yu, Diaoyi Tan, Daojia Miao, Wen Li, Xuejiao Dong, Jiemin Li, Yu Jiao, Guixiao Huang, Xiaoping Zhang, Hongmei Yang.
      Cancer-associated cachexia (CAC) is a devastating multifactorial syndrome characterized by progressive skeletal muscle atrophy. Its mechanisms remain incompletely clarified, with limited effective therapeutic targets. NUB1, a negative regulator of ubiquitin-like proteins mediating protein degradation, has not been fully elucidated in CAC-induced muscle atrophy. Here, NUB1 was significantly upregulated in skeletal muscles of Lewis lung carcinoma (LLC) cachexia mice and C2C12 myotube atrophy models stimulated with LLC tumor-conditioned medium (LCM). Silencing NUB1 alleviated LCM-induced myotube atrophy in vitro and enhanced muscle mass, fiber cross-sectional area and function in LLC cachectic mice in vivo. Mechanistically, upregulated NUB1 recruited IκBα to bind proteasomal subunit S5a, promoting IκBα degradation, thus increasing NF-κB nuclear translocation and transcription of Atrogin1 and MuRF1. Silencing NUB1 inhibited NF-κB activation, while TNFα reversed its protective effect. These findings identified NUB1 as a novel driver of CAC-related muscle atrophy and highlighted the NUB1/IκBα/NF-κB axis as a promising therapeutic target.
    Keywords:  NF‐κB signaling; NUB1; cancer‐associated cachexia; muscle atrophy
    DOI:  https://doi.org/10.1002/advs.78492
  12. Mol Ther Nucleic Acids. 2026 Dec 08. 37(4): 103115
    Plasma-membrane proteins in human skeletal muscle for targeted drug delivery: An annotated resource.
    Nemanja Stanojević, Jørgen Kjems, Louise T Dalgaard.
      Skeletal muscle is essential for metabolic regulation, energy homeostasis, and physical function. Its dysfunction contributes to disorders such as type 2 diabetes, muscular dystrophies, sarcopenia, cachexia, and muscle wasting linked to aging, cancer, and immobilization. Despite advances in RNA-based therapeutics, achieving efficient and selective delivery to skeletal muscle remains a major translational barrier. Targeting muscle-enriched cell-surface proteins represents a promising strategy to improve therapeutic specificity while limiting systemic exposure. Here, we combine a systematic literature review with database-driven analyses to identify and prioritize skeletal muscle-enriched plasma membrane proteins as candidate entry points for targeted delivery. The review summarizes current targeting approaches, highlighting their strengths and limitations. In parallel, integrative mining of the Human Protein Atlas, Genotype-Tissue Expression (GTEx), and CellxGene datasets identified 76 high-confidence skeletal muscle-enriched membrane-associated proteins. These were further functionally annotated and ranked using multi-parameter criteria, including relevance to internalization and suitability for nucleic acid-based delivery. In addition, we discuss potential disease contexts in which to employ these. Together, these analyses generate a curated resource of candidate targets and provide a conceptual framework for developing next-generation delivery platforms for RNA therapeutics and other modalities aimed at skeletal muscle across a broad range of muscle-related diseases.
    Keywords:  MT: Delivery Strategies; diabetes mellitus; emerging technologies; metabolic disorders; muscular dystrophy; plasma membrane proteins; receptor-mediated endocytosis; skeletal muscle; targeted drug delivery; tissue specificity
    DOI:  https://doi.org/10.1016/j.omtn.2026.103115
  13. Skelet Muscle. 2026 Aug 05. pii: 39. [Epub ahead of print]16(1):
    Human iPSC-based skeletal muscle model of LAMA2-related congenital muscular dystrophy.
    Jaquelyn M Villalba, Andrea Canahui, Francesca I Malit, George Lawless, Vladimir Zhemkov, April D Pyle, Kyu Shik Mun, Sujung Yi, Clive N Svendsen, Michelle R Allen-Sharpley.
       BACKGROUND: Congenital muscular dystrophies (CMDs) are rare, devastating pediatric conditions with no specific treatment or cure. The most common form, LAMA2-related CMD, or LAMA2-CMD (previously known as merosin-deficiency and MDC type 1 A), is caused by myofiber instability from loss of the laminin α2 subunit, a critical extracellular matrix protein in skeletal muscle. Progressive weakness from diffuse skeletal muscle degeneration and fibrosis leads to death in childhood. Animal models significantly enhanced the understanding of LAMA2-CMD and spearheaded innovative rescue strategies. However, limitations of animal models including difficulty recapitulating human muscular dystrophy phenotypes and a lack of validated studies with relevant human tissues have stalled clinical translation. In vitro models of human skeletal muscle exhibiting measurable characteristics of patient disease can significantly improve our ability to study disease mechanisms and further advance therapeutics.
    METHODS: Skeletal muscle progenitor cells (SMPCs), mature myoblasts and 3-dimensional (3D) skeletal muscle tissue were derived from induced pluripotent stem cells of a LAMA2-CMD patient and her unaffected parents as controls. The 3D skeletal muscle constructs were embedded in hydrogel with and without co-seeding with human fibroblasts as supporting cells. Cell fusion, tissue remodeling, contractility and attachment were then analyzed.
    RESULTS: The 3D skeletal muscle model forms into bundles of multinucleated myotubes, with spontaneous and induced contractions mirroring in vivo muscle tissue. During the skeletal muscle progenitor cell differentiation phase, the LAMA2-CMD neuroectoderm clusters were smaller and less complex than control cases. Despite this, SMPCs were robust and purified at equivalent rates from the patient and control lines. With further differentiation to mature myotubes, LAMA2-CMD cells had reduced cellular fusion compared to control cells. In engineered 3D-skeletal muscle tissues anchored to micropillars, the LAMA2-CMD skeletal muscle demonstrated dystrophic features such as poor attachment, reduced remodeling into compact skeletal muscle bundles, and reduced ability to withstand acetylcholine-induced contractions. The LAMA2-CMD skeletal muscle fibers consistently rupture upon contraction.
    CONCLUSION: A patient-derived in vitro model of LAMA2-CMD was established that exhibits a dystrophic phenotype closely resembling the human disease. This platform represents a valuable human tissue model to enhance translational research and therapeutic development efforts for CMDs.
    Keywords:  Congenital muscular dystrophy; Human iPSC; Laminin; MDC1A; Merosin; Muscle disease modeling; Skeletal muscle progenitor cells
    DOI:  https://doi.org/10.1186/s13395-026-00438-1
  14. J Cachexia Sarcopenia Muscle. 2026 Dec;pii: e70419. [Epub ahead of print]17(6):
    S100A9 Mediates Neuroblastoma-Associated Skeletal Muscle Atrophy via O-GlcNAcylation Repression and Activate Mitophagy Activation.
    Jianwei Lin, Yuxin Zhang, Qi Wang, Jingchun Lv, Bingqiang Han, Dapeng Jiang.
       BACKGROUND: In patients with neuroblastoma (NB), skeletal muscle atrophy is a key factor linked to poor survival and decreased long-term quality of life. Nevertheless, there are still insufficient therapeutic methods that work, and the underlying mechanisms remain unclear. As persistent inflammation is a hallmark of tumour-related muscle atrophy, this study aims to identify the key inflammatory mediators causing NB-related muscle atrophy and systematically elucidate the downstream molecular mechanism.
    METHODS: The adverse biological features of NB were used to identify potential inflammatory mediators causing muscle atrophy. Serum samples from NB patients and NB mouse models were then used to confirm the clinical relevance of these candidates to skeletal muscle atrophy. Recombinant inflammatory proteins and certain inhibitors were given in vivo to define the functional impact of mediators. Additionally, RNA sequencing (RNA-seq), quantitative real-time PCR (qPCR) and Western blotting were used to methodically examine the underlying molecular pathways of NB-induced muscle atrophy.
    RESULTS: Both NB patients with muscle atrophy and NB mouse models had considerably higher serum levels of the pro-inflammatory mediator S100A9 protein (p < 0.001). Recombinant mouse S100A9 protein functionally reduced skeletal muscle weight and upregulated the atrophy markers TRIM63/FBXO32 in mice (p < 0.05), whereas its inhibitor, ABR-238901, successfully reduced muscle atrophy and downregulated these atrophy markers in the NB model (p < 0.001). Mechanistically, S100A9 inhibited skeletal muscle protein O-GlcNAcylation via its receptor RAGE (p < 0.05). Muscle atrophy was ultimately caused by the abnormal activation of BNIP3/BNIP3L-mediated mitophagy that resulted from this suppression. Lastly, by inhibiting this mitophagy route, in vivo administration of the O-GlcNAcylation agonist Thiamet G considerably reduced skeletal muscle atrophy in NB mice (p < 0.05).
    CONCLUSIONS: Our study identifies S100A9 as a critical mediator of NB-associated skeletal muscle atrophy through a novel RAGE/O-GlcNAcylation/mitophagy axis, establishing S100A9 as a potential therapeutic target and providing a rationale for early interventional strategies to preserve muscle mass and improve patient outcomes.
    Keywords:  O‐GlcNAcylation; S100A9; mitophagy; muscle; neuroblastoma
    DOI:  https://doi.org/10.1002/jcsm.70419
  15. Aging Cell. 2026 Nov;pii: e70791. [Epub ahead of print]25(11):
    Sexually Dimorphic Response to Dietary Restriction-Induced Longevity and Muscle Preservation in Nothobranchius furzeri.
    Sonia Sandhi, Hannah Somers, Matthew Cox, Celeste Nobrega, Ryan Seaman, Elizabeth Baker, Olivia Lentchner, Robyn Reeve, Romain Menard, James Godwin, Anastasia Paulmann, Aric Rogers, Dario Riccardo Valenzano, Joel H Graber, Hermann Haller, Romain Madelaine.
      Age-related skeletal muscle decline (sarcopenia) contributes to frailty and mortality, yet how sex influences muscle aging and dietary interventions remains unclear. Using the short-lived vertebrate Nothobranchius furzeri, we investigated how sex and intermittent fasting (IF) interact to regulate lifespan and skeletal muscle aging. We establish an IF regimen that extends lifespan in both males and females, despite trade-offs including reduced growth and reproductive output. Importantly, IF improves swimming performance in aged animals of both sexes. Under normal feeding, muscle aging exhibits pronounced sexual dimorphism. Males show age-associated myofiber hyperplasia, whereas females preserve fiber number but undergo hypertrophic remodeling. IF partially attenuates both phenotypes, maintaining a youthful fiber size distribution in males and females. Single-nucleus RNA-sequencing reveals sex-specific remodeling of muscle-fiber composition with age: females shift toward oxidative slow-twitch fibers under normal feeding, a change attenuated by IF, while males maintain relatively stable fiber-type proportions across diets. Cell-cell communication analyses show a global age-associated decline in intercellular signaling, with IF restoring distinct pathways in a sex-specific manner, including IGF signaling in females and metabolic ANGPTL signaling in males. Bulk transcriptomic profiling indicates largely sexually dimorphic aging trajectories, whereas IF induces both shared and sex-specific responses. Notably, IF upregulates ribosome biogenesis and genes supporting myofibrillar organization and contraction in both sexes, likely contributing to preserved muscle function. Together, these findings demonstrate that IF promotes longevity and muscle health through conserved anabolic mechanisms alongside sex-specific cellular preservation and adaptation, underscoring the importance of sex as a biological variable in interventions for healthy aging.
    Keywords:  killifish; longevity; sarcopenia; skeletal muscle; youthful
    DOI:  https://doi.org/10.1111/acel.70791
  16. Apoptosis. 2026 Nov 03. pii: 258. [Epub ahead of print]31(11):
    Nr1d1 regulates ER-mitochondria interactions and calcium transfer, and muscle cell apoptosis.
    Alexis Boulinguiez, Christian Duhem, Alicia Mayeuf-Louchart, Nadia Bendridi, Jérôme Kluza, Yasmine Sebti, Nicolas Barois, Elisabeth Werkmeister, Quentin Thorel, Justine Beauchamp, Stéphane Delhaye, Lise Ferri, Marie Couvelaere, Cécilia Bellengier, Mathilde Zecchin, Benoît Pourcet, Jennifer Rieusset, Bart Staels, Hélène Duez, Steve Lancel.
      The Endoplasmic Reticulum (ER) and mitochondria interact within specific structures called Mitochondria-ER Contact sites (MERCs). MERCs are involved in calcium exchange and apoptosis. However, factors controlling MERC formation and functions are not fully identified. Since the nuclear receptor Nr1d1 (also known as Rev-erbα) modulates both mitochondrial function and reticular calcium homeostasis in skeletal muscle, we explored whether Nr1d1 could also impact MERC formation and as such modulate calcium fluxes and apoptosis of muscle cells upon ER stress.Here, we observe that Nr1d1 overexpression in C2C12 muscle cells and human myotubes increases MERC formation, favoring calcium transfer from the ER toward mitochondria. Upon tunicamycin-induced ER stress, Nr1d1 overexpression causes greater calcium influx into mitochondria, subsequently triggering a deeper reduction in mitochondrial efficiency and exacerbating apoptosis. Pharmacological inhibition of MERCs formation partly abolishes Nr1d1 effects on ER stress-induced calcium transfer and apoptosis.These findings identify Nr1d1 as a new modulator of MERCs in muscle cells.
    Keywords:  Apoptosis; Calcium transfer; Endoplasmic reticulum; Mitochondria; Mitochondria-ER Contact sites; Rev-erbα
    DOI:  https://doi.org/10.1007/s10495-026-02466-0
  17. J Clin Invest. 2026 Nov 05. pii: e207716. [Epub ahead of print]
    Cellular senescence mediates facioscapulohumeral muscular dystrophy.
    Usuk Jung, Erdong Wei, Ana Mitanoska, Philipp Heher, Kenric Chen, Haseeb Ahsan, Xu Zhang, Giorgio Tasca, Paul D Robbins, Nathan K LeBrasseur, Michael Kyba, Darko Bosnakovski.
      Facioscapulohumeral muscular dystrophy (FSHD) is driven by aberrant expression of the early embryonic transcription factor Double Homeobox 4 (DUX4), yet the mechanisms linking low, sporadic DUX4 activity to progressive muscle degeneration remain unclear. Here, we identify cellular senescence as a central and early mechanism in FSHD pathogenesis. Analysis of patient muscle transcriptomes revealed strong enrichment of senescence and senescence-associated secretory phenotype (SASP) programs that correlated with DUX4 activity, clinical severity, and histopathological changes. Notably, these signatures were detectable even in STIR-negative muscles, defining a prodystrophic state characterized by early molecular alterations preceding overt MRI-detectable inflammation and highlighting their potential utility as early biomarkers of disease activity. Using an FSHD mouse model, we show that DUX4-induced muscle injury rapidly triggers senescence, which then progressively expands. Fibroadipogenic progenitors and macrophages emerged as the principal senescent populations and key sources of pro-inflammatory and profibrotic SASP signals. Importantly, senescence was therapeutically modifiable. Treatment with the nucleoside reverse transcriptase inhibitor lamivudine (3TC), which inhibits LINE-1 reverse transcriptase activity, significantly reduced senescence, inflammation, and fibrosis while promoting muscle regeneration. These findings identify cellular senescence as a tractable driver of FSHD and warrant senotherapeutic strategies, particularly lamivudine, for clinical intervention in FSHD.
    Keywords:  Cell biology; Cellular senescence; Fibrosis; Muscle biology; Skeletal muscle
    DOI:  https://doi.org/10.1172/JCI207716
  18. Sci Adv. 2026 Nov 06. 12(45): eaee6166
    Local translational program at the muscle-tendon junction endows domain identity in muscle syncytia.
    Nour El Khazen, Juliana de Carvalho Neves, Vedran Franke, Coalesco Smith, Sakulrat Mankhong, Edgar Jauliac, Laura Yedigaryan, Elise Lefebvre, Altuna Akalin, Pascal Maire, Minchul Kim.
      How cells establish specialized subdomains is a fundamental question in cell and tissue biology. Skeletal muscle fibers, among the largest cells in the body, are multinucleated and form distinct regions such as the neuromuscular and myotendinous junctions (MTJs), the latter forming a critical interface between muscle and tendon that transmits contractile force. While transcriptional heterogeneity among myonuclei has been described, whether local translation contributes to domain identity remains unknown, largely due to the lack of tools for domain-specific manipulation. Here, we introduce MTJ-AAV, a viral system that enables selective genetic targeting of MTJ myonuclei. This approach allowed MTJ-specific ribosome tagging and revealed extensive translational regulation underlying MTJ biology and its remodeling during exercise. Untranslated regions of these transcripts were sufficient to control regionalized translation. Notably, the Krüpper-like factor-family transcription factors emerged as translationally up-regulated targets at the MTJ, where they drive local gene expression. Our findings establish local translation as a key layer of subcellular specialization and provide a versatile toolkit for dissecting spatial molecular regulation within muscle syncytia.
    DOI:  https://doi.org/10.1126/sciadv.aee6166
  19. Arch Gerontol Geriatr. 2026 Nov 04. pii: S0167-4943(26)00345-6. [Epub ahead of print]153 106477
    Integrated single-cell and bulk transcriptomic analysis suggest a possible association between M1-like macrophage cuproptosis and angiogenic impairment in exercise-deficiency-associated sarcopenia.
    Shuyao Li, Xiaoqing Wu, Rong Jia, Jie Liu, Chunling Jia, Lihua Deng, Qian Xue, Xia Li, Fangyuan Cong, Shuchun Wang, Yanan Wei, Jingtong Wang.
      Sarcopenia is a geriatric syndrome characterized by the progressive loss of skeletal muscle mass and function. While physical inactivity is a primary risk factor of sarcopenia, the underlying molecular mediators remain poorly studied. By combined analysis of human bulk transcriptomic data and single-cell RNA sequencing data, we identified a cuproptosis-associated transcriptional signature significantly enriched in both human sarcopenia and exercise-deprivation models. Our analyses suggest that M1-like macrophage may be particularly vulnerable to cuproptosis due to elevated SLC31A2 expression, potentially contributing to their depletion in the sedentary muscle microenvironment. Intercellular communication modeling further implied that the reduction in M1-like macrophage may impair CXCL8-mediated (or its murine functional analogs) signaling to endothelial tip cells, a process essential for microvascular maintenance. To provide physiological context, we validated these findings in an aged sarcopenia murine model (24-month-old C57BL/6 J). In the gastrocnemius muscle of sarcopenic mice, we observed a significant decrease in muscle fiber cross-sectional area (CSA) alongside a concurrent reduction in F4/80⁺CD86⁺ M1-like macrophage and VEGFR2⁺/CD31⁺ endothelial tip cells. Collectively, our study provides associative link for a candidate mechanistic axis-SLC31A2-mediated cuproptosis in M1-like macrophage-that potentially links physical inactivity to vascular rarefaction in sarcopenia. These findings offer a new framework for investigating the immune-vascular crosstalk in muscle aging and highlight potential therapeutic targets for intervention.
    Keywords:  Angiogenesis; Cuproptosis; Exercise intervention; Macrophage; Sarcopenia
    DOI:  https://doi.org/10.1016/j.archger.2026.106477
  20. Exp Gerontol. 2026 Nov 06. pii: S0531-5565(26)00362-1. [Epub ahead of print] 113382
    Zebrafish models for investigating skeletal muscle aging and sarcopenia.
    SeungEun Lee, Haeun Lee, Seyoung Park, Seok-Hyung Kim, Seong-Kyu Choe.
      Sarcopenia is characterized by progressive loss of skeletal muscle strength, mass, and function during aging, driven by impaired proteostasis, mitochondrial dysfunction, altered metabolism, regenerative failure, and neuromuscular decline. Experimental models are needed to determine how these processes drive muscle degeneration and identify testable therapeutic mechanisms. Zebrafish combine whole-animal physiology with genetic manipulation, live imaging, and scalable phenotypic analysis, making them well suited to this purpose. Natural-aging, telomerase-deficient, dexamethasone-induced, high-fat-diet, and genetically defined zebrafish models each reproduce distinct structural, functional, metabolic, regenerative, or neuromuscular changes relevant to sarcopenia. In this Review, we compare study designs, measured endpoints, and mechanistic evidence to distinguish age-associated phenotypes from responses to induced stresses or defined molecular perturbations. Natural-aging models capture spontaneous age-associated changes in muscle structure, performance, and mitochondrial integrity; telomerase-deficient models reveal defects in tissue maintenance and regeneration; and dexamethasone- and high-fat-diet-induced models enable controlled analysis of proteostatic and metabolic stress. Genetic models directly test relationships between molecular perturbations and muscle phenotypes. Current studies, however, have notable limitations: swimming performance reflects whole-animal physiology rather than muscle strength, many markers do not directly measure pathway activity, and some models represent specific stress rather than primary sarcopenia. Across these models, shared phenotypes do not establish a common causal mechanism; model-specific findings require validation during natural aging and in mammalian and human studies.
    Keywords:  Mitochondria; Muscle regeneration; Neuromuscular junction; Sarcopenia; Skeletal muscle aging; Zebrafish
    DOI:  https://doi.org/10.1016/j.exger.2026.113382
  21. J Cachexia Sarcopenia Muscle. 2026 Dec;pii: e70416. [Epub ahead of print]17(6):
    Mitochondrial Transplantation Preserves Regenerative Capacity of Denervated Skeletal Muscle by Disrupting a Ca2+ Overload-Mitophagy-Ferroptosis Circuit.
    Haiqi Ding, Jiagu Huang, Jiayao Zhang, Zhizhen He, Jun Luo, Zhao Lin, Linhai Yang, Yibin Su, Mingjuan Zhang, Fuli Wen, Yuan Lin, Cheng Chang, Hanhao Dai, Xuehui Ge, Jie Xu.
       BACKGROUND: Denervation-induced muscle atrophy progresses during the interval between nerve injury and reinnervation, and depletion of muscle satellite cells (MuSCs) contributes to impaired functional recovery. Although mitochondrial dysfunction and impaired quality control are implicated in muscle wasting, whether excessive mitochondrial turnover drives MuSC failure after denervation remains unclear. This study aimed to identify the pathogenic mechanisms underlying MuSC depletion and determine whether mitochondrial transplantation therapy (MTT) preserves regenerative capacity.
    METHODS: A sciatic nerve transection model was established in mice to induce denervation-associated muscle atrophy. Mitochondria isolated from differentiated MuSCs were transplanted into denervated gastrocnemius muscles beginning 6 h after injury and repeated every 3 days for 6 weeks. RNA sequencing, calcium imaging, mitochondrial ultrastructural analysis, mito-mKeima-based mitophagic flux assessment, flow cytometry and molecular analyses were performed to investigate disease mechanisms and therapeutic effects. In vitro calcium overload models combined with Mdivi-1 treatment and Pink1 knockdown were used to define the regulatory pathway linking calcium stress, mitophagy and ferroptosis.
    RESULTS: Denervated muscle exhibited early calcium dyshomeostasis (Fluo-4 AM fluorescence increased 6.7-fold vs. Sham, p < 0.0001) and mitochondrial dysfunction within 3 days, followed by iron accumulation (nonheme iron increased 1.5-fold, p = 0.0046) and ferroptotic changes by 2 weeks. Mechanistically, sustained calcium overload activated the Ampk-Tsc2-mTorc1 pathway in MuSCs, inducing Pink1-dependent excessive mitophagic flux. Mito-mKeima flow cytometry confirmed increased mitophagic flux after denervation, with approximately tenfold elevation at Day 3 and persistent activation at 2 weeks. Excessive mitophagy promoted Fth1 degradation (reduced by 47.5%, p = 0.0181) and increased Tfr1 expression (1.9-fold, p = 0.0035), thereby enhancing ferroptotic susceptibility. Inhibition of mitochondrial fission or Pink1 knockdown reduced iron accumulation (Fe2+ fluorescence reduced by 58.3% and 69.2%, respectively, both p < 0.01) and protected MuSCs from ferroptosis. MTT restored mitochondrial homeostasis by reducing calcium overload (73.7% decrease vs. A23187, p < 0.0001), increasing ATP production (36.9%, p < 0.01), suppressing excessive mitophagic flux, normalizing iron metabolism (39.9% reduction, p = 0.0015) and preserving MuSCs (30.0% increase vs. DN_PBS, p = 0.0196). Consequently, MTT attenuated denervation-induced muscle fibre atrophy and improved functional recovery following delayed nerve repair.
    CONCLUSIONS: This study identifies an early pathogenic cascade linking calcium overload, excessive mitophagic flux and ferroptotic susceptibility as a critical driver of MuSC dysfunction during denervation-induced muscle wasting. MTT preserves regenerative capacity by interrupting this degenerative circuit and restoring mitochondrial quality control, providing a potential therapeutic strategy for denervation-associated muscle atrophy and other muscle wasting disorders.
    Keywords:  calcium overload; denervation atrophy; ferroptosis; mitochondrial transplantation therapy; mitophagy; muscle satellite cells
    DOI:  https://doi.org/10.1002/jcsm.70416
  22. PeerJ. 2026 ;14 e21903
    Identification of Endoplasmic reticulum Homeostasis-associated diagnostic biomarkers for Sarcopenia through integrated Bioinformatics and Experimental Validation.
    Long Shi, Hongyu Yan, Junliang Lu, Wenkai Yu, Yang Li, Zhiwen Zhang.
      Sarcopenia is an age-related skeletal muscle disorder characterized by progressive loss of muscle mass and function, yet reliable biomarkers for early diagnosis remain limited. Emerging evidence suggests that disruption of endoplasmic reticulum (ER) homeostasis contributes to skeletal muscle aging, however, the diagnostic relevance of ER stress- and reticulophagy-related alterations in sarcopenia remains poorly understood. In this study, three skeletal muscle transcriptomic datasets (GSE25941, GSE28422, and GSE38718) were integrated following batch-effect correction to identify differentially expressed genes (DEGs) between sarcopenic and control samples. DEGs were intersected with ER stress and reticulophagy related gene sets to obtain sarcopenia-associated candidate genes. Subsequently, three machine-learning algorithms, including least absolute shrinkage and selection operator (LASSO), random forest (RF), and support vector machine (SVM), were applied to identify key hub genes. Functional enrichment analyses, transcription factor (TF)-miRNA regulatory network construction, protein-chemical interaction analyses, external validation, nomogram development, and quantitative real-time PCR (qRT-PCR) verification were performed. A total of 236 DEGs were identified, comprising 34 upregulated and 202 downregulated genes. Intersection analysis with 1,772 ER stress and reticulophagy related genes yielded 10 candidate genes, from which five hub genes (ACTC1, NPY, CDKN2B, GADD45G, and GRIA1) were consistently identified by machine-learning analyses. Functional enrichment analysis indicated significant involvement in extracellular matrix organization, cytokine-cytokine receptor interaction, mitochondrial translation, and respiratory electron transport pathways. Regulatory network analyses further revealed potential interactions with multiple transcription factors, miRNAs, and chemical compounds. In the independent validation cohort (GSE1428), ACTC1 showed strong individual discriminative performance, NPY and GADD45G showed moderate performance, whereas GRIA1 showed limited discrimination and CDKN2B showed near-chance individual performance, whereas the combined gene signature exhibited improved discriminative ability. A predictive nomogram was established. Moreover, qRT-PCR analysis of human skeletal muscle biopsy specimens confirmed significantly increased expression of ACTC1, NPY, CDKN2B, and GRIA1, together with decreased expression of GADD45G in sarcopenic muscle tissues compared with controls (all p < 0.05). Collectively, our findings identified a five-gene signature associated with ER stress and reticulophagy related molecular networks in sarcopenia. Although these genes are not established core regulators of ER stress or reticulophagy, they exhibited promising diagnostic value and may reflect ER homeostasis-related molecular alterations during skeletal muscle aging, providing novel biomarkers and potential insights into the molecular basis of sarcopenia.
    Keywords:  Diagnostic value; ER-stress; Function information; Sarcopenia
    DOI:  https://doi.org/10.7717/peerj.21903
  23. J Biol Chem. 2026 Nov 02. pii: S0021-9258(26)02585-8. [Epub ahead of print] 113713
    Identification of substrates for the skeletal muscle-specific lysine methyltransferases METTL21C and METTL21E.
    Kamilla Nygård, Jędrzej M Małecki, Erna Davydova, Janica Lea Nolte, Manuel Ramirez-Garrastacho, Mads Bengtsen, Kristian Gundersen, Frederik Tellkamp, Marcus Krüger, Pål Ø Falnes.
      Protein lysine methylation, catalyzed by S-adenosylmethionine (AdoMet)-dependent methyltransferases (MTases), plays important roles in regulating and fine-tuning protein function. The related mammalian lysine-specific MTases METTL21C and METTL21E are predominantly expressed in skeletal muscle, but their substrates have remained unclear and controversial. Here, we found that METTL21C methylated only a single protein, namely fast myosin-binding protein C (fMyBPC; gene: MYBPC2), in METTL21C-deficient mouse skeletal muscle extracts. METTL21C also showed strong activity on recombinant fMyBPC in vitro, introducing trimethylation at Lys-242. This methylation event was also observed in vivo, and abolished by Mettl21c knockout (KO). The observed in vitro activity of METTL21C on fMyBPC was >100-fold stronger than that observed on AARS1 (alanine-tRNA ligase), a previously reported METTL21C substrate. Interestingly, the two other MyBPC paralogs, which are expressed in cardiac and slow skeletal muscle, were not methylated by METTL21C. For METTL21E, we could not detect in vitro activity. However, we found that monomethylation of Lys-35 (K35) in myosin heavy chain (MYH), a methylation event previously reported in various vertebrate muscles, was abolished by Mettl21e KO in mouse muscle, but not by Mettl21c KO. In human muscles, we detected MYH-K35 methylation at a level similar to that observed in mice, suggesting that the current annotation of human METTL21E as a pseudogene (METTL21EP) may be re-evaluated. Taken together, our results provide new insights into protein methylation in skeletal muscle by identifying fMyBPC as a bona fide muscle-specific substrate of METTL21C, and demonstrating that METTL21E is required for MYH-K35 methylation, thus likely representing the responsible MTase.
    Keywords:  METTL21C; METTL21E; MYBPC2; Methylation; human; mammal; mass spectrometry; mouse; myosin; myosin binding protein; post-translational modification; protein lysine methyltransferase; substrate specificity
    DOI:  https://doi.org/10.1016/j.jbc.2026.113713
  24. J Clin Invest. 2026 Nov 02. pii: e202378. [Epub ahead of print]136(21):
    A single liver-sparing myotropic AAV ameliorates muscular dystrophy in humanized mice by base editing.
    Yu-Chung Pien, Hui Li, Gabrielle Bulliard, Huachun Liu, Mateusz Z Durbacz, Zhisheng Xu, Andreas C Chai, Francesco Chemello, Efrain Sanchez-Ortiz, Nerea Zabaleta, Luk H Vandenberghe, Ning Liu, Eric N Olson.
      Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene, most of which are large exon deletions that result in loss of dystrophin protein. Adenine base editing (ABE) enables permanent gene correction by modifying splice sites to cause exon skipping and restoration of the DMD open reading frame. We previously demonstrated that adeno-associated virus 9-mediated (AAV9-mediated) delivery of adenine base editors allows efficient gene editing in mouse models of DMD. However, conventional AAV-based gene delivery approaches are complicated by their limited packaging capacity and high-dose-related toxicity. Here, we describe a single AAV vector encoding a compact adenine base editor, SlugABE8e, and a single-guide RNA, which enable efficient editing in a humanized DMD mouse model at a lower dose using the muscle-tropic MyoAAV4 capsid. Systemic MyoAAV4A delivery in juvenile DMD mice efficiently restored dystrophin expression in the heart and skeletal muscles. This molecular rescue was accompanied by reduced serum creatine kinase activity and diminished muscle pathology. A liver-detargeted MyoAAV4E-off capsid eliminated viral entry and editing in the liver. We also explored a high-fidelity base editor, SlugHF-ABE8e(V106W), which showed similar on-target and off-target editing to SlugABE8e. Together, these findings establish an all-in-one AAV strategy that efficiently mitigates DMD disease progression.
    Keywords:  Genetics; Muscle biology; Skeletal muscle
    DOI:  https://doi.org/10.1172/JCI202378
  25. J Physiol. 2026 Oct 31.
    Vortex wave stimulation: A novel anabolic stimulus for ageing muscle?
    Guilherme Soderini Erlich, Sâmella de Oliveira Ananias Gonçalves, Guilherme Domingos Brisque.
      
    Keywords:  ageing; anabolic resistance; skeletal muscle; vortex wave stimulation
    DOI:  https://doi.org/10.1113/JP292545
  26. Geroscience. 2026 Nov 04.
    GLP-1 and GIP receptor agonism does not directly drive skeletal muscle atrophy or impair myogenesis in primary human myotubes.
    Caitlin Ditchfield, Michael Macleod, Joshua M J Price, Edward T Davis, Simon W Jones.
      GLP-1 and GIP/GLP-1 receptor agonists produce substantial weight loss in clinical trials but significant loss of lean body mass is reported. Whether this reflects a direct pharmacological effect on skeletal muscle or an indirect consequence of caloric restriction and reduced mechanical loading is unknown. Primary myoblasts were isolated from skeletal muscle of older adults with obesity undergoing orthopaedic surgery. GIPR and GLP-1R expression was characterised by RT-qPCR and flow cytometry. Differentiated myotubes were treated with semaglutide or GIP peptide and assessed for atrophy-related gene expression (qPCR), secretome perturbation (Olink Reveal), mitochondrial and glycolytic bioenergetics (Seahorse XF Real-Time ATP Rate Assay, glucose uptake, lactate secretion) and myotube morphology and myogenesis (immunofluorescence). GIPR mRNA was consistently detected across all donors; GLP-1R mRNA was undetectable by PCR, though LUXendin645 flow cytometry in a subset of three donors identified low-level surface GLP-1R protein in 51-66% of myoblasts. Neither semaglutide nor GIP altered atrophy-related gene expression or the secretome, with no proteins reaching significance. Semaglutide reduced glycolytic and total ATP production rates, accompanied by reduced lactate secretion, suggesting modest suppression of glycolytic flux; mitochondrial parameters were unaffected. Neither treatment impaired myotube thickness or differentiation; GIP increased myotube thickness after 8 days. Direct GLP-1 and GIP receptor activation did not produce major atrophic, inflammatory, morphological, myogenic, or mitochondrial effects on primary human skeletal muscle myotubes. These findings are consistent with an indirect mechanism underlying the lean mass loss observed with incretin-based therapies, a question of particular relevance as these agents are increasingly used in older adults at risk of sarcopenia.
    Keywords:  GIP receptor; GLP-1 receptor; Incretins; Muscle atrophy; Sarcopenia; Semaglutide
    DOI:  https://doi.org/10.1007/s11357-026-02625-w
  27. Life Sci. 2026 Nov 02. pii: S0024-3205(26)00566-7. [Epub ahead of print] 124757
    P2Y6R is associated with adipose inflammation and muscle wasting in pancreatic cancer cachexia.
    Jinyoung Kim, Jeehoon Chae, Junjeong Choi.
       BACKGROUND: Pancreatic cancer has one of the highest incidences of cancer-associated cachexia, a multi-organ wasting syndrome driven by complex tumor-host interactions. Although adipose tissue functions as an active endocrine organ contributing to systemic inflammation, the mechanisms linking adipose inflammation to skeletal muscle wasting remain incompletely understood.
    METHODS: An orthotopic pancreatic tumor mouse model was combined with pharmacological P2Y6R inhibition using MRS2578. Cachexia-associated targets were identified by transcriptomic analysis of mouse datasets, and P2Y6R function was examined in vitro cancer-associated adipocyte (CAA) and C2C12 myotube models.
    RESULTS: Transcriptomic analysis identified P2Y6R as a cachexia-associated gene, with expression selectively upregulated in visceral adipose tissue and CAAs under pancreatic cancer conditions. In contrast, P2Y6R expression was minimal in skeletal muscle and comparatively low in tumor tissue. In the orthotopic model, pharmacological inhibition of P2Y6R with MRS2578, initiated before overt weight loss, attenuated body weight loss. This was accompanied by reduced serum IL-6 and IL-1β levels (IL-1β at 3 mg/kg only) and decreased expression of the atrogenes mRNA expression in skeletal muscle. In vitro, conditioned medium from CAAs suppressed myotube differentiation, whereas P2ry6 knockdown in adipocytes attenuated this effect. Mechanistically, the P2Y6R-dependent secretome of cancer-associated adipocytes was associated with increased atrogene expression and altered FOXO3 phosphorylation in myotubes.
    CONCLUSIONS: Our findings indicate that P2Y6R is associated with adipose inflammation and muscle wasting in pancreatic cancer cachexia, and that pharmacological P2Y6R inhibition attenuates cachexia progression in a preventive setting. These results suggest a potential contribution of adipocyte P2Y6R to adipose-muscle crosstalk and highlight P2Y6R as a candidate therapeutic target for cancer-associated muscle loss.
    Keywords:  Adipose-muscle crosstalk; Atrogenes; MRS2578; Muscle wasting; P2Y6R antagonist; Pancreatic cancer cachexia
    DOI:  https://doi.org/10.1016/j.lfs.2026.124757
  28. Eur J Appl Physiol. 2026 Oct 31.
    Aerobic exercise preconditioning enhances skeletal muscle resistance and recovery after contusion: involvement of the SIRT1/PGC-1α axis.
    Wei Wang, Zhao Tian, Peijin Li, Changjun Zuo, Jin Ye, Churan Bai, Zhaowen Li.
       OBJECTIVE: Compared with passive recovery after injury, exercise preconditioning may provide an active strategy for improving the subsequent response of skeletal muscle to injury. This study aimed to investigate the effects of aerobic exercise preconditioning (AEP) on skeletal muscle injury (SMI) and post-injury repair, with particular focus on the involvement of the SIRT1/PGC-1α axis and changes in PGC-1α acetylation.
    METHODS: This study initially investigated the effects of continuous aerobic exercise on skeletal muscle in healthy mice. Subsequently, the influence of AEP on injury severity and regenerative repair of the gastrocnemius muscle was examined in mice with SMI. Western blotting was used to determine the expression levels of SIRT1 and PGC-1α proteins, immunoprecipitation was performed to assess the acetylation status of PGC-1α, and qRT-PCR was used to analyze the expression of genes associated with mitochondrial biogenesis-related markers and muscle regeneration. Finally, the involvement of SIRT1 signaling in the AEP-associated response to SMI was further examined using the pharmacological SIRT1 inhibitor EX527.
    RESULTS: Continuous aerobic exercise was associated with increased SIRT1/PGC-1α signaling and changes in mitochondrial biogenesis-related markers in the gastrocnemius muscle of healthy mice. AEP was associated with reduced injury-related changes and an improved post-injury repair profile in mice with SMI. During the early stage after injury, AEP was accompanied by sustained SIRT1/ PGC-1α signaling and reduced PGC-1α acetylation. Pharmacological inhibition of SIRT1 with EX527 partially attenuated the AEP-associated protective and reparative effects on the injured gastrocnemius muscle.
    CONCLUSION: These findings suggest that AEP establishes an adaptive state in skeletal muscle that is associated with reduced injury-related damage and an enhanced post-injury reparative response. The SIRT1/PGC-1α axis and altered PGC-1α acetylation may contribute to these AEP-associated effects.
    Keywords:  Aerobic exercise preconditioning; Muscle repair; PGC-1α acetylation; SIRT1/PGC-1α axis; Skeletal muscle contusion
    DOI:  https://doi.org/10.1007/s00421-026-06483-4
  29. EMBO Rep. 2026 Nov 04.
    CD90 delineates distinct muscle stem cell states of quiescence and activation.
    Eyemen Kheir, Michela Libergoli, Serena Di Savino, Samuele Metti, Jonas Brorson Jensen, Jakob Wang, Niels Jessen, Francesca Florio, Francesca Murganti, Lorenzo Marramiero, Marzia Belicchi, Chiara Villa, Kristian Vissing, Mayank Verma, Lorenzo Giordani, Paolo Bonaldo, Yvan Torrente, Jean Farup, Stefano Biressi.
      Stem cell transition from quiescence to activation is crucial to guarantee productive tissue regeneration. Here, we show that CD90 expression diversifies quiescent muscle stem cells (MuSCs) in murine and human muscle into two subsets differing in the kinetics of activation. CD90+ve MuSCs exhibit a faster exit from quiescence and predominate the initial phases of regeneration compared to CD90-ve MuSCs. In the absence of injury, the CD90+ve fraction is primed towards activation through an active CD90-AMPK axis but is maintained in quiescence through signals from the extracellular matrix. We further show that Collagen VI, which is preferentially expressed by CD90+ve MuSCs, binds to the Calcitonin receptor. Moreover, while the number of CD90+ve and CD90-ve MuSCs is similar in healthy muscles, the CD90-ve fraction predominates in muscles of murine models of Duchenne and Ullrich congenital muscular dystrophies. These findings provide novel insights into the mechanistic determinants of MuSCs functional heterogeneity and have implications for understanding the stimulation of repair in dystrophic muscle.
    DOI:  https://doi.org/10.1038/s44319-026-00980-5
  30. J Cachexia Sarcopenia Muscle. 2026 Dec;pii: e70369. [Epub ahead of print]17(6):
    Chronic Exercise Accelerates Disease Progression in a Rat Model of Desminopathy.
    Henning T Langer, Natalie Haritonow, Aniket S Joshi, Alec M Avey, Alec Bizieff, Hussein Mohammad, Hermann Zbinden-Foncea, Marc Hellerstein, Katrin Hahn, Werner Stenzel, Keith Baar, Agata A Mossakowski.
       BACKGROUND: Desminopathy is a progressive myopathy and the most common intermediate filament disease in humans. Desmin is an essential part of the filamentous network that aligns myofibrils, anchors nuclei and mitochondria and connects the z discs to the sarcolemma. We challenged a rat model with a mutation in R349P Des, analogous to the most frequent R350P DES missense mutation in humans, through eccentric-biassed exercise training.
    METHODS: R349P Des rats (Des) and their wild type (WT) and heterozygous (HET) littermates were subjected to 4 weeks of downhill running. At the end of 4 weeks, muscles were collected and assessed histologically and biochemically.
    RESULTS: Des rats demonstrated significantly lower running capacity compared to wild type and heterozygous littermates (p < 0.0001), which exacerbated over the course of the study (p < 0.001). Running performance in Des rats decreased by ~50% after 4 weeks of downhill running. Desmin-positive skeletal muscle aggregates, a histopathological hallmark of desminopathy, were ~2-fold higher after downhill running in the Des group (p < 0.05). On a protein level, we found a differential exercise response of Des compared to WT affecting various cellular pathways concerning autophagy, proteasomal activity, energy metabolism and cytoskeletal proteins.
    CONCLUSIONS: Our results suggest an impaired ability of Des muscle to adapt to chronic eccentric-biassed exercise and a subsequent exacerbation of the functional and histopathological phenotype.
    Keywords:  chronic injury; desminopathy; intermediate filament; mechanical vulnerability; muscular dystrophy; protein aggregation myopathy
    DOI:  https://doi.org/10.1002/jcsm.70369
  31. J Physiol. 2026 Nov 03.
    Steady state or not? Understanding muscle protein turnover during disuse atrophy.
    Matthew S Brook.
      
    Keywords:  muscle; protein breakdown; protein synthesis; stable isotope
    DOI:  https://doi.org/10.1113/JP292782
  32. Front Physiol. 2026 ;17 1943433
    Branched-chain amino acids in skeletal and cardiac muscles: a review of metabolic variations and cancer's impact.
    Julian Chrzanowski, Wojciech Graboń, Karolina Buchajska, Agnieszka Cudnoch-Jędrzejewska.
      Branched-chain amino acids (BCAA) - leucine, isoleucine, and valine - serve as essential regulators of energy homeostasis, protein turnover, and nutrient signaling in striated muscle. However, their metabolic processing varies substantially across tissues. This review contrasts BCAA metabolism in skeletal versus cardiac muscle and evaluates how cancer alters it. Skeletal muscle functions as the main site for whole-body BCAA transamination and oxidation, distributing these amino acids between protein synthesis and oxidative catabolism in line with physiological needs. In comparison, the myocardium maintains low baseline BCAA oxidation, depends primarily on fatty acids and glucose, and tightly limits BCAA catabolic flux to prevent the buildup of intermediates that would undermine mitochondrial function. In malignancies, BCAA metabolism is reconfigured in a way that depends on tumor type: many tumors increase BCAA uptake and suppress catabolism in order to preserve intracellular stores, as a result maintaining mechanistic target of rapamycin complex 1 (mTORC1) signaling and supporting proliferation. Using lung, pancreatic and colorectal cancers as main examples, we outline how this tumor-driven metabolic rewiring is linked to cancer cachexia - a multi-organ syndrome in which inflammation, mitochondrial dysfunction, and impaired anabolic signaling promote muscle and cardiac wasting rather than simple substrate limitation. We describe first the mechanisms shared by skeletal and cardiac muscle, then the features specific to each tumor type, and we distinguish throughout between cardiac evidence obtained in tumor-bearing hosts and inferences extrapolated from heart failure. We conclude that interventions directed at BCAA are most reasonable early in the disease course, and only when paired with approaches that suppress inflammation and restore mitochondrial quality control. We also identify priorities for tissue-specific biomarkers and for future research.
    Keywords:  BCAA catabolism; branched-chain amino acids; cancer cachexia; cardiac muscle; muscle wasting; skeletal muscle
    DOI:  https://doi.org/10.3389/fphys.2026.1943433
  33. Life Sci. 2026 Nov 03. pii: S0024-3205(26)00579-5. [Epub ahead of print] 124770
    Cisplatin induces skeletal muscle dysfunction, oxidative stress, and senescence-associated responses in male and female rats.
    Ibrahim Turkel, Tugba Fatsa, Firat Akat, Oner Ulger, Meral Sarper, Gizem Duran Erdogan, Gulcin Simsek, Ayca Balci, Zeynep Ergun, Keshav K Singh, Gokhan Burcin Kubat.
       AIMS: Cisplatin-induced skeletal muscle dysfunction contributes to functional decline, but molecular mechanisms remain unclear. This study investigated cisplatin-induced changes in contractile function, oxidative stress, senescence-associated signaling, and senescence-associated secretory phenotype (SASP) in soleus (SOL) and extensor digitorum longus (EDL) muscles of male and female rats.
    MATERIALS AND METHODS: Male and female rats received cisplatin (5 mg/kg, i.p.) or saline on days 1, 8, and 15 and were euthanized 24 h after the final injection. SOL and EDL muscles were analyzed for contractile function, oxidative damage, antioxidant gene expression, senescence markers, SASP-related factors, and fiber cross-sectional area (CSA).
    KEY FINDINGS: Cisplatin caused body weight loss without detectable changes in muscle mass or fiber CSA. Contractile force decreased in SOL of both sexes and male EDL, whereas no significant reduction was observed in female EDL. H₂O₂ and protein carbonyl levels increased in SOL, whereas MDA and 8-OHdG increased in both muscles and sexes. CAT and GPX mRNA decreased in SOL of both sexes, while SOD, CAT, and GPX decreased in male EDL, with no significant changes detected in female EDL. p53 protein increased in both muscles of both sexes, whereas p21 and p16 proteins increased only in female SOL. At the transcript level, p53, p21, and p16 were upregulated in male SOL and female EDL. SASP-related genes showed group-specific increases in inflammatory cytokines and matrix-remodeling genes.
    SIGNIFICANCE: Cisplatin impaired contractile function without detectable changes in muscle mass or fiber CSA, with different molecular response patterns observed across the examined sex and muscle groups.
    Keywords:  Cisplatin; Contractile dysfunction; Oxidative stress; Senescence-associated secretory phenotype; Senescence-associated signaling; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.lfs.2026.124770
  34. Nat Commun. 2026 Oct 07. pii: 11390. [Epub ahead of print]17(1):
    Neonatal overfeeding accelerates age-related sarcopenia and metabolic disorders through lifelong gut mucosa and microbiota programming in mice.
    Yeyu Song, Jingyi Xu, Jingjie Zhao, Rong Yang, Yuandi Ma, Yi-Ming Hou, Yutang Cao, Jiaqi Li, Shuwu Yu, Xinyu Liang, Yongxin Zhang, Kanglong Wang, Lijuan An, Yameng Liu, Zhuo-Xian Meng, Jian-Gao Fan, Cen Xie.
      Early-life nutrition shapes lifelong health, yet the long-term consequences of childhood overnutrition, particularly on musculoskeletal aging, remain unclear. Here, we show that neonatal overfeeding acts as a developmental insult that accelerates age-related sarcopenia in both sexes. Using different mouse models, early overnutrition shortens lifespan and exacerbates late-life muscle atrophy, accompanied by metabolic dysfunction. Mechanistically, neonatal overfeeding disrupts goblet cell development, leading to persistent mucus barrier defects and consequently reduced Akkermansia muciniphila (A. muciniphila) colonization during aging. Fecal microbiota transplantation transfers the sarcopenic phenotype, implicating gut dysbiosis in disease propagation. Loss of A. muciniphila reduces acetate production, impairs muscle mitochondrial function at least in part via suppressed GPR43 signaling, and aggravates sarcopenia. Conversely, A. muciniphila reconstitution or acetate supplementation restores mitochondrial homeostasis and improves muscle performance in aged mice. These findings reveal a developmental origin of age-related sarcopenia and define a gut-muscle axis linking early-life overnutrition to muscle aging, highlighting the preventive potential of optimizing early nutrition to support healthy aging.
    DOI:  https://doi.org/10.1038/s41467-026-78216-2
  35. Cell Rep. 2026 Nov 04. pii: S2211-1247(26)01325-2. [Epub ahead of print]45(11): 118246
    The YAP/TAZ-Tgfbr2-stiffness feedback loop governs divergent cell fates of muscle-resident mesenchymal progenitors.
    Kanako Iwamori, Momoka Horikiri, Atsushi Kubo, Kosuke Tokiwa, Taku Fukushima, Nanami Sakurai, Daiki Mori, Ayasa Nakamura, Miyu Kimura, Nana Taniguchi, Tamaki Kurosawa, Madoka Ikemoto-Uezumi, Lidan Zhang, Shuichi Watanabe, Hiroshi Y Yoshikawa, Thomas Braun, Akiyoshi Uezumi, Takahisa Matsuzaki, So-Ichiro Fukada.
      Mesenchymal progenitors are essential for muscle regeneration, but also contribute to fat accumulation and fibrosis. Several extrinsic and intrinsic factors regulating adipogenic or fibrogenic differentiation of mesenchymal progenitors have been identified. However, it remains unclear how different cues are integrated to determine cell fate. Here, we demonstrate that interstitial stiffness and the mechanosensitive hippo pathway regulate mesenchymal progenitor cell fate. Fat accumulation model reduced interstitial stiffness and nuclear YAP/TAZ-positive mesenchymal progenitors compared with a regeneration model, whereas YAP/TAZ deficiency in mesenchymal progenitors enhanced fat deposition. Mechanistically, YAP/TAZ induced expression of the anti-adipogenic genes Aldh1a2 and Wnt5a, and the pro-fibrogenic gene Tgfbr2, which mediates TGF-β binding. Loss of Tgfbr2 in mesenchymal progenitors reduced transient collagen deposition, decreased stiffness, and increased fat accumulation during regeneration. We propose a stiffness-YAP/TAZ-Tgfbr2-collagen regulatory loop governing mesenchymal progenitor cell fate and highlight its importance for optimal muscle regeneration.
    Keywords:  CP: stem cell research; FAP; TAZ; TGF-β; Tgfbr2; YAP; adipocyte; fibrosis; mesenchymal progenitor; regeneration; stiffness
    DOI:  https://doi.org/10.1016/j.celrep.2026.118246
  36. Stem Cell Res Ther. 2026 Aug 07. pii: 406. [Epub ahead of print]17(1):
    Wnt5a/Ca2+ signal promotes myogenic differentiation by mediating a slow and sustained influx of Ca2.
    Mao-Yuan Wang, Jin-Guo Cao, Yan-Biao Zhong, Yun Luo, Fu-Hua Xie, Mei-Xuan Zou, Wen-Juan Wu, Xin-Ye Ouyang, Jia-Ming Yang, Rui-Lian Xie.
      The extracellular Ca2+ is crucial for the regeneration of skeletal muscles, but there is still uncertainty regarding the channels through which it enters the cells. The purpose of this study is to investigate how the Wnt5a/Ca²⁺ signaling pathway promotes myogenic differentiation by regulating which calcium channels on the cell membrane. Myogenic regulatory factors (MRFs) play an important regulatory role in the occurrence and development of skeletal muscle, while overexpression or knockdown of Wnt5a can affect the expression levels of MRFs. Increased expression of Wnt5a resulted in significant increase of intracellular Ca2+ levels, and knockdown of TRPC3 could partially reverse the effect of Wnt5a. This indicates that in addition to the TRPC3 channel, there are other Ca2+ channels involved in the process of transporting extracellular Ca2+ into the cells. When we treated with verapamil, we found that it could significantly reduce the level of Ca2+ entering the cells, indicating that this unknown Ca2+ channel is a slow calcium channel. Through co-immunoprecipitation, we found that CaV1.1 was abundantly accumulated in the TRPC3 pull-down complex, indicating that this slow calcium channel is CaV1.1, and the expression of CaV1.1 is influenced by TRPC3. In simple terms, the activated TRPC3 activates Cav1.1, inducing a slow and sustained inward flow of extracellular Ca2+, leading to the increase of intracellular levels of Ca2+, and finally promote myogenic differentiation.
    Keywords:  Cav1.1; L-type Ca2+ channel; Myogenic differentiation; Slow and sustained; TRPC3; Wnt5a
    DOI:  https://doi.org/10.1186/s13287-026-05218-8
  37. Mol Metab. 2026 Oct 31. pii: S2212-8778(26)00152-3. [Epub ahead of print] 102468
    Differentiated obesity treatment: Pharmacological CRF2 agonism drives fat loss, skeletal muscle hypertrophy and improved glucose metabolism in preclinical obesity.
    Kristoffer Niss, Sofia Lundh, Rucha Patel, Johannes Josef Fels, Albrecht Gruhler, Suzi Høgh Madsen, Fabrice Chimienti, Sarah Bau, Dennis Åsberg, Lennart Lykke, Nick Cox, Birgitte S Wulff, Nikolaj Kulahin Roed, Chien Li, Berit Ø Christoffersen.
       OBJECTIVE: Loss of lean mass during weight reduction may compromise metabolic health and physical function. Urocortin 2 (UCN2) activates corticotropin-releasing factor receptor 2 (CRF2) and has been linked to beneficial effects on skeletal muscle and glucose metabolism. We evaluated an acylated UCN2 analogue (acyUCN2), alone or combined with an acylated GLP-1 analogue (acyGLP-1), in preclinical obesity models.
    METHODS: Diet-induced obese (DIO) Sprague Dawley rats and DIO Göttingen Minipigs were treated with vehicle or acyUCN2 (rats, pigs) or acyGLP-1 or combination therapy (rats only). Food intake, body weight (BW), body composition, glucose tolerance and energy expenditure (rats only) were assessed. Histology and RNA-sequencing were used to characterize muscle remodelling and transcriptional responses.
    RESULTS: In rats, acyUCN2 reduced food intake and fat mass, increased lean mass and muscle weight, and improved glucose tolerance despite limited effects on BW. Energy expenditure was not affected. Histology demonstrated hypertrophy across fibre types and a shift from type 2A to type 2X/B fibres. Transcriptomic analyses supported muscle growth and fibre type switch, relative reduced vasculature, regulation of neuromuscular junction-associated genes, and overlap to human acute exercise-response signatures. In obese minipigs, acyUCN2 increased lean mass and improved insulin sensitivity, with modest effects on BW and fat mass, alongside regulation of genes linked to muscle biology and metabolism.
    CONCLUSIONS: Pharmacological CRF2 agonism promotes favourable body composition, muscle hypertrophy, and improved glucose metabolism despite limited weight loss, supporting clinical development of UCN2 analogues as a differentiated obesity treatment, particularly in combination with appetite-regulating therapies and in settings where preservation of functional muscle mass is critical.
    Keywords:  CRF2 agonism; Glucose metabolism; Muscle hypertrophy; Neuromuscular junction; Obesity; Skeletal muscle fibre remodelling; Transcriptomics; Urocortin 2
    DOI:  https://doi.org/10.1016/j.molmet.2026.102468
  38. Hum Mol Genet. 2026 10 28. pii: ddag115. [Epub ahead of print]35(22):
    Identifying fundamental properties of neuromuscular disorder genes through genomic feature analysis.
    Alexandria Martin, M Alejandra Llanes-Cuesta, Jessica N Hartley, Patrick Frosk, Britt I Drögemöller, Galen E B Wright.
      Neuromuscular disorders (NMDs) encompass conditions that affect the peripheral nervous system. They are often caused by genetic alterations that impair skeletal muscle function. Molecular diagnosis remains challenging because some causal genes have not yet been identified. We therefore used feature-selection approaches to characterize genomic properties that distinguish NMD genes from other protein-coding genes. Curated genes implicated in NMDs (n = 639; GeneTable of NMDs) were merged with 134 genomic features for autosomal protein-coding genes spanning gene complexity, genetic variation, expression patterns, and other gene traits. Machine-learning-based feature selection using Boruta was combined with statistical analyses to compare NMD genes with other protein-coding genes. We also evaluated NMD genes against high-confidence non-NMD disease genes, examined variation across NMD subgroups, and assessed genes added to the NMD catalogue between 2020 and 2024. Compared with other protein-coding genes, NMD genes showed higher expression in disease-relevant tissues, including skeletal muscle and heart; greater transcript complexity and population genetic constraint, and stronger conservation across several evolutionary measures. Of 33 features that distinguished NMD genes from both high-confidence non-NMD disease genes and other autosomal genes, 28 were expression measures. Feature profiles varied across NMD subgroups, while genes added between 2020 and 2024 showed profiles similar to established NMD genes across all Boruta-confirmed features. This study identified genomic features that distinguish NMD genes from high-confidence disease genes and broader autosomal protein-coding genes. These findings provide insight into the gene architecture, expression, constraint, and evolutionary conservation of NMD genes and may inform candidate-gene prioritization in genetically unresolved NMDs.
    Keywords:  Bioinformatics; disease gene prioritisation; genomic feature analysis; genomics; neurogenetics; neuromuscular disorders; rare disease
    DOI:  https://doi.org/10.1093/hmg/ddag115
  39. bioRxiv. 2026 Oct 29. pii: 2026.10.27.762011. [Epub ahead of print]
    Proteomic clocks reveal organ-specific signatures of aging in mice.
    Sean Lim, Andrew M Pickering.
      Aging alters protein abundance throughout the body, but whether proteomic aging signatures are shared across organs, and how they are represented in RNA, remains unclear. Plasma proteomics does not measure protein abundance directly within individual organs. Here, we developed organ-specific proteomic aging clocks for eight mouse organs. The clocks retained age associations across independent cohorts but transferred poorly between organs of the same mice, indicating predominantly organ-specific aging signatures. This organ specificity extended to RNA. Applied to the transcriptomes of the genes encoding each clock's protein features, with protein-derived weights unchanged, the scores retained age associations in independent transcriptomic cohorts, with stronger associations in the corresponding organs. The strength of age associations across molecular layers also differed by organ: in paired analysis, protein scores tracked age more strongly than RNA scores in brain and skeletal muscle, with no statistically detectable difference in kidney, liver or lung, suggesting a greater post-transcriptional contribution to proteomic aging in brain and muscle. In spatial transcriptomes, protein-derived RNA scores rose with age within tissue niches, usually without detectable changes in relative niche abundance. In the brain, white matter and glia-enriched microdomains showed elevated proteomic scores compared to other regions since young age. Together, these findings support organ-specific regulation of proteomic aging and identify molecular remodeling within persistent tissue compartments.
    DOI:  https://doi.org/10.64898/2026.10.27.762011
  40. J Biomech. 2026 Oct 28. pii: S0021-9290(26)00498-7. [Epub ahead of print]209 113642
    Cross bridges, tendons and titin: evolving roles in muscle mechanics.
    Kiisa Nishikawa, Stan L Lindstedt.
      All fields of science evolve over time as interpretation of the evidence changes with the discovery of new facts, and muscle physiology is no exception. Ideas once thought preposterous may eventually become accepted dogma, as was the case for the sliding filament theory itself. The currently accepted sliding-filament - swinging cross-bridge paradigm views muscles as motors with static isometric force-length and isotonic force-velocity properties that necessarily limit their ability to store and recover viscoelastic energy. These limitations understandably led to the plausible explanation that tendons must be responsible for energy storage and recovery. However, recent advances in technology have enabled investigation of muscle properties in moving humans and other animals, providing significant new data on dynamic muscle function. Bridging the gap between laboratory studies of ex vivo muscle preparations and in vivo muscle mechanics has resulted in a paradigm shift toward the idea that muscles are tunable viscoelastic actuators that can harvest substantial energy from interactions with the environment. Here, we provide a somewhat chronological account of the contentious history of the field of muscle physiology and the evolution of ideas about muscle function, focusing particularly on muscle viscoelastic properties and energy storage. We argue that accumulating data position titin as a length- and activation-dependent viscoelastic element whose properties can be inferred from, and indeed are critical for, in vivo muscle function. We also provide ideas for future directions to stimulate progress in understanding titin's role in dynamic muscle function.
    Keywords:  Damping; Energy storage and release; Residual force enhancement; Stiffness; Viscoelasticity
    DOI:  https://doi.org/10.1016/j.jbiomech.2026.113642
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