bims-moremu Biomed News
on Molecular regulators of muscle mass
Issue of 2026–03–01
forty-nine papers selected by
Anna Vainshtein, Craft Science Inc.
  1. Repeated Disuse Atrophy Imprints a Molecular Memory in Skeletal Muscle: Transcriptional Resilience in Young Adults and Susceptibility in Aged Muscle.
  2. Mitochondrial Permeability Transition in Skeletal Muscle Phenocopies Muscle Alterations seen in Cancer Cachexia and other Wasting Conditions.
  3. Top-Down Proteomics of Skinned Human Muscle Fibers Reveals Proteoform-Resolved Fiber-to-Fiber Variability.
  4. Hypoxia and hypercapnia elicit overlapping but distinct skeletal muscle toxicities.
  5. Resistance-exercise-induced stress intervenes in TGF-β signaling by cooperatively downregulating nuclear αB-crystallin and SMAD4 in human skeletal muscle fibers.
  6. A network-based atlas of human skeletal muscle aging.
  7. Functional and structural pathologies in skeletal muscle of a rat model of Duchenne muscular dystrophy.
  8. Exercise preconditioning prevents immobilization-induced skeletal muscle atrophy by activating Prmt1-p38/ATF2-Sesn1 signaling axis in C57BL/6J mice.
  9. Senescent-Like Myofibers Contribute to Anti-Regenerative Cytokine Signaling in Duchenne Muscular Dystrophy.
  10. Senolytics and exercise: Dual modalities for rejuvenating muscle.
  11. Molecular Basis of Muscle Wasting and Emerging Therapeutic Strategies Targeting Degenerative Muscle Disorders.
  12. Myonuclear loss, rather than senescent myonuclei, associates with fiber type-specific atrophy in aging human skeletal muscle.
  13. CD146 + interstitial cells contribute to the dystrophic skeletal muscle phenotype in vitro.
  14. Entropy of Muscle Fiber Histology Predicts Mobility in Older Adults: The Study of Muscle, Mobility, and Aging.
  15. Muscle-specific expression of Atg2 and high-fat diet influence age-related deterioration of skeletal muscle in aged drosophila via the ATGL/Sirt1/PGC-1α pathway.
  16. Chronic hypoxia induces skeletal muscle atrophy in mice: Potential roles of antioxidant imbalance and FOXO1.
  17. AUF1 therapy blocks atrophy, promotes regeneration, re-innervation and strength for severe muscle injury.
  18. Regulation of PERM1 and select target genes in human skeletal muscle following fasting and exercise.
  19. Ampk alpha2 T172 activation dictates exercise performance and energy transduction in skeletal muscle.
  20. Macroscopic to Ultrastructural Analyses Identify the Loss of Myofibrils as the Primary Mediator of Muscle Fiber Atrophy in Aging and Disuse.
  21. Erk3 deletion drives oxidative adaptations in skeletal muscle.
  22. Activating FGFR1 restores Integrin-β1-mediated fibronectin sensing in satellite cells of aged mice.
  23. Exercise beneficially reshapes fasted rat skeletal muscle involving the combined action of beta-hydroxybutyrate and palmitoleic acid.
  24. Menopause and Muscle: Closer to Answers, but Significant Questions Remain.
  25. Intramuscular neutrophil-derived immunometabolic niches locally boost insulin-responsive GLUT4 translocation after muscle contraction.
  26. The role of CXCL10 in high-fat diet-induced skeletal muscle inflammation and atrophy.
  27. Intramuscular pathways of maladaptation in overtraining syndrome.
  28. DUSP29 does not regulate melanoma-myoblast interactions in a skeletal muscle co-culture model.
  29. The Preservation of Muscle Mitochondrial Machinery During Hypometabolic Hibernation in Scandinavian Brown Bears (Ursus arctos).
  30. Decoding the Endocrine Code of Skeletal Muscle: Myokines, Exerkines, and Inter-Organ Crosstalk in Metabolic Health and Disease.
  31. Transcriptomic suppression of immune and ECM stability in skeletal muscle of patients with chronic kidney disease.
  32. Advanced glycation end product-its receptor axis participates in myoblast senescence in vitro and delayed muscle regeneration of senescence/aging skeletal muscles in vivo.
  33. Atrophic Skeletal Muscle-Derived Extracellular Vesicles Transfer miR-125a-5p to Inhibit Bone Formation in Osteoporosis during Aging.
  34. Metabolomic profiling of skeletal muscle in GSDMD-knockout mice reveals distinct metabolic alterations in sepsis-induced myopathy.
  35. Unraveling the metabolic pathways between atherosclerosis and sarcopenia.
  36. MicroAge mission: experimental design and hardware for a bespoke culture system supporting tissue-engineered skeletal muscle.
  37. Myosin Filaments of Vertebrate Skeletal and Cardiac Muscle are Highly Similar, but not Identical.
  38. Mitochondrial-derived peptides MOTS-c and humanin attenuate dexamethasone-induced atrophy in human skeletal muscle cells.
  39. The Muscle Function Deficit Concept and Inflammaging.
  40. Circulating Senescence Protein Links Exercise Adaptation to Health Outcomes.
  41. Ribosome heterogeneity and specialization in musculoskeletal physiology and pathology.
  42. A ketogenic diet enhances aerobic exercise adaptation and promotes muscle mitochondrial remodeling in hyperglycemic male mice.
  43. NRMLncR, a myocyte-enriched long non-coding RNA, enhances myogenesis in mouse.
  44. Single-cell RNA sequencing and integrated bioinformatics reveal new mitochondrial biomarkers in sarcopenia.
  45. Resistance training partially restores age-related differences in skeletal muscle amino acid transporters - secondary analysis from two randomized controlled trials.
  46. NF-κB Signaling as a Central Driver of Cancer Cachexia.
  47. Enhanced muscle uptake of chemically optimized miR-23b antisense oligonucleotides as lead compounds for myotonic dystrophy type 1.
  48. Age-related sarcopenia and the gut microbiome: mechanistic insights into the gut-muscle axis and potential microbiome based therapeutic interventions.
  49. High Fat Diet and Obesity Each Increase Tumor Cell Proliferation and Muscle Wasting in Experimental Cancer Cachexia.
  1. Adv Sci (Weinh). 2026 Feb 25. e22726
    Repeated Disuse Atrophy Imprints a Molecular Memory in Skeletal Muscle: Transcriptional Resilience in Young Adults and Susceptibility in Aged Muscle.
    Daniel C Turner, Truls Raastad, Max Ullrich, Stian F Christiansen, Hazel Sutherland, James Boot, Eva Wozniak, Charles Mein, Emilie Dalbram, Jonas T Treebak, Daniel J Owens, David C Hughes, Sue C Bodine, Jonathan C Jarvis, Adam P Sharples.
      Disuse-induced muscle atrophy commonly occurs following illness, injury, or falls and becomes increasingly frequent with ageing. Whether skeletal muscle retains a "memory" of repeated disuse remains unknown. We investigated repeated lower-limb immobilization in young adults and a refined aged rat model, integrating physiological, multi-omic, immunohistochemical, biochemical, and primary human muscle stem cell (MuSC) analyses. To enable robust age comparisons, we integrated previously published young rat data with newly generated aged rat data. In young human muscle, repeated disuse elicited attenuated transcriptional perturbations in oxidative and mitochondrial pathways, suggestive of a protective molecular memory, despite similar atrophy to initial disuse. In contrast, aged muscle exhibited a detrimental memory, characterized by greater atrophy, exaggerated suppression of aerobic metabolism genes despite recovery after initial disuse, NAD+ and mitochondrial DNA depletion, and activation of proteasomal, extracellular-matrix, and DNA-damage pathways. Whereas young rats recovered muscle mass after initial disuse, aged rats failed to do so. Across species, repeated disuse induced DNA hypermethylation and downregulation of aerobic metabolism and mitochondrial gene networks. NR4A1 and NR4A3 were among the strongest disuse-suppressed genes; NR4A1 acquired recovery-phase hypermethylation that maintained its transcriptional repression, while NR4A3 was the most downregulated gene after initial atrophy and remained persistently suppressed into recovery. Acetylcholine receptor subunit genes (CHRNA1, CHRND) were epigenetically primed, demonstrating hypomethylation and strong upregulation after disuse, and further amplification after repeated atrophy, while CHRNG was selectively induced after repeated atrophy only. NMRK2, an NAD+ biosynthesis gene, was the most downregulated gene across both atrophy periods, and supplementation with its substrate, nicotinamide riboside (NR), improved myotube size in MuSCs derived post-atrophy. Overall, repeated disuse atrophy imprints a molecular memory in skeletal muscle shaping transcriptional resilience in young adults and exaggerated susceptibility in aged muscle.
    Keywords:  AChR (CHRNA1, CHRND, CHRNG); DNA methylation; NAD+ metabolism; NMRK2; NR4A1; NR4A3 ; aerobic metabolism; aging; disuse atrophy; mtDNA; muscle memory; muscle stem cells; nicotinamide riboside; skeletal muscle; transcriptome
    DOI:  https://doi.org/10.1002/advs.202522726
  2. bioRxiv. 2026 Feb 13. pii: 2026.02.12.705530. [Epub ahead of print]
    Mitochondrial Permeability Transition in Skeletal Muscle Phenocopies Muscle Alterations seen in Cancer Cachexia and other Wasting Conditions.
    Maya Semel, Cole Lukasiewicz, Sarah Skinner, Mark R Viggars, Martin Picard, Abbey-Gale Mannings, Michael Cohen, Dennis Wolan, Terence E Ryan, Russell T Hepple.
       Background: Skeletal muscle in wasting conditions often exhibits a common set of phenotypes that include atrophy, mitochondrial respiratory dysfunction, and fragmentation of the acetylcholine receptor (AChR) cluster at the endplate. Mitochondria are frequently implicated in driving muscle pathology in these conditions, although which aspects of mitochondrial function are most relevant is poorly understood.
    Methods: To address this gap, we focused on mitochondrial permeability transition (mPT), a well-established pathological mechanism in ischemia-reperfusion injury and neurodegeneration but poorly studied in skeletal muscle. We performed a broad assessment of the consequences of mPT in skeletal muscle, focusing on features that are common in wasting conditions. We then tested whether tumor-host factors could promote mPT and compared differentially expressed genes (DEGs) with mPT and a mouse model of pancreatic cancer cachexia.
    Results: Inducing mPT in mouse skeletal muscle bundles in a Ca 2+ retention capacity assay progressively altered mitochondrial morphology, beginning with cristae swirling and condensation, progressing to mitochondrial cristae displacement, and culminating in breach of the outer mitochondrial membrane; features that are common in wasting conditions. Inducing mPT with Bz423 in single mouse muscle fibers increased mROS and Caspase 3 (Casp3) activity and was prevented by inhibitors of mPT, mROS or Casp3. Incubating single muscle fibers with Bz423 for 24 h reduced fiber diameter by ∼20% which was prevented by inhibiting mPT, mROS, or Casp3. Inducing mPT caused a complex I-specific mitochondrial respiratory impairment and increased co-localization of lysosomes with mitochondria. Inducing mPT also fragmented the AChR cluster at the muscle endplate and was prevented by inhibiting mPT or Casp3. The Ca 2+ threshold for mPT and mitochondrial calcein colocalization were reduced by pancreatic tumor-conditioned media in skeletal muscle or C2C12 myoblasts, respectively, and these effects were counteracted by mPT inhibition or cyclophilin D knockout. Finally, there was significant overlap between the transcriptome of mPT and that seen in diaphragm muscle in a mouse model of pancreatic cancer cachexia, particularly during the muscle wasting phase.
    Conclusions: We conclude that inducing mPT in skeletal muscle recapitulates muscle phenotypes common with muscle wasting conditions like cachexia. Furthermore, mPT is engaged by tumor-host factors and had significant overlap with DEGs seen during the muscle wasting phase in a mouse model of pancreatic cancer cachexia, warranting further investigation of mPT as a therapeutic target.
    DOI:  https://doi.org/10.64898/2026.02.12.705530
  3. J Mass Spectrom. 2026 Mar;61(3): e70040
    Top-Down Proteomics of Skinned Human Muscle Fibers Reveals Proteoform-Resolved Fiber-to-Fiber Variability.
    Mallory C Wilson, Zhan Gao, Justin R Lopez, Yanlong Zhu, Szczepan S Olszewski, Adam R Konopka, Gary M Diffee, Ying Ge.
      Human skeletal muscle is composed of highly heterogeneous single muscle fibers (multinucleated single cells) that are commonly classified as fast or slow fiber types, yet proteoform-resolved characterization of individual human muscle fibers remains lacking. Herein, we establish a high sensitivity top-down proteomics method for the analysis of single human muscle fibers (hSMFs). Specifically, we have optimized the surfactant-free extraction protocol for analysis of chemically permeabilized ("skinned") hSMFs, a common preparation used to isolate the sarcomere prior to contractile measurements. This approach enables robust and reproducible proteoform-level coverage of key sarcomeric proteins from individual fibers using top-down LC-MS/MS. With this method, we identified extensive inter- and intra-donor fiber-to-fiber variability in isoform expression and proteoform abundance in hSMFs extracted from the heterogeneous vastus lateralis muscles. Together, these results demonstrate the capability of single-fiber top-down proteomics to resolve proteoform-level heterogeneity in human skeletal muscle and establish a methodological foundation for future studies towards elucidating skeletal muscle biology and understanding muscle-related diseases. Source data for this manuscript is available via the MassIVE repository at massive.ucsd.edu with identifier: MSV000100493.
    Keywords:  human muscle fiber; sensitivity; single cell heterogeneity; top–down proteomics
    DOI:  https://doi.org/10.1002/jms.70040
  4. J Physiol. 2026 Feb 24.
    Hypoxia and hypercapnia elicit overlapping but distinct skeletal muscle toxicities.
    Joseph Balnis, Ariel Jaitovich.
      Skeletal muscle dysfunction is strongly associated with elevated mortality in acute and chronic pulmonary diseases. Hypoxaemia and hypercapnia, which are central hallmarks of respiratory failure, represent critical cellular signals regulating muscle loss, causing disruption of skeletal muscle mass, myofibre metabolic profile and oxidative capacity, and regenerative potential after injury. Both hypoxaemia and hypercapnia elicit alterations in protein synthesis and degradation, myogenesis and autophagy - key cellular processes that significantly impact skeletal muscle integrity. Recent data have also implicated epigenetic mechanisms such as microRNAs and DNA methylation as regulators of skeletal muscle phenotypes following hypoxic and hypercapnic insults. Hypoxia and hypercapnia engage overlapping pathways, including hypoxia-inducible factor 1 and AMP-activated protein kinase, suggesting that despite being distinct phenomena, hypoxaemia and hypercapnia share mechanisms orchestrating cellular programmes regulating various skeletal muscle adaptations. Both CO2 and O2 modulate key cellular hubs controlling muscle mass, including AKT, mammalian target of rapamycin complex 1 and others. Finally, in this article we outline some current gaps in knowledge in the field that we believe merit future research.
    Keywords:  AMPK; autophagy; carbon dioxide (CO2); hypercapnia; hypoxia; skeletal muscle
    DOI:  https://doi.org/10.1113/JP289079
  5. FEBS J. 2026 Feb 23.
    Resistance-exercise-induced stress intervenes in TGF-β signaling by cooperatively downregulating nuclear αB-crystallin and SMAD4 in human skeletal muscle fibers.
    Kirill Schaaf, Cassandra Duda, Tihomir Kostov, Patrick Diel, Käthe Bersiner, Wilhelm Bloch, Sebastian Gehlert, Daniel Jacko.
      Alpha-crystallin B chain (αB-crystallin; CRYAB) helps to maintain proteostasis following cellular stress. Additionally, recent studies in fibroblasts have shown its function in the transforming growth factor beta (TGF-β) pathway, where it stabilizes mothers against decapentaplegic homolog 4 (SMAD4) in the nucleus, enabling target gene transcription. Specifically in skeletal muscle fibers (SkMFs), TGF-β/SMAD4 signaling via myostatin regulates fiber size by inducing growth inhibitors and suppressing the serine/threonine-protein kinase (mTOR) pathway. Conversely, resistance exercise (RE) promotes muscle growth and should therefore affect CRYAB/SMAD4 interaction. However, in human SkMFs, CRYAB's nuclear localization and role in TGF-β/SMAD4 signaling, at rest or after RE, remain undescribed. Therefore, we first validated CRYAB's nuclear localization by small interfering RNA (siRNA)-mediated CRYAB silencing in C2C12 cells (mouse skeletal muscle myoblast cell line) and in human SkMFs via subcellular fractionation and confocal microscopy. To determine the effect of RE on this pathway, skeletal muscle biopsies were taken at rest and 60 min post-RE and analyzed for nuclear localization and phosphorylation of CRYAB and SMAD4, CRYAB/SMAD4 colocalization, and anabolic signaling. CRYAB was localized to C2C12 myoblast nuclei during proliferation but disappeared early during differentiation and was absent in nuclei of myotubes. In contrast, CRYAB was present in nuclei of resting human SkMFs. However, acute RE reduced total CRYAB in SkMF nuclei and increased its phosphorylation at serine 59, which likely promotes its export. Acute RE also reduced both nuclear and cytoplasmic SMAD4 while enhancing anabolic signaling by mTOR and small ribosomal subunit protein eS6 (rpS6) phosphorylation. We conclude that CRYAB and SMAD4 interact in nuclei of human SkMFs and have a coordinated regulation in response to RE-induced mechanical stress, revealing a new perspective on a yet-undescribed mechanism contributing to skeletal muscle adaptation.
    Keywords:  CRYAB; HSPB5; SMAD4; TGF‐β; muscle; nuclei; resistance exercise
    DOI:  https://doi.org/10.1111/febs.70468
  6. medRxiv. 2026 Feb 17. pii: 2026.02.15.26346348. [Epub ahead of print]
    A network-based atlas of human skeletal muscle aging.
    Tanner Stokes, Changhyun Lim, Muhammad Ali, Jonathan C Mcleod, Jack Gisby, Katia Mariniello, Hannah Crossland, Jalil-Ahmad Sharif, Colleen Deane, Thomas C Moseley, Nasim M Ismail, M E Lixandrao, C H Volmar, Peter J McCormick, Robert J Brogan, James Whiteford, H Roschel, Stuart M Phillips, Iain J Gallagher, Gregory Slabaugh, Bethan E Phillips, William E Kraus, Philip J Atherton, J Paul Chapple, James A Timmons.
      Skeletal muscle metabolic and physical capacities are influenced by both genetics and load status and decline with age. Recent advances in sequencing have detailed cell types at unprecedented detail; yet these approaches do not scale to adequately model human muscle physiological heterogeneity. We produced a powerful resource for ageing studies, including consistent deep transcriptomic profiles of 1,675 human muscle biopsies (∼28,000 genes per profile) and multiple single-cell spatial transcriptomic technologies. We present several novel models of tissue ageing. Five Quantitative network models (QNMs), built using >40 trillion calculations and 930 human muscle transcriptomes, modelled aging and the influence of load status. Additional differential expression (DE) signatures for atrophy, hypertrophy and cardio-respiratory adaptation were integrated with single-cell RNAseq and cell-specific bulk profiles to reveal cell-enriched modules and the topology of human skeletal aging. Rapamycin transcriptomes from cultured muscle and endothelial cells, along with in vivo signatures for insulin resistance and sex, were integrated into these analyses. We show that >3,000 genes are DE with muscle age (equally up and down); that a novel pre-frailty signature in elderly subjects has a remarkably strong overlap with the response of healthy muscle during experimental atrophy and that the hypertrophy signature in elderly muscle, but not young muscle, opposes the age-regulated transcriptome. We report that non-responders for hypertrophy or gains in cardio-respiratory capacity have highly distinct genome-level response to exercise. QNM revealed cell-specific processes in endothelial cells and fibroblasts, including novel interactions between insulin sensitivity, age and senescence. From two hundred and eighty-six hub genes consistent in both young and old muscle network models, 27% had known roles in muscle biology, while of the top 50 hub genes (45% protein coding), 80% were newly linked to human muscle biology, including ARHGAP4, CEP131 and IFITM10 and many short- and long-noncoding RNAs. Many genes demonstrated extreme changes in topology in old muscle, such as the neddylation and aging linked gene, DCUN1D5. GeoMX-based spatial muscle fibre-type profiling (57 regions), along with Xenium (8 regions) and Merscope (54 regions) single-cell spatial technologies located key aging, frailty and load-responsive genes to individual cell types and provided novel insight into the location of autocrine/paracrine secreted factors such as GDNF, while IL6 was located to rare endothelial cells. A machine-learning model ranked the factors most associated with the topological changes with age. This prioritised network features over DE signatures, highlighting positive correlating edges to down-regulated genes during atrophy, genes up-regulated by Rapamycin and both positive and negative correlating insulin sensitivity features, along with gene hub status, best explained muscle ageing. Genome level modelling produced an independently validated transcriptomic 'age clock' and found it to be invariant to muscle load status in people >50y, while we revealed novel interactions between gene length and age. Release of an unprecedented level of consistently aligned genomic data, along with QNMs with >7,000 searchable modules, provides a powerful resource for the aging research communities.
    DOI:  https://doi.org/10.64898/2026.02.15.26346348
  7. Skelet Muscle. 2026 Feb 25.
    Functional and structural pathologies in skeletal muscle of a rat model of Duchenne muscular dystrophy.
    Young Il Lee, Cora C Hart, C Spencer Henley-Beasley, Jeffrey S Herr, Eli Zerpa, Elisabeth R Barton, David W Hammers, H Lee Sweeney.
       BACKGROUND: Duchenne muscular dystrophy (DMD) is a lethal pediatric degenerative muscle disease for which there is no cure. Robust preclinical models that recapitulate major clinical features of DMD are required to investigate efficacy of potential DMD therapeutics. Rat models of DMD have emerged as promising small animal models to accomplish this; however, there have been no comprehensive studies investigating the functional skeletal muscle decrements associated with the modeling of DMD in rats.
    METHODS: CRISPR/Cas9 gene editing was used to generate a dystrophin-deficient Sprague-Dawley muscular dystrophy rat (MDR). Biochemical and immunofluorescent analyses were performed to confirm loss of dystrophin in striated muscles of this rat model. In situ and ex vivo muscle function was assessed in wild-type (WT) and MDR muscles at 3, 6, and 12 months of age, followed by histopathological analyses.
    RESULTS: MDR muscle tissues exhibited loss of full-length dystrophin and reduced content of other dystrophin glycoprotein complex members. MDR extensor digitorum longus (EDL) muscles and diaphragms displayed pronounced and progressive muscle weakness beginning at 3 months of age, compared to WT littermates. EDLs also exhibit susceptibility to eccentric contraction-induced damage. Functional deficits in soleus muscles were less severe and were associated with a right shift in force-frequency relationship. MDR muscles display progressive histopathology including degenerative lesions, fibrosis, regenerative foci, and modest adipose deposition.
    CONCLUSIONS: MDR is a preclinical model of DMD that exhibits many translational features of the human disease, including a large dynamic range of muscle decrements, that has high utility for the evaluation of potential therapeutics for DMD.
    Keywords:  CRISPR/Cas9; Duchenne muscular dystrophy; Dystrophin; Fibrosis; Muscle function; Regeneration; Translational research
    DOI:  https://doi.org/10.1186/s13395-026-00419-4
  8. Sports Med Health Sci. 2026 Mar;8(2): 197-209
    Exercise preconditioning prevents immobilization-induced skeletal muscle atrophy by activating Prmt1-p38/ATF2-Sesn1 signaling axis in C57BL/6J mice.
    Xuege Yang, Yuchen Zou, Haoyu Wang, Yanmei Niu, Li Fu.
       Purpose: This study aimed to explore the effects of a 10-week combined exercise regimen on immobilization-induced muscle atrophy and elucidate the possible function of Protein arginine methyltransferase 1 (Prmt1) in this process.
    Methods: 8-week-old male C57BL/6J mice were carried out combined exercise for 10 weeks. One week before the end of the intervention, mice underwent cast immobilization. Additionally, to investigate the potential mechanism in exercise-induced protection of skeletal muscle, mice in the exercise preconditioning group were administered TC-E-5003(an inhibitor of Prmt1 enzymatic activity). Exercise performance, muscle mass, and the cross-sectional area (CSA) of muscle fibers were analyzed. Besides, Prmt1 and Sestrin1 (Sesn1) were either overexpressed or inhibited in C2C12 myotubes to elucidate the underlying mechanism.
    Results: Exercise preconditioning not only significantly improved muscle mass and motor ability in immobilized mice but also inhibited excessive activation of degradation pathways and enhanced protein synthesis. Importantly, Prmt1 mediated the protective effects of exercise preconditioning on muscle atrophy. Mechanistically, Prmt1 regulated the p38 mitogen-activated protein kinase (p38)/activating transcription factor 2 (ATF2) pathway, which modulates Sesn1 expression. Sesn1 acts as a downstream of Prmt1 and ATF2, contributing to the myoblast differentiation and skeletal muscle regeneration through AMP-Activated protein kinase α2 (AMPKα2)/transcriptional co-activator PPAR-γ co-activator-1 α (PGC-1α) signaling pathway.
    Conclusions: Taken together, our results highlighted the effectiveness of exercise preconditioning in preventing muscle atrophy via the Prmt1-Sesn1 pathway.
    Keywords:  ATF2; Immobilization; PGC-1α; Prmt1; Sesn1; Skeletal muscle atrophy
    DOI:  https://doi.org/10.1016/j.smhs.2025.04.001
  9. FASEB J. 2026 Feb 28. 40(4): e71567
    Senescent-Like Myofibers Contribute to Anti-Regenerative Cytokine Signaling in Duchenne Muscular Dystrophy.
    Masanari Ikeda, Yukie Tanaka, Hidetoshi Sugihara, Takashi Matsuwaki, Keitaro Yamanouchi.
      Duchenne muscular dystrophy (DMD) is a genetic muscular disease characterized by progressive muscle degeneration. p16 is expressed in skeletal muscles and induces cellular senescence in a rat model of DMD, whereas its ablation enhances muscle regeneration. However, the mechanism underlying this phenomenon remains unclear. This study aimed to elucidate the mechanism for p16-induced DMD exacerbation. RNA-seq analysis revealed p16-dependent upregulation of cytokine gene expression in DMD rat skeletal muscles, which also altered the systemic blood cytokine profile. Furthermore, the effect of an altered humoral environment on muscle regeneration was assessed using the transplanted extensor digitorum longus muscle. Regeneration of grafted muscles from wild-type rats was suppressed in DMD rats but was significantly improved by p16 ablation. Notably, p16 was expressed in the myofibers of DMD rats, and enzymatically isolated myofibers from DMD rats also showed p16-dependent cytokine expression. Thus, cytokines secreted by senescent-like myofibers mediate the anti-regenerative niche in DMD rats, uncovering a novel mechanism for disease progression and potential therapeutic targets.
    Keywords:  animal; cellular senescence; cyclin‐dependent kinase inhibitor p16; disease models; duchenne; muscle fibers; muscle regeneration; muscular dystrophy; senescence‐associated secretory phenotype; skeletal
    DOI:  https://doi.org/10.1096/fj.202500098R
  10. J Physiol. 2026 Feb 26.
    Senolytics and exercise: Dual modalities for rejuvenating muscle.
    Zeynep Elif Yesilyurt-Dirican, Ce Qi, Uchenna Okpechi, Maya Strand Ford, Georgina M Ellison-Hughes.
      Mammalian ageing is defined as a gradual loss of the capacity to maintain tissue homeostasis or to repair tissues after injury or stress. Cellular senescence is induced by various cellular stressors, and there is accumulation of senescent cells in all tissues with ageing and chronic disease, which contributes to pathophysiology and organ deterioration. Long-term persistence of senescent cells and their senescence-associated secretory phenotype (SASP) impairs tissue homeostasis and regenerative capacity, leading to tissue and physiological dysfunction. Senolytics are senotherapeutic agents that systemically eliminate senescent cells, and have been shown in pre-clinical and clinical studies to improve cardiac and skeletal muscle regeneration, remodelling and physiological function. Exercise training and physical activity have also been shown to have senolytic effects. In this review, we evaluate whether targeting cell senescence using senolytics can rejuvenate the heart and skeletal muscle, reversing the ageing phenotype.
    Keywords:  FAPs; ageing; age‐related heart disease and failure; cardiomyocytes; exercise; heart; muscle wasting; muscular dystrophy; satellite cells; senescent cells; senolytics ; senotherapeutics; skeletal muscle
    DOI:  https://doi.org/10.1113/JP287702
  11. Exp Cell Res. 2026 Feb 25. pii: S0014-4827(26)00086-8. [Epub ahead of print] 114969
    Molecular Basis of Muscle Wasting and Emerging Therapeutic Strategies Targeting Degenerative Muscle Disorders.
    Magdalin Jude, Sheeja Rajasingh, Stephen Alway, Johnson Rajasingh.
      Muscle degenerative conditions, including sarcopenia, muscular dystrophies, and trauma-induced muscle loss, severely compromise mobility, metabolism, and overall health. These disorders result from multifactorial causes such as imbalances in protein homeostasis, satellite cell dysfunction, mitochondrial stress, and chronic inflammation. Central molecular regulators such as FOXO, AMPK, mTOR, and the myostatin/SMAD axis, play pivotal roles in driving muscle atrophy. Current regenerative strategies seek to restore muscle structure and function through stem cell-based therapies (MSCs, iPSC-derived muscle progenitors, and satellite cells), gene editing, exosome-mediated delivery, and biomaterial scaffolds. Emerging evidence highlights the therapeutic potential of engineered exosomes, pro-regenerative cytokines, and biomimetic scaffolds in enhancing angiogenesis, myogenesis, and immune modulation. In parallel, advances in multi-omics and artificial intelligence are accelerating the identification of key molecular targets and the development of personalized interventions. Combination therapies that integrate cellular, molecular, and structural approaches demonstrate synergistic benefits for improving outcomes. This review summarizes current knowledge of the molecular mechanisms underlying muscle degeneration and discusses emerging therapeutic strategies that hold promise for effective muscle regeneration.
    Keywords:  Exosomes; Muscle atrophy; Muscle regeneration; Muscle wasting; Sarcopenia; Stem cell-based therapy
    DOI:  https://doi.org/10.1016/j.yexcr.2026.114969
  12. bioRxiv. 2026 Feb 13. pii: 2026.02.11.705446. [Epub ahead of print]
    Myonuclear loss, rather than senescent myonuclei, associates with fiber type-specific atrophy in aging human skeletal muscle.
    Carlos S Zepeda, Isabell Dobrzycki, Paige N Acklie, Cory M Dungan, Ronald G Jones, Kevin A Murach, Christopher W Sundberg.
      Age-related reductions in whole-muscle function are attributed, in part, to pronounced atrophy of muscle fibers expressing the fast myosin heavy chain (MyHC) II isoforms. Senescence, a state of irreversible cell cycle arrest that can be characterized by DNA damage (γH2AX) and chromatin remodeling (loss of nuclear HMGB1), may contribute to skeletal muscle aging. Muscle nuclei (myonuclei) maintain fiber size and function and could exhibit senescence-associated features; however, the prevalence of senescent myonuclei and whether they contribute to fast fiber atrophy in older adults remains unknown. Vastus lateralis biopsies from 20 young (19-34yr; 10 females) and 20 older (65-84yr; 10 females) adults were analyzed via immunohistochemistry for myonuclei positive for γH2AX (γH2AX+) and negative for HMGB1 (HMGB1-). MyHC II cross-sectional area (CSA) was ~70% larger in young compared with old, whereas MyHC I CSA did not differ with age. The relative abundance of γH2AX+/HMGB1- myonuclei did not differ with age and was not associated with CSA in either fiber type. Single-nucleus RNA-sequencing corroborated no age-related difference in the prevalence of myonuclei with senescence-associated features. Myonuclear content of MyHC II fibers was ~30% higher in young compared with old and was closely associated with CSA in both fiber types. Size-cluster analysis revealed a pronounced age-related leftward shift in MyHC II CSA that paralleled the reductions in myonuclear number, consistent with myonuclear loss. These data suggest that age-related fast fiber atrophy is not attributed to an increased prevalence of senescent myonuclei but instead occurs concomitantly with fiber type-specific myonuclear loss across the lifespan.
    DOI:  https://doi.org/10.64898/2026.02.11.705446
  13. Sci Rep. 2026 Feb 24.
    CD146 + interstitial cells contribute to the dystrophic skeletal muscle phenotype in vitro.
    Bartosz Mierzejewski, Zuzanna Michalska, Dominika Kulma, Aleksandra Bos, Wladyslawa Streminska, Zbigniew Bartoszewicz, Edyta Brzoska.
      
    Keywords:  CD146; Differentiation; Fibro-adipogenic progenitor cells; MCAM; Muscular dystrophy; Pericyte; Skeletal muscle
    DOI:  https://doi.org/10.1038/s41598-026-38311-2
  14. Aging Cell. 2026 Mar;25(3): e70421
    Entropy of Muscle Fiber Histology Predicts Mobility in Older Adults: The Study of Muscle, Mobility, and Aging.
    Namki Hong, Sang Wouk Cho, Alan A Cohen, Russell T Hepple, Paul M Coen, Bumsoo Ahn, Anne B Newman, Stephen B Kritchesky, Paul J Laurenti, Warren S Browner, Steven R Cummings.
      Entropy may play an underappreciated role in human aging, such as in skeletal muscle functional declines. Histologically, muscle appears increasingly disorganized with aging, with greater fiber size variability and fiber-type grouping. We tested the hypothesis that entropy is associated with reduced physical performance and muscle function, independent of muscle mass. We quantified a homeostatic dysregulation index of muscle (HDIM) as a proxy for entropy of muscle fiber disorganization based on cross-sectional images of vastus lateralis biopsies from 299 adults age 70 or older. HDIM was derived from three traits: fiber area diversity, fiber-type heterogeneity, and the mean of the shortest path lengths through adjacent fiber networks. HDIM derived from muscle fibers was highly correlated with Shannon entropy, a different measure of entropy of muscle fiber traits. Higher HDIM derived from participants was associated with slower 400-m walk speed, lower peak VO2, muscle power, and decreased maximum rate of oxidative phosphorylation by mitochondria in muscle. These findings suggest that muscle fibers accumulate entropy with aging which contributes to decline in physical performance, muscle power, and mitochondrial energetics, advancing the entropy framework in aging research.
    Keywords:  aging; computer‐assisted; entropy; image processing; mobility limitation; muscles
    DOI:  https://doi.org/10.1111/acel.70421
  15. Biochem Biophys Res Commun. 2026 Feb 19. pii: S0006-291X(26)00271-8. [Epub ahead of print]809 153507
    Muscle-specific expression of Atg2 and high-fat diet influence age-related deterioration of skeletal muscle in aged drosophila via the ATGL/Sirt1/PGC-1α pathway.
    Jingfeng Wang, Nijia Meng, Dengtai Wen.
      Atg2 plays a vital role in regulating the ageing process. Autophagy and lysosomal repair depend on the lipid transport function of Atg2. The molecular mechanisms of the muscle Atg2 gene resistance to high-fat diet (HFD)-induced age-related damages of skeletal muscle are not known. In this study, we achieved overexpression and knockdown of the muscle Atg2 gene in drosophila by constructing the Atg2UAS/MhcGal4 system. Drosophila was subjected to an HFD intervention for three weeks. The findings demonstrated that an HFD markedly reduced climbing endurance and speed, down-regulated muscle Atg2, Atg8a (a mammalian ortholog of LC3 and an autophagy marker), ATGL, Sirt1, and PGC-1α gene expression, and raised MDA and TG in elderly drosophila. Age-related muscle degeneration caused by a high-fat diet was worsened by knocking down muscle Atg2. In contrast, age-related muscle degeneration brought on by a high-fat diet was avoided by overexpressing the Atg2 gene in muscles. Therefore, the present findings demonstrated that the muscle Atg2 gene was essential for skeletal muscle resistance against age-related damages caused by a high-fat diet by controlling the activity of the ATGL/Sirt1/PGC-1α pathway, oxidative balance, and lipid metabolism.
    Keywords:  ATGL/Sirt1/PGC-1α; Atg2; Autophagy; High-fat diet; Skeletal muscle aging
    DOI:  https://doi.org/10.1016/j.bbrc.2026.153507
  16. Biochim Biophys Acta Gen Subj. 2026 Feb 21. pii: S0304-4165(26)00022-X. [Epub ahead of print]1870(5): 130922
    Chronic hypoxia induces skeletal muscle atrophy in mice: Potential roles of antioxidant imbalance and FOXO1.
    Xiangyun Luo, Si Tang, Xingdan Luo, Sonam Wangmo, Ruohan Xia, Xianwang Wang.
      Skeletal muscle atrophy, characterized by progressive loss of muscle mass and strength, severely impairs quality of life. Chronic hypoxia is a well-recognized inducer of this condition, but its potential pathophysiological mechanisms remain unclear. This study aims to investigate the effects of chronic hypoxia on skeletal muscle atrophy and to elucidate the key molecular mechanisms involved. C57BL/6 J mice were subjected to continuous hypobaric hypoxia (simulating an altitude of 5000 m) for 36 days to establish a chronic hypoxia model. Western blot was used to detect oxidative stress regulator, muscle atrophy/growth markers, and associated proteins; H&E staining to evaluate muscle fiber morphology; and Sirius Red to assess the degree of muscle fibrosis. Complementary in vitro experiments were conducted using C2C12 mouse myoblasts. Results showed that chronic hypoxia induced gastrocnemius muscle atrophy in mice, as evidenced by a significant reduction in the muscle fibers cross-sectional area and increased fibrosis. In C2C12 cells, chronic hypoxia downregulated the protein levels of NF-κB, SOD1 and NOX4. In the in vivo mouse model, chronic hypoxia upregulated FOXO1 and Trim63 expression while inhibiting MyoD1. Collectively, this study demonstrates that chronic hypoxia drives skeletal muscle atrophy by simultaneously suppressing the cellular antioxidant defense system and activating the FOXO1-mediated proteolytic signaling.
    Keywords:  Antioxidant imbalance; FOXO1; Hypoxia; Muscle atrophy
    DOI:  https://doi.org/10.1016/j.bbagen.2026.130922
  17. Mol Ther. 2026 Feb 23. pii: S1525-0016(26)00119-X. [Epub ahead of print]
    AUF1 therapy blocks atrophy, promotes regeneration, re-innervation and strength for severe muscle injury.
    Dounia Abbadi, Olga Katsara, Riley McConnell, Beth Walters, Karol Granados Blanco, Alberto Canfrán-Duque, Sophie Dornbaum, John J Andrews, Robert J Schneider.
      There are currently no approved therapeutic interventions to promote skeletal muscle regeneration following a severe muscle injury, among the most common of debilitating injuries. We developed a novel therapeutic approach, gene or mRNA delivery encoding RNA binding protein AUF1, which orchestrates the end-to-end process of myogenesis, for severe muscle injury. AUF1 supplementation significantly prevents muscle atrophy after severe injury while promoting rapid and complete functional muscle regeneration, and reinnervation by coordinating stability and translation of key myogenic mRNAs. In preclinical mouse models of skeletal muscle injury, prophylactic systemic administration of muscle-specific AAV8 AUF1 or intramuscular administration of AAV8 AUF1, as well as LNP AUF1 mRNA 24 hours after injury, were all highly effective in blocking muscle atrophy and accelerating muscle regeneration. Histologic, ultrastructural and biochemical analyses show that AUF1 supplementation strongly reduces muscle atrophy, and accelerates muscle regeneration and re-innervation. Animals receiving AUF1 therapy following muscle injury preserve near-normal muscle strength and function, whereas control animals demonstrate a significant, persistent decline in strength. These findings identify AUF1 therapy as a potential new approach to accelerate muscle recovery and repair, and reduce atrophy following injury.
    DOI:  https://doi.org/10.1016/j.ymthe.2026.02.033
  18. Appl Physiol Nutr Metab. 2026 Feb 27.
    Regulation of PERM1 and select target genes in human skeletal muscle following fasting and exercise.
    Eveline S Menezes, Hashim Islam, Benjamin B Arhen, Zeyu Wu, Lauren J Pacitti, Natalia Lyra E Silva, Alessandra Chiarot, Sean Y Ng, Jennifer Wilkinson, Joshua P Nederveen, Craig A Simpson, Chris McGlory, Fernanda G De Felice, Brendon J Gurd.
       BACKGROUND: PERM1 has been identified as a key regulator of muscle energy metabolism, contractile function, and mitochondrial biogenesis.
    OBJECTIVES: To investigate the impact fasting and acute and chronic high-intensity exercise on p38MAPK, pCaMKII, PGC-1α, ERRα, and PERM1 and on PERM1 target genes (CKMT2, GLUT4, and SIRT3) in human skeletal muscle.
    METHODS: We performed secondary analyses of muscle biopsy samples from two previously published studies, and from one unpublished study. Muscle biopsies were analyzed from the following protocols: 1) nine men pre-, during, and post- an 8 hour fast with or without two hours of arm ergometer exercise; 2) nine men and eight women pre- and 3 hours post- acute high-intensity interval cycling exercise (HIIE); and 3) eleven men and eight women pre- and post- a 6-week period of high-intensity interval training (HIIT) or non-exercise control. We used RT-PCR and western blotting to determine the mRNA and protein levels, respectively. Immunolabelling, microscopy, and subcellular fractionation were also performed to assess PERM1 cellular localization.
    RESULTS: Fasting did not induce detectable changes in the PERM1-related pathways. HIIE significantly increased p-p38MAPK (p<0.05, d=1.27) protein, and PERM1 (p<0.05, d=0.781) and PGC-1α (p<0.05, d=1.51) mRNA. Six weeks of HIIT increased the protein levels of PERM1 isoform 2 (p<0.05, ƞ2=0.168) and CKMT2 (p<0.05, ƞ2=0.226). PERM1 was localized in the perinuclear region and enriched in the mitochondria.
    CONCLUSIONS: Our results suggest that only some components of PERM1-related pathways are preserved in human skeletal muscle, highlighting the importance of future studies examining PERM1 function in humans.
    DOI:  https://doi.org/10.1139/apnm-2025-0401
  19. Sci Adv. 2026 Feb 27. 12(9): eaeb3338
    Ampk alpha2 T172 activation dictates exercise performance and energy transduction in skeletal muscle.
    Ryan N Montalvo, Xiaolu Li, Gina M Many, Tyler J Sagendorf, Qing Yu, Wenqing Shen, Nishikant Wase, A Robert Burgardt, Tong Zhang, Marina A Gritsenko, Matthew J Gaffrey, Hemangi Bhonsle, Yuntian Guan, Xuansong Mao, Mei Zhang, Wei-Jun Qian, Zhen Yan.
      Adenosine 5'-monophosphate-activated protein kinase (AMPK) is an energetic sensor for metabolic regulation and integration. Here, we used CRISPR-Cas9 to generate nonactivatable Ampkα knock-in (KI) mice with mutation of threonine-172 phosphorylation site to alanine (T172A), circumventing the limitations of previous genetic interventions that disrupt the protein stoichiometry. KI mice of Ampkα2, but not Ampkα1, demonstrated phenotypic changes with increased fat-to-lean mass, impaired endurance exercise capacity, and diminished mitochondrial maximal respiration and conductance in skeletal muscle. Integrated temporal multiomics analysis (proteomics/phosphoproteomics/metabolomics) in skeletal muscle at rest and during exercise establishes a pleiotropic yet imperative role of Ampkα2 T172 activation for glycolytic and oxidative metabolism, mitochondrial respiration, and contractile function. There is a substantial overlap of skeletal muscle proteomic changes in Ampkα2 T172A KI mice with that of patients with type 2 diabetes. Our findings suggest that Ampkα2 T172 activation is critical for exercise performance and energy transduction in skeletal muscle and may serve as a therapeutic target for type 2 diabetes.
    DOI:  https://doi.org/10.1126/sciadv.aeb3338
  20. bioRxiv. 2026 Feb 18. pii: 2026.02.16.706166. [Epub ahead of print]
    Macroscopic to Ultrastructural Analyses Identify the Loss of Myofibrils as the Primary Mediator of Muscle Fiber Atrophy in Aging and Disuse.
    Ramy K A Sayed, Anthony N Lange, Hector G Paez, Jamie E Hibbert, Marius Meinhold, Corey G K Flynn, Matilde B Z Vergara, Isabell Dobrzycki, David J Wrucke, Carlos S Zepeda, Jessica J James, Christopher W Sundberg, Troy A Hornberger.
       Background: Aging and disuse are two of the most clinically relevant conditions associated with the loss of skeletal muscle mass, yet the ultrastructural adaptations that drive these losses remain poorly defined. In particular, it is unclear whether radial atrophy of muscle fibers is driven by a reduction in the size of the existing myofibrils, and/or the loss of myofibrils. Accordingly, the objective of this study was to define the macro-to-ultrastructural adaptations that mediate aging- and disuse-induced loss of muscle mass.
    Methods: Skeletal muscle structure was assessed at the macroscopic, microscopic, and ultrastructural levels in humans and mice. In humans, magnetic resonance imaging was used to quantify knee extensor muscle volume and cross-sectional area (CSA) in young (19 - 40 years) and old (65 - 84 years) adults, and vastus lateralis biopsies were analyzed for microscopic and ultrastructural adaptations using immunohistochemistry and fluorescence imaging of myofibrils with image deconvolution (FIM-ID). Parallel studies were performed in young (4 months) and aged (24 months) mice, along with the use of unilateral hindlimb immobilization to model disuse.
    Results: Aging led to a robust loss of skeletal muscle mass that was mediated by coordinated macro-to-ultrastructural adaptations. In humans, aging reduced knee extensor muscle volume (34%, P < 0.005) and CSA (32%, P < 0.001) in a sex-independent manner, and these effects were associated with radial atrophy of SERCA1-positive fibers (23%, P < 0.05). Ultrastructural analyses revealed that the radial atrophy was driven by a reduction in the number of myofibrils per fiber (23%, P < 0.05) without changes in myofibril CSA. In mice, aging produced similar macro-to-ultrastructural adaptations in various flexor muscles; however, radial atrophy of the highly glycolytic/Type IIb fibers, which are not present in human limb muscles, was also associated with a decrease in the CSA of the myofibrils (9%, P < 0.005). We also determined that disuse led to radial atrophy of SERCA1-positive fibers (24%, P < 0.001), and this was mediated by a decrease in both the number (22%, P < 0.005) and size of the myofibrils (4%, P < 0.05). Notably, the results also revealed that the magnitude of the disuse-induced adaptations was significantly blunted with aging.
    Conclusion: This study identifies the loss of myofibrils as a central and conserved mediator of the radial atrophy of muscle fibers that occurs in response to disuse and aging, while also highlighting smaller context-dependent contributions that can arise from changes in myofibril size.
    DOI:  https://doi.org/10.64898/2026.02.16.706166
  21. Mol Metab. 2026 Feb 24. pii: S2212-8778(26)00022-0. [Epub ahead of print] 102338
    Erk3 deletion drives oxidative adaptations in skeletal muscle.
    Angel Loza-Valdes, Carlos Acosta-Gallo, Toufic Kassouf, Andrei Belykh, Małgorzata Stelmach, Dominika Malińska, Katia El Ghoz, Rabih El-Merahbi, Filip Dziaczkowski, Katarzyna Kolczyńska-Matysiak, Grzegorz Sumara.
       BACKGROUND: Skeletal muscle plays a central role in whole-body energy expenditure and metabolic homeostasis, and improving its mitochondrial function and oxidative fiber profile is considered an effective strategy to counteract diet-induced metabolic impairments, although the molecular regulators of these adaptations are not yet fully understood. Erk3 has been implicated in myotube differentiation and in skeletal muscle adaptations to aerobic exercise; however, its potential role in skeletal muscle during diet-induced metabolic dysfunction remains to be determined.
    METHODS: In this study, we used mice with striated muscle-specific Erk3 deletion alongside in vitro cultured myotubes, integrating metabolic phenotyping, indirect calorimetry, multi-omics profiling, and analyses of muscle morphology and fiber-type composition.
    RESULTS: Deletion of Erk3 in striated muscle protected mice from diet-induced obesity, glucose intolerance, and insulin resistance, accompanied by increased energy expenditure and elevated mitochondrial content. In cultured myotubes, silencing Erk3 or its putative interaction partner Mapkapk5 (Mk5) enhanced mitochondrial respiration and mitochondrial abundance, particularly under lipid overload. Global transcriptomic and proteomic analyses in myotubes deficient for either Erk3 or Mk5 revealed largely distinct molecular signatures for both kinases. However, consistent with increased oxidative respiration in the absence of Erk3 or Mk5, markers of oxidative fiber types were elevated while glycolic-fiber-specific proteins were diminished in the absence of one or the other kinase. Consistent with these findings, high-fat diet-fed Erk3-deficient mice showed fewer centrally located nuclei and were protected from the fiber-type remodeling associated with metabolic dysfunction.
    CONCLUSIONS: Our study demonstrates that Erk3 is a key regulator of skeletal muscle oxidative remodeling and metabolic resilience. The deletion of Erk3 in muscles promotes energy expenditure in the myotubes by enhancing mitochondrial function and shifting fiber identity toward oxidative types. Thus, deletion of this kinase protects against high-fat diet-induced obesity, glucose intolerance, and insulin resistance.
    Keywords:  Erk3; Mapkapk5; Mk5; Skeletal muscle; fiber types; obesity; oxidative metabolism
    DOI:  https://doi.org/10.1016/j.molmet.2026.102338
  22. bioRxiv. 2026 Feb 19. pii: 2026.02.18.706475. [Epub ahead of print]
    Activating FGFR1 restores Integrin-β1-mediated fibronectin sensing in satellite cells of aged mice.
    Tze-Ling Chang, Tenaya K Vallery, Thea S Zlatkov, Alicia A Cutler, Jesse V Kurland, Carson H Butcher, Kristi S Anseth, Bradley B Olwin.
      Muscle satellite cells (SCs), essential for skeletal muscle regeneration, decline in number and function with age, contributing to sarcopenia. A fully defined viscoelastic hydrogel that preserves SC-myofiber interactions and supports tunable densities of fibronectin-derived RGD ligands was used to investigate age-related defects in extracellular matrix sensing by SCs. Elevating RGD density increased the number of activating and proliferating SCs on myofibers from young mice, whereas SCs from aged mice were unresponsive. Loss of FGF receptor 1 signaling in SCs from aged mice abrogated the coordinated Syndecan-4 and Integrin-β1 matrix response observed in SCs from young mice. Activating Integrin-β1 promoted asymmetric division and self-renewal in SCs from young mice whereas combined FGFR1 and Integrin-β1 signaling drove symmetric expansion. In SCs from aged mice, FGFR1 dysfunction disrupted this balance, impairing asymmetric division, but constitutive FGFR1 activation restored receptor co-localization, self-renewal, and fibronectin responsiveness. Therefore, FGFR1 integrates matrix and growth factor signals, suggesting that targeting the FGFR1-Integrin-β1 axis may enhance SC regenerative potential in aging organisms.
    DOI:  https://doi.org/10.64898/2026.02.18.706475
  23. Am J Physiol Cell Physiol. 2026 Feb 25.
    Exercise beneficially reshapes fasted rat skeletal muscle involving the combined action of beta-hydroxybutyrate and palmitoleic acid.
    Nicole Alejandra Lara Castillo, Hira Khan, Tiziana Zotti, Gabriella Pinto, Antonia Giacco, Luigi Cerulo, Arianna Cuomo, Gaetano Cardinale, Angela Amoresano, Serena Camerini, Pasquale Vito, Assunta Lombardi, Antonia Lanni, Maria Moreno, Pieter de Lange.
      We previously observed that mild exercise causes structural and functional modifications in fasted skeletal muscle, both in rodents and humans. Wistar rats, housed at thermoneutrality, were submitted to mild exercise during a 66h-period of fasting by five 30-min-treadmill runs at 15 m/min without inclination. To gain deeper insight in the underlying mechanisms/factors we studied alterations in the proteome, lipidome, and cellular signaling/metabolic pathways comparing the combined intervention to each separate intervention. Untargeted proteome analysis of gastrocnemius muscle revealed that exercise with fasting inversely modulated proteome networks involved in the proteasome, cellular respiration and muscle development with respect to fasting alone. Targeted lipidomic analysis revealed palmitoleic acid (P) to be increased by exercise in fasted muscle, an observation that adds to the previously observed increase in muscle beta-hydroxybutyrate (BHB). In muscle L6 myoblasts, cultured under conditions that mimicked fasting, we studied P vs BHB-induced alterations in Akt, AMPK, and mTOR signaling, crucial for glucose metabolism and myogenesis. We observed that P counteracted the repressing effect of BHB in L6 muscle cells on Akt Ser 473 phosphorylation and did not induce AMPK Thr172 phosphorylation, as opposed to BHB. These observations reflect the response to exercise we previously observed in fasting muscle. Both compounds increased sarcolemmal GLUT4 levels. BHB normalized P-induced inhibition of mTOR signaling. Finally, the myogenic factors Myogenin and MyoD expression were inversely regulated by BHB and P. In conclusion, we identify P and BHB as important players in the response to exercise during fasting regarding glucose sensitivity and muscle maintenance.
    Keywords:  beta-hydroxybutyrate; exercise; fasting; muscle; palmitoleic acid
    DOI:  https://doi.org/10.1152/ajpcell.00864.2025
  24. J Cachexia Sarcopenia Muscle. 2026 ;17(2): e70248
    Menopause and Muscle: Closer to Answers, but Significant Questions Remain.
    Stuart M Phillips.
      
    DOI:  https://doi.org/10.1002/jcsm.70248
  25. J Physiol. 2026 Feb 24.
    Intramuscular neutrophil-derived immunometabolic niches locally boost insulin-responsive GLUT4 translocation after muscle contraction.
    Weijian Chen, Makoto Kanzaki.
      Exercise is well known to enhance insulin sensitivity in skeletal muscle, yet the underlying mechanisms remain incompletely understood. We have previously shown that neutrophil recruitment contributes to contraction-induced GLUT4 translocation and local myokine induction, but whether these immune cells also participate in the post-exercise increase in insulin sensitivity has been unclear. Here using GLUT4-EGFP transgenic mice and sciatic nerve-mediated in situ contraction of the hindlimb, with analyses focused on extensor digitorum longus (EDL) muscle, we demonstrate that neutrophil recruitment and subsequent formation of neutrophil extracellular traps (NETs) are crucial for the well-known post-exercise increase in insulin sensitivity. Two-photon imaging revealed that NET-like cell-free DNA (cfDNA) structures persisted for hours after contraction, forming spatially confined perivascular immunometabolic niches along the capillary meshwork. Strikingly insulin-stimulated GLUT4 translocation was preferentially enriched at these NET-rich sites, whereas DNase-mediated NET degradation eliminated cfDNA signals and abolished the contraction-induced enhancement of GLUT4 translocation, glucose uptake and attenuated AS160 (T642) phosphorylation under low-dose insulin. Our findings demonstrate that neutrophils are essential components of the mechanism underlying enhanced post-exercise insulin sensitivity involving, at least in part, the local formation of NETs. These NET-governed immunometabolic niches constitute a structural and spatial framework underlying the exercise-induced acute improvement of insulin-responsive metabolic efficiency in skeletal muscle. KEY POINTS: Neutrophil extracellular traps (NETs) establish spatially confined immunometabolic niches that are indispensable for the post-exercise increase in insulin sensitivity. High-resolution imaging revealed that insulin-stimulated GLUT4 translocation is markedly enhanced predominantly in NET-rich perivascular regions, indicating a spatially restricted mechanism of post-exercise insulin sensitization. DNase-mediated degradation of NETs abolished this enhancement, establishing their essential role in local insulin-responsive GLUT4 translocation. These NETs are formed by neutrophils rapidly recruited to skeletal muscle after contraction and deposited along the capillary network.
    Keywords:  GLUT4; NETs; exercise; immunometabolic niche; insulin sensitivity; neutrophil
    DOI:  https://doi.org/10.1113/JP290203
  26. J Diabetes Investig. 2026 Feb 22.
    The role of CXCL10 in high-fat diet-induced skeletal muscle inflammation and atrophy.
    An Liyuan, Yu Hirata, Tomoya Inoue, Kenji Sugawara, Wataru Ogawa.
       AIMS/INTRODUCTION: Obesity is often accompanied by skeletal muscle atrophy, which aggravates insulin resistance and metabolic dysfunction. Chronic inflammation is implicated in this process, but the molecular mediators linking obesity-induced inflammation to muscle wasting have remained unclear. We investigated the role of the chemokine CXCL10 in skeletal muscle inflammation and atrophy induced by a high-fat diet (HFD).
    MATERIALS AND METHODS: Male C57BL/6J mice were fed an HFD or normal diet for 2 weeks and received either neutralizing antibodies to CXCL10 or control immunoglobulin G. Muscle morphology, macrophage infiltration, and gene expression were examined by histology, immunohistochemistry, reverse transcription-quantitative polymerase chain reaction analysis, and RNA sequencing. Cultured C2C12 myotubes were also treated with recombinant CXCL10 or lipopolysaccharide (LPS), with or without antibodies to CXCL10, for assessment of direct effects on myotube atrophy.
    RESULTS: HFD feeding upregulated Cxcl10 expression in skeletal muscle. It also induced fiber atrophy, macrophage infiltration, and increased expression of individual inflammation- or proteolysis-related genes in muscle, with these effects being attenuated by CXCL10 neutralization. Transcriptomic analysis further revealed a broad reversal of HFD-induced changes in gene expression related to protein catabolism and myofiber structure by anti-CXCL10 administration. Both CXCL10 and LPS reduced myotube diameter and increased expression of catabolism- or inflammation-related genes in cultured C2C12 myotubes, whereas CXCL10 blockade prevented these effects of LPS.
    CONCLUSIONS: CXCL10 mediates HFD-induced skeletal muscle atrophy by promoting inflammation and proteolysis. CXCL10 neutralization mitigates such muscle loss and may represent a novel therapeutic strategy to preserve skeletal muscle mass under metabolic stress.
    Keywords:  CXCL10; Muscle atrophy; Obesity
    DOI:  https://doi.org/10.1111/jdi.70270
  27. J Physiol. 2026 Feb 26.
    Intramuscular pathways of maladaptation in overtraining syndrome.
    Emily Shorter, Oscar Horwath, Sabrina Tzivia Barsky, Ferdinand von Walden, Johanna T Lanner.
      Planned and progressive exercise, that is, exercise training, is essential for promoting skeletal muscle adaptation and improvements in athletic performance. However when the training demands exceed the ability to recover, it may lead to a state of persistent maladaptation. A prolonged imbalance between training or competition and recovery can cause extended periods of performance impairment, known as functional or non-functional overreaching, which may progress to overtraining syndrome (OTS). This condition can significantly impair athletic development and, in severe cases, cause athletes to retire earlier than expected. Skeletal muscle is key for physical performance, including the ability to move and utilise energy. Impaired physical performance is a hallmark of OTS, reflecting the central role of skeletal muscle dysfunction in its development and progression. In this review we discuss the potential mechanisms contributing to skeletal muscle impairments in OTS. These include central and peripheral neural fatigue, endocrine dysregulation and altered hormonal responses, impaired mitochondrial bioenergetics and oxidative stress and systemic inflammation. We also draw parallels between maladaptive response in overreaching and OTS and those typically observed in chronic inflammatory and catabolic conditions, as these may offer insights into underlying mechanistic understanding of OTS, as well as future treatment strategies. Because replicating the full clinical picture of OTS in humans in experimental settings is constrained by practical challenges, we further discuss animal models that may allow for controlled investigations of external variables and thus enable enhanced understanding of its complex pathophysiology.
    Keywords:  maladaptation; overtraining; performance; skeletal muscle
    DOI:  https://doi.org/10.1113/JP287708
  28. Sci Rep. 2026 Feb 25.
    DUSP29 does not regulate melanoma-myoblast interactions in a skeletal muscle co-culture model.
    Sercan Ön, Harika Atmaca İlhan, Damla Günenç, Latife Merve Oktay-Çelebi, Şaziye Burçak Karaca Yayla, Erhan Gökmen.
      Skeletal muscle, despite constituting nearly half of human body mass, is rarely affected by metastatic spread. The biological mechanisms underlying this relative resistance remain poorly understood. Dual-specificity phosphatases (DUSPs) have emerged as important regulators in tumor biology; however, the role of DUSP29 (also known as DUPD1), a phosphatase highly enriched in skeletal muscle, remains uninvestigated in the context of tumor-muscle interactions. We hypothesized that myoblasts may exert tumor-suppressive effects through muscle-specific signaling pathways and that DUSP29 could contribute to this interaction. A co-culture model of murine myoblasts (C2C12) and melanoma cells (B16F10) was established to evaluate tumor-muscle interactions under direct-contact and paracrine conditions. DUSP29 expression in myoblasts was selectively silenced using small interfering RNA (siRNA). Tumor cell responses were assessed by measuring cell viability and apoptosis across multiple co-culture ratios and time points using MTT assays and flow cytometry. Co-culture with myoblasts did not significantly alter melanoma cell viability or apoptosis compared with monoculture controls. Similarly, siRNA-mediated knockdown of DUSP29 in myoblasts did not affect tumor cell viability under co-culture conditions. Transfection reagents and control siRNAs alone showed no cytotoxic effects, confirming that the observed outcomes were not attributable to experimental artifacts. Under the experimental conditions tested, skeletal muscle myoblasts do not exert direct tumor-suppressive effects on melanoma cells, and inhibition of the muscle-enriched phosphatase DUSP29 is insufficient to modify tumor cell behavior. Although negative, these findings provide valuable quantitative insights into tumor-muscle interactions and suggest that skeletal muscle resistance to metastatic colonization is likely mediated by mechanisms beyond direct myoblast-tumor cross-talk or DUSP29-dependent signaling.
    Keywords:  DUSP29; Dual-specificity phosphatases; Melanoma; Muscle cells; Neoplasm metastasis; Skeletal muscle; Tumor microenvironment
    DOI:  https://doi.org/10.1038/s41598-026-41300-0
  29. Acta Physiol (Oxf). 2026 Apr;242(4): e70177
    The Preservation of Muscle Mitochondrial Machinery During Hypometabolic Hibernation in Scandinavian Brown Bears (Ursus arctos).
    Audrey Bergouignan, John Noone, Charlotte Brun, Laura Cussonneau, Alexandre Geffroy, Cecile Coudy-Gandilhon, Isabelle Chery, Alina Lynn Evans, Jon Martin Arnemo, Jonas Kindberg, Guillemette Gauquelin-Koch, Donal O'Gorman, Etienne Lefai, Fabrice Bertile.
       AIM: Unlike humans, brown bears (Ursus arctos) uniquely preserve skeletal muscle mass and function during months of hibernation despite prolonged fasting and inactivity. We investigated how mitochondrial energetics respond in skeletal muscle to support this remarkable resilience.
    METHODS: Muscle biopsies from eight wild brown bears were collected during hibernation and again in the active summer season. We assessed mitochondrial respiration using high-resolution respirometry and evaluated changes in protein expression, enzyme activity, and mitochondrial content through proteomics, Western blotting, enzymatic assays, and DNA quantification.
    RESULTS: Hibernation was associated with lower mitochondrial respiratory capacity, largely due to a reduction in mitochondrial density rather than damage or dysfunction. Despite reduced SDH subunit expression in the whole skeletal muscle, SDH activity remained stable. This likely reflects post-translational regulation and increased, or at least maintained, functional efficiency of the remaining Complex II, allowing mitochondrial respiration to shift toward Complex II-mediated electron entry during hibernation. Proteomic analyses revealed targeted adjustments that maintained energy efficiency, supported both fat and carbohydrate oxidation at low temperatures, and minimized energy loss. Additionally, selective downregulation of mitochondrial dynamic proteins may help protect against muscle degradation.
    CONCLUSION: These findings highlight a temperature-sensitive, multifaceted strategy that preserves mitochondrial energetics during prolonged inactivity, despite reduced mitochondrial density. The selective maintenance of electron flow and fuel flexibility offers novel insights for mitigating muscle wasting in sedentary or immobilized humans.
    Keywords:  bear; electron transport chain; hibernation; mitochondria; muscle physiology; oroboros; proteomics
    DOI:  https://doi.org/10.1111/apha.70177
  30. Cells. 2026 Feb 08. pii: 318. [Epub ahead of print]15(4):
    Decoding the Endocrine Code of Skeletal Muscle: Myokines, Exerkines, and Inter-Organ Crosstalk in Metabolic Health and Disease.
    Young-Sool Hah, Jeongyun Hwang, Seung-Jun Lee, Seung-Jin Kwag.
      Skeletal muscle is increasingly recognized as a dynamic endocrine and paracrine organ that communicates with distal tissues through a diverse secretome of peptides, proteins, metabolites, and extracellular vesicles (EVs), collectively referred to as myokines and exerkines. Beyond cataloging individual factors, emerging evidence suggests that muscle-derived signals can convey information through an integrated, context-dependent "endocrine code"-a pattern defined by secretion kinetics, co-released signal combinations, delivery modalities, and target-tissue receptor landscapes. This review synthesizes current evidence on (i) conceptual and experimental criteria for defining bona fide myokines, (ii) mechanisms governing myokine expression, processing, and release across exercise modes and physiological states, and (iii) major muscle-organ axes that connect physical activity to systemic metabolic homeostasis, immune remodeling, tissue regeneration, and neurocognitive adaptation. We further discuss non-protein mediators such as lactate, succinate, and β-aminoisobutyric acid, and highlight EVs as a multiplexed delivery modality whose interpretation requires stringent isolation, contamination controls, and functional validation. Finally, we evaluate translational opportunities-including biomarker panels, therapeutic targeting of the myostatin/activin, fibroblast growth factor 21 (FGF21), and growth differentiation factor 15 (GDF15) pathways, and precision exercise prescriptions informed by multi-omics and artificial intelligence-while emphasizing analytical standardization, causal validation, and transparent reporting as prerequisites for clinical impact.
    Keywords:  FGF21; GDF15; endocrine organ; exercise; exerkines; extracellular vesicles; insulin resistance; myokines; myostatin; skeletal muscle
    DOI:  https://doi.org/10.3390/cells15040318
  31. PLoS One. 2026 ;21(2): e0328947
    Transcriptomic suppression of immune and ECM stability in skeletal muscle of patients with chronic kidney disease.
    Luke A Baker, Nicholas Eastley, Robert U Ashford, Matthew Denniff, Matthew Graham-Brown, Emma L Watson.
       BACKGROUND: Chronic kidney disease (CKD) is a growing public health emergency with a global prevalence of approximately 14%. Sarcopenia is a common complication of CKD contributing to functional decline and poor outcomes. However, the molecular mechanisms driving muscle wasting in CKD remain incompletely understood. This study aimed to characterise the transcriptomic profile in individuals with CKD compared to healthy control counterparts, to identify key pathways implicated in muscle dysfunction.
    METHODS: Vastus lateralis muscle biopsy samples were obtained from n = 10 people with CKD and n = 9 healthy controls matched for age, sex, ethnicity and physical activity. Bulk RNA sequencing was performed on all samples. Differential gene expression was assessed using DESeq2 and pathway enrichments analyses were conducted using Gene Ontology (GO) and KEGG databases.
    RESULTS: Seventy-six genes were differentially expressed in CKD muscle (FDR < 0.05, |log₂FC| ≥ 1), with 62 downregulated and 14 upregulated. he most consistent signature was suppression of immune-related and extracellular matrix transcripts, including CD163, C1QC, MPEG1, CXCL14, ITIH5, PODN, and CCDC80, suggesting attenuated immune surveillance and reduced ECM stability. In contrast, haemoglobin subunit genes (HBB, HBA1) were upregulated, potentially reflecting compensatory adaptation in oxygen transport. Several genes linked to regenerative processes (e.g., MEGF10, SOX4) were differentially expressed, but canonical myogenic and catabolic regulators remained unchanged, indicating that CKD muscle exists in a transcriptionally blunted state rather than one of overt inflammation or proteolysis.
    CONCLUSIONS: CKD skeletal muscle is characterised by suppression of immune and ECM regulatory programmes, with limited evidence for activation of classical inflammatory or degradative pathways. This distinct transcriptional profile suggests an immunologically and structurally quiescent state that may impair repair capacity and contribute to progressive sarcopenia. These findings refine current understanding of CKD-associated muscle dysfunction and highlight potential targets for mechanistic and therapeutic exploration.
    DOI:  https://doi.org/10.1371/journal.pone.0328947
  32. Arch Biochem Biophys. 2026 Feb 19. pii: S0003-9861(26)00045-7. [Epub ahead of print] 110774
    Advanced glycation end product-its receptor axis participates in myoblast senescence in vitro and delayed muscle regeneration of senescence/aging skeletal muscles in vivo.
    Ding-Cheng Chan, Jia-Hua Jhuang, Fang-Yu Chang, Meei-Ling Sheu, Kuo-Cheng Lan, Shing-Hwa Liu.
      The global population is rapidly aging, leading to a significant increase in age-related diseases in the coming years. Muscle dysfunction is a prevalent chronic condition among older adults, posing significant public health challenges. One of the key age-related changes in muscle tissue is the accumulation of advanced glycation end products (AGEs). Previous studies have reported that AGEs are highly associated with muscle dysfunction, particularly in diabetes. However, the relationship between AGEs and muscle aging still remains to be clarified. This study aimed to investigate the effects of AGEs on muscle repair function and regeneration through cellular and senescence/aging animal models. In cell model, the non-cytotoxic concentrations of AGEs induced cell senescence and inhibited myogenic differentiation in C2C12 myoblasts, as evidenced by senescence-associated β-galactosidase staining and hematoxylin and eosin (H&E) staining. These effects by AGEs could be restored by the treatment of neutralized antibody for receptor for AGEs (RAGE). In a D-galactose-accelerated senescence/aging mouse model, the immunohistochemistry staining showed a substantial AGEs accumulation and RAGE expression in the muscles, which could be reversed by AGEs inhibitor aminoguanidine treatment. In a model of muscle regeneration by glycerol injection in the tibialis anterior muscle, the muscle regeneration/repair capacity was significantly impaired and the Pax7 and MyoD expression was reduced in aging mice, which could also be reversed by aminoguanidine treatment. These findings suggest that AGEs-RAGE axis promote myoblast senescence, inhibit their differentiation, and it may impair muscle repair capacity in aging animals. Further research is needed to elucidate the underlying mechanisms.
    Keywords:  advanced glycation end products; aging mice; muscle regeneration; myoblasts; myogenesis
    DOI:  https://doi.org/10.1016/j.abb.2026.110774
  33. Adv Sci (Weinh). 2026 Feb 26. e15362
    Atrophic Skeletal Muscle-Derived Extracellular Vesicles Transfer miR-125a-5p to Inhibit Bone Formation in Osteoporosis during Aging.
    Xiaoyan Shao, Pan Zhang, Zhidan Fan, Jiaquan Lin, Xiang Chen, Na Liu, Wang Gong, Yi He, Yining Zhou, Tianshu Shi, Yong Shi, Yuze Ma, Wentian Gao, Haosheng Wang, Depeng Fang, Chengzhi Wang, Wenshu Wu, Wenjin Yan, Jianghui Qin, Dongyang Chen, Haiguo Yu, Qing Jiang, Baosheng Guo.
      Understanding how skeletal muscle influences bone formation is essential for uncovering the mechanisms of muscle-bone communication and developing therapies for osteoporosis. Here, we demonstrate that extracellular vesicles (EVs) derived from atrophic skeletal muscle (Aged-SKM-EVs) inhibit bone formation during aging. Utilizing a muscle-specific EV tracking transgenic mouse model, we found that Aged-SKM-EVs were significantly increased and taken up by osteoblasts in bone during aging. Notably, pharmacological blockade of muscle EV generation via a skeletal muscle-targeted delivery of GW4869 significantly restored osteoblast activity and alleviated bone loss in aged mice. Functional studies revealed that Aged-SKM-EVs suppressed bone formation and inhibited osteogenic differentiation both in vivo and in vitro. Mechanistically, we identified miR-125a-5p as a key cargo enriched in EVs from sarcopenic patients and aged mice. Muscle-specific overexpression of miR-125a-5p inhibited osteogenesis and exacerbated muscle atrophy and bone loss, whereas silencing miR-125a-5p in skeletal muscle effectively reversed these effects. Further investigation demonstrated that miR-125a-5p inhibits osteogenic differentiation by directly targeting Sirt7 in preosteoblasts, thereby disrupting SIRT7-mediated histone deacetylation at the Sp7 promoter and suppressing Sp7 transcription. Our findings reveal a novel endocrine pathway from muscle to bone mediated by EV-associated miRNA and highlight miR-125a-5p as a promising therapeutic target for sarcopenia-related osteoporosis.
    Keywords:  MiR‐125a‐5p; bone formation; extracellular vesicles; muscle atrophy; osteoporosis
    DOI:  https://doi.org/10.1002/advs.202515362
  34. Open Med (Wars). 2026 Jan;21(1): 20251311
    Metabolomic profiling of skeletal muscle in GSDMD-knockout mice reveals distinct metabolic alterations in sepsis-induced myopathy.
    Yongsheng Zhang, Qinxin Liu, Ligang Xu, Dongfang Wang, Xiangjun Bai, Zhanfei Li, Yukun Liu, Yuchang Wang.
       Objective: Gasdermin D (GSDMD), a key pyroptosis effector, is implicated in systemic inflammation during sepsis. However, its role in skeletal muscle metabolism remains largely unexplored.
    Methods: GSDMD-knockout (GSDMD-KO) and wild-type (WT) mice were used to establish a septic model. Skeletal muscle samples were collected and subjected to non-targeted metabolomic analysis via UHPLC-QE-MS. Multivariate statistical analysis and KEGG pathway enrichment were performed to identify differential metabolites and explore the underlying metabolic alterations.
    Results: GSDMD knockout resulted in significant changes in skeletal muscle metabolism, notably in pathways related to taurine and hypotaurine metabolism, amino acid biosynthesis, bile acid biosynthesis, oxidative stress response, and nucleotide metabolism. These alterations suggest that GSDMD regulates energy, amino acid, lipid, and redox metabolism during sepsis. A panel of potential biomarkers was identified, which may contribute to muscle injury and repair.
    Conclusions: GSDMD deficiency profoundly alters skeletal muscle metabolic profiles in sepsis. Identified metabolites may serve as diagnostic markers and therapeutic targets for sepsis-associated myopathy, offering insights into GSDMD's role in muscle metabolism and potential intervention strategies.
    Keywords:  GSDMD; metabolomic profiling; pyroptosis; sepsis; sepsis-induced muscle myopathy
    DOI:  https://doi.org/10.1515/med-2025-1311
  35. Front Endocrinol (Lausanne). 2025 ;16 1762825
    Unraveling the metabolic pathways between atherosclerosis and sarcopenia.
    Mei Yu, Lichao Ge, Chen Fu, Rujia Zhao.
      Sarcopenia and atherosclerosis are age-related conditions pathologically intertwined through a self-reinforcing, bidirectional cycle. This review dissects the core mechanistic pillars of this synergy such as insulin resistance, chronic low-grade inflammation, ectopic lipid deposition, and hormonal dysregulation. We detail how skeletal muscle dysfunction exacerbates systemic insulin resistance and inflammatory cascades that accelerate endothelial damage and atherogenesis. Conversely, atherosclerotic vascular impairment compromises microcirculatory function, inducing muscle ischemia and metabolic decline. Beyond pathogenesis, we evaluate integrated intervention, including combined exercise, anti-inflammatory diets, and pleiotropic pharmacotherapies, that concurrently target shared pathways in muscle and vasculature. By framing this comorbidity within the context of aging hallmarks, we advocate a paradigm shift from organ-specific management toward a holistic, geroscience-based approach to mitigate frailty and disability in the aging population.
    Keywords:  aging; atherosclerosis; inflammaging; insulin resistance; sarcopenia
    DOI:  https://doi.org/10.3389/fendo.2025.1762825
  36. NPJ Microgravity. 2026 Feb 21.
    MicroAge mission: experimental design and hardware for a bespoke culture system supporting tissue-engineered skeletal muscle.
    Samantha W Jones, Shahjahan Shigdar, Jonathan Temple, Benjamin Tollitt, Adam Janvier, Fiona Mutter, James R Henstock, Jessica Ohana, David A Turner, Christopher McArdle, Gianluca Neri, William Blackler, Georgi Olentsenko, Kai F Hoettges, Anne McArdle, Malcolm J Jackson.
      Microgravity provides a unique model for accelerated skeletal muscle loss and potentially muscle ageing. During spaceflight, astronauts experience pronounced muscle atrophy, similar to age-related decline on Earth but over a much shorter timescale. Despite daily aerobic and resistance exercise on the International Space Station (ISS), countermeasures remain suboptimal, reflecting similar challenges seen in ageing populations. The MicroAge Mission used microgravity on the ISS to assess whether the molecular mechanisms behind reduced adaptive responses to contractile activity during ageing resemble those triggered by spaceflight. It also tested proof-of-concept genetic interventions, including Heat Shock Protein 10 (HSP10) overexpression, to mitigate muscle atrophy and functional loss. A tissue-engineering approach was used to fabricate human skeletal muscle constructs secured to 3D-printed scaffolds. These scaffolds incorporated microfluidic channels to interface with the flight hardware's fluid-handling system. The hardware, developed by Kayser Space Ltd, was designed to operate with the European Space Agency's (ESA) Kubik incubator on the ISS. This research addresses key methodological constraints in low Earth orbit (LEO) experimentation, outlining pre-flight protocol development, muscle construct biofabrication methods, and operational considerations. The findings provide a translational framework for future studies on musculoskeletal degeneration, with implications for therapies targeting both terrestrial ageing and astronaut musculoskeletal health.
    DOI:  https://doi.org/10.1038/s41526-026-00579-z
  37. bioRxiv. 2026 Feb 18. pii: 2026.02.16.706210. [Epub ahead of print]
    Myosin Filaments of Vertebrate Skeletal and Cardiac Muscle are Highly Similar, but not Identical.
    Pouria Gholami Tilko, Hosna Rastegarpouyani, Behrouz Ghazi Esfahani, Jose Renato Pinto, Kenneth A Taylor.
      Striated muscles consist of two filament types, one composed mostly of actin and the other composed mostly of myosin 1,2 . Actin filaments are highly similar across different muscle types and species both invertebrate and vertebrate 3 . Myosin filaments of vertebrate striated muscle are quite homogeneous in structure having identical lengths, governed by the giant protein titin 4,5 , and rotational symmetries while varying mostly in the isoforms of its proteins. Conversely, myosin filaments from invertebrate striated muscle are highly heterogeneous in multiple ways even within a single organism. Myosin filaments from vertebrate cardiac muscle have been shown to be highly similar in structure between mice and humans 6-8 . Conversely, thick filaments from the highly specialized insect indirect flight muscle have been shown to be highly variable in structure 9-14 . Here we used the drug mavacamten to stabilize a myosin head conformation known as the interacting heads motif in a fast skeletal muscle of rabbits, a highly studied model system. We show that the structure of relaxed rabbit skeletal muscle thick filaments is highly similar to those of relaxed human and mouse cardiac muscle, differing primarily in the positioning of some domains of myosin binding protein C vis-à-vis titin. In the context of the very different structures from indirect flight muscle, the result highlights different solutions to the same problems, control of muscle force and the requirements of endothermy, the internal generation of heat. In mammals, thick filaments are poised for varying levels of myosin activation 15 , while indirect flight muscle is poised for narrowly defined, high frequency contraction. In mammals, endothermy is a continuous problem; in insects, endothermy is primarily necessary for flight 16 .
    DOI:  https://doi.org/10.64898/2026.02.16.706210
  38. Physiol Rep. 2026 Feb;14(4): e70791
    Mitochondrial-derived peptides MOTS-c and humanin attenuate dexamethasone-induced atrophy in human skeletal muscle cells.
    Rabie Elhusseiny, Mohammed Ihsan, Théo Bellefroid, Abdulaziz Farooq, Sébastien Racinais, Louise Deldicque.
      Glucocorticoids, such as dexamethasone (DEXA), are effective therapeutics but cause severe muscle wasting. Mitochondrial-derived peptides (MDPs) are promising countermeasures, but their effectiveness is largely unexplored. We tested the hypothesis that the MDP S14G-humanin (HNG) and the mitochondrial open reading frame of the 12S rRNA-c (MOTS-c) mitigate DEXA-induced atrophy in human skeletal myotubes. Fully differentiated primary human myotubes were exposed to 10 μM DEXA ±10 μM HNG or 10 μM MOTS-c. DEXA decreased myotube size (area, p < 0.001) and differentiation (Fusion Index, p = 0.05). Additionally, DEXA increased both muscle ring finger protein 1 (MURF1, p < 0.001) and muscle atrophy F-box (MAFbx, p = 0.01) as well as peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC1α, p < 0.001). MOTS-c co-treatment with DEXA completely preserved myotube area (p < 0.001) and fusion index (p = 0.02), increased Akt phosphorylation (p = 0.0015) and blunted both MURF1 upregulation (p = 0.03) and STAT3 activation (p = 0.005) compared to DEXA alone. HNG co-treatment with DEXA preserved myotube area (p < 0.001), blunted DEXA-induced STAT3 activation (p = 0.027), but had no effect on fusion index or E3 ligase mRNA levels. Those findings suggest that MOTS-c could be an effective inhibitor of glucocorticoid-induced atrophy in human muscle, not only through selective inhibition of MURF1 but also by enhancing Akt signaling and suppressing STAT3 activation.
    Keywords:  atrogenes; fusion index; glucocorticoid; mitokines; myotubes
    DOI:  https://doi.org/10.14814/phy2.70791
  39. Biomedicines. 2026 Feb 06. pii: 383. [Epub ahead of print]14(2):
    The Muscle Function Deficit Concept and Inflammaging.
    Giada Mariano, Matteo Candeloro, Raffaello Pellegrino, Roberto Paganelli, Angelo Di Iorio.
      Aging-related muscle dysfunction has been conceptualized through the model of sarcopenia, but it embraces several other characteristics, e.g., dynapenia, myosteatosis, and powerpenia. Our perspective reframes muscle aging from a different point of view, the Skeletal Muscle Function Deficit (SMFD), a unifying approach that integrates muscle quality and mass into a single functional definition. An SMFD score has been adopted in the InCHIANTI study against many geriatric outcomes, such as risk of disability, physical performance, hospitalizations and falls, and incidence of major diseases, highlighting its potential value as a primary indicator of muscle failure and/or of healthy aging. At the core of SMFD lies inflammaging, the chronic, low-grade, age-related inflammation, linking functional outcomes to muscular and neural aging. Inflammatory mediators alter the anabolic/catabolic balance, accelerate myosteatosis, impair neuromuscular junction, and influence denervation. These findings support the idea of a common pathway that links neuro-muscular deficit and inflammation, which simultaneously targets cortical motor circuits, spinal motor neurons, peripheral nerves, and muscle fibers. The SMFD approach facilitates early detection, risk stratification, and possible intervention for muscle deterioration with aging.
    Keywords:  inflammaging; sarcopenia; skeletal muscle function deficit
    DOI:  https://doi.org/10.3390/biomedicines14020383
  40. medRxiv. 2026 Feb 12. pii: 2026.02.09.26345899. [Epub ahead of print]
    Circulating Senescence Protein Links Exercise Adaptation to Health Outcomes.
    Nicholas Houstis, Qiulian Zhou, Yuling Chen, Sonja Mittag, Vinita Chowdhury, Chao Wu, Meixi Quan, Azrul Kadir, Giulia Guerra, Sashi Weerawarana, Danielle Szczesniak, Justin Guerra, James Rhee, J Sawalla Guseh, Haobo Li, Bo Li, Aurel B Leuchtmann, Jorge Ruas, Ulrik Wisloff, Dorthe Stensvold, Anthony Rosenzweig.
      Adaptation to physiological stress is fundamental to health but varies widely among individuals. In humans, this heterogeneity is evident in markedly different gains in fitness in response to identical exercise training. The molecular determinants of this variable "trainability" remain poorly understood. Here we identify insulin-like growth factor binding protein-7 (IGFBP7), a senescence-associated secreted protein, as a circulating constraint on exercise adaptation. Plasma proteomics in older adults enrolled in a randomized exercise trial revealed that IGFBP7 levels inversely predicted fitness gains after one year of high-intensity interval training despite similar baseline fitness. In mice, genetic deletion of IGFBP7 markedly amplified training-induced gains in exercise capacity across distinct training protocols, whereas somatic overexpression abolished this advantage. In the UK Biobank, lower IGFBP7 levels were associated with reduced mortality and multiple incident age-related diseases, mirroring the breadth of ties between fitness and healthspan. Together, these findings identify circulating IGFBP7 as a molecular brake on physiological plasticity in response to exercise, linking training responsiveness, aging biology, and health outcomes.
    DOI:  https://doi.org/10.64898/2026.02.09.26345899
  41. JBMR Plus. 2026 Mar;10(3): ziag018
    Ribosome heterogeneity and specialization in musculoskeletal physiology and pathology.
    Alzbeta Chabronova, Guus G H van den Akker, Tim J M Welting, Mandy J Peffers.
      Musculoskeletal (MSK) tissues are highly dynamic systems that rely on tightly regulated protein synthesis to maintain homeostasis and structural integrity, adapt to physiological stimuli, and respond to injury. The deregulation of protein synthesis is implicated in a wide range of MSK pathologies. At the core of protein synthesis are ribosomes, complex molecular nanomachines that translate mRNAs and generate proteins. Once considered uniform entities passively exerting their function, ribosomes are now recognized to be heterogeneous in their composition and capable of specialized functions. These emerging concepts of ribosome heterogeneity and specialization are increasingly recognized as key regulators of physiological and pathological cellular processes across fields. Although the MSK field has yet to fully embrace and integrate ribosome-centered research, accumulating evidence suggests that ribosome heterogeneity and specialization might have profound implications for MSK (patho)biology. In this review, we summarize the emerging data across MSK tissues (bone, skeletal muscle, articular cartilage, tendons, and ligaments), highlighting the roles of ribosomes in supporting development, maintaining homeostasis, and facilitating cellular and tissue functions and adaptations, but also driving pathological changes and disease progression. Furthermore, we also outline recent key technological and methodological advances that are critical for uncovering the full scope, significance, and dynamic regulation of ribosome heterogeneity and specialization in MSK (patho)biology. As the field moves forward, ribosome-centered research holds great promise in revealing new mechanisms underlying MSK biology and identifying novel therapeutic targets.
    Keywords:  2′-O-methylation; protein synthesis; pseudouridylation; ribosomal RNA; ribosomal proteins; ribosome heterogeneity; ribosome specialization; ribosome-associated proteins; snoRNAs; translation regulation
    DOI:  https://doi.org/10.1093/jbmrpl/ziag018
  42. Nat Commun. 2026 Feb 25. pii: 1656. [Epub ahead of print]17(1):
    A ketogenic diet enhances aerobic exercise adaptation and promotes muscle mitochondrial remodeling in hyperglycemic male mice.
    Pattarawan Pattamaprapanont, Roberto C Nava, Rea Grover, Mia Formato, Eileen M Cooney, Ana Paula Pinto, Ana B Alves-Wagner, Anamica Das, Yuntian Guan, Meghana Annambhotla, Saanvi Acharya, Donato A Rivas, Sarah J Lessard.
      VO2peak is a key health benefit of aerobic exercise; however, chronic hyperglycemia is associated with persistently low VO2peak due to an impaired adaptive response to training. Here, we show that reducing blood glucose with a carbohydrate-restricted, high fat ketogenic diet can restore aerobic exercise adaptation in male mice with hyperglycemia. Hyperglycemic mice received standard high-carbohydrate chow (CHOW), which sustains high blood glucose; or a ketogenic diet (KETO), which normalizes blood glucose levels. After aerobic exercise training, improvements in VO2peak are blunted in CHOW, but restored by KETO. Increased VO2peak in KETO is associated with enhanced aerobic remodeling of skeletal muscle, including a more oxidative fiber-type and increased capillary density. Moreover, KETO induces exercise-independent effects on muscle mitochondrial remodeling and substrate selection, significantly increasing fatty acid oxidation and down-regulating glucose metabolism. We identify a ketogenic diet as a potential therapy to improve aerobic exercise adaptation in the growing population with hyperglycemia.
    DOI:  https://doi.org/10.1038/s41467-026-69349-5
  43. bioRxiv. 2026 Feb 14. pii: 2026.02.11.704964. [Epub ahead of print]
    NRMLncR, a myocyte-enriched long non-coding RNA, enhances myogenesis in mouse.
    Yufen Li, Yumei Zhou, Qing Ying Li, Justine Arrington, Mostafa F Abdelhai, Yubo Wang, Junxiao Ren, Yung-Yu Cheng, Mingyi Xie, W Andy Tao, Shihuan Kuang, Feng Yue.
      Myogenesis is a stepwise process encompassing myogenic progenitor proliferation, lineage commitment, differentiation, myocyte fusion, and myotube maturation, and it is orchestrated by myogenic regulatory factors (MRFs) together with signaling pathways that coordinate these transitions. Long noncoding RNAs (lncRNAs) have emerged as important regulators of muscle development and regeneration, yet how lncRNAs integrate with canonical signaling networks to shape myogenic progression remains incompletely defined. Here, we identify a novel myocyte-enriched, Notch-repressed myogenic lncRNA ( NRMLncR, known as A930003A15Rik ), as a previously uncharacterized regulator of mouse myogenesis. The expression of NRMLncR is robustly induced during primary myoblast activation and differentiation. Loss-of-function analyses show that knockdown of NRMLncR impairs myogenic differentiation, accompanied by reduced expression of key myogenic genes. In contrast, adenovirus-mediated overexpression of NRMLncR enhances myogenic differentiation in vitro and is associated with increased muscle fiber size in vivo . Mechanistically, MyoD and MyoG occupy the NRMLncR promoter and promote its transcription during myogenic differentiation. NRMLncR knockdown alerts the transcription of nearby genes, suggesting its function through a cis-regulatory mechanism. RNA pull-down assays further identify an interaction between NRMLncR and the RNA-binding protein CELF1. Together, these findings establish NRMLncR as a novel Notch-associated lncRNA that promotes myogenic differentiation and provide insight into lncRNA-dependent regulation of the myogenic program.
    DOI:  https://doi.org/10.64898/2026.02.11.704964
  44. Front Mol Biosci. 2026 ;13 1694362
    Single-cell RNA sequencing and integrated bioinformatics reveal new mitochondrial biomarkers in sarcopenia.
    Hongan Ying, Wenhan Wang, Lili Huang, Weiwen Hong, Lingchang Yang.
       Background: Sarcopenia, characterized by age-related skeletal muscle loss and dysfunction, affects approximately 10% of adults over 60 years worldwide. Current diagnostic methods often detect sarcopenia only after substantial muscle deterioration has occurred, highlighting the critical need for early diagnostic biomarkers.
    Methods: We conducted an integrated analysis of several public transcriptomic datasets (GSE1428, GSE117525, GSE167186, GSE111006, GSE111010, and GSE111016) employing differential gene expression analysis, weighted gene co-expression network analysis, and machine learning techniques. Single-cell RNA sequencing (scRNA-seq) was employed to determine cell type-specific expression. Quantitative PCR validated the findings in C2C12 myoblasts cultured under sarcopenia-like conditions. A nomogram-based predictive model was developed and assessed through ROC analysis and decision curve analysis.
    Results: We discovered a conserved three-gene mitochondrial signature (CHCHD10, SAMM50, MDH2) significantly dysregulated across multiple independent cohorts. Single-cell RNA sequencing identified distinct expression patterns across cell types, highlighting significant mitochondrial changes in myocytes. A nomogram model integrating these three genes demonstrated superior diagnostic accuracy (AUC = 0.883, 95% CI: 0.732-1.000) compared to conventional clinical parameters. In vitro validation confirmed significant downregulation of all three biomarkers in a sarcopenia-like state (CHCHD10, p < 0.01; SAMM50, p < 0.05; MDH2, p < 0.01).
    Conclusion: Our findings suggest that a three-gene mitochondrial signature, comprising CHCHD10, SAMM50, and MDH2, could serve as a valuable biomarker for early sarcopenia diagnosis. This signature underscoring the contribution of mitochondrial dysfunction to muscle aging. By potentially bridging basic research with clinical application, this panel may offer novel targets for developing mitochondria-targeted therapies and monitoring their efficacy.
    Keywords:  biomarkers; diagnosis; mitochondrial dysfunction; sarcopenia; single-cell RNA sequencing
    DOI:  https://doi.org/10.3389/fmolb.2026.1694362
  45. J Nutr Health Aging. 2026 Feb 21. pii: S1279-7707(26)00039-4. [Epub ahead of print]30(4): 100808
    Resistance training partially restores age-related differences in skeletal muscle amino acid transporters - secondary analysis from two randomized controlled trials.
    E Lander, H Hamarsland, M J Lees, D Moore, T Raastad.
       OBJECTIVE: Postprandial stimulation of muscle protein synthesis depends on intracellular amino acid (AA) availability and effective transmembrane AA transporters (AATs). AA transport may be impaired in sedentary and older adults. We compared skeletal muscle AATs between young and older adults and examined effects of resistance training combined with increased protein intake.
    DESIGN: Secondary analysis from two randomized controlled trials SETTING: Participants were enrolled in trials comparing milk and native whey effects on anabolic signaling, muscle mass, and strength.
    PARTICIPANTS: Healthy young (n = 32; 14♀/18♂, 20-45 yrs) and older (n = 28; ♀/17♂, 70-80 yrs) adults INTERVENTION: Whole-body progressive resistance training 3×/week for 11-12 weeks with protein supplementation.
    MEASUREMENTS: Pre- and post-intervention assessments included lean leg mass (LLM), one-repetition maximum (1RM) leg press, and AAT protein levels in m. vastus lateralis biopsies. Western blots quantified L-Type Amino Acid Transporter 1 (LAT1) and 3 (LAT3), 4 F2 heavy chain (CD98) and solute carrier 38 member 9 (SNAT9) in cytosol (C), membrane (M) and nuclear (N) fractions. LAT1 membrane (IF-M) and intracellular (IF-IC) distribution were assessed by immunofluorescence.
    RESULTS: Training increased LLM by ∼1 kg and 1RM leg press by ∼31% in both groups (p < 0.001). At baseline, older adults showed higher SNAT9M and IF-M LAT1 and lower LAT1C versus young (p < 0.05). Training produced age-dependent changes: LAT3C increased in young (p = 0.39) and CD98M increased in old (p = 0.26) yielding significant time × age interactions (p < 0.05). Across groups, training reduced LAT1 intensity and SNAT9M and increased CD98N (p < 0.01-05). In young participants, IF-IC LAT1 decreased 9 ± 14% (p < 0.05) and CD98N increased 59 ± 97%(p < 0.01). Posttraining, older adults displayed higher IF-M LAT1 and lower CD98M than young (p < 0.05).
    CONCLUSION: Resistance training with protein supplementation improved muscle mass and strength and modified AAT profiles. Age was associated with higher membrane LAT1 and SNAT9, while training attenuated some age-related differences and produced distinct effects on LAT3 and CD98 by age. Exercise may partially counteract age-related alterations in muscle AA transport, with implications for muscle health in aging.
    Keywords:  Aging; Amino acid transporters; Anabolic resistance; Muscle biopsy; Resistance training
    DOI:  https://doi.org/10.1016/j.jnha.2026.100808
  46. Cancers (Basel). 2026 Feb 09. pii: 557. [Epub ahead of print]18(4):
    NF-κB Signaling as a Central Driver of Cancer Cachexia.
    Yan Li, Hao Jiang, Rui Chen, Haitao Huang, Shengguang Ding.
      Cancer cachexia is a multifactorial metabolic syndrome characterized by progressive skeletal muscle wasting, chronic systemic inflammation, and profound metabolic imbalance. Sustained activation of the nuclear factor κB (NF-κB) signaling pathway lies at the core of its pathogenesis, driving muscle proteolysis, impairing regenerative capacity, disrupting adipose tissue homeostasis, and promoting insulin resistance and anorexia. By transcriptionally regulating catabolic and pro-inflammatory gene programs across skeletal muscle, adipose tissue, the liver, and the central nervous system, NF-κB establishes a self-amplifying inflammatory-metabolic loop that perpetuates tissue wasting and systemic dysfunction. Accumulating preclinical and clinical evidence identifies NF-κB as a viable therapeutic target in cancer cachexia. Pharmacologic inhibitors (e.g., SR12343, DHMEQ), anti-inflammatory strategies (e.g., nonsteroidal anti-inflammatory drugs and IL-6 receptor-targeting antibodies), and nutritional interventions (e.g., omega-3 fatty acids) have shown efficacy in attenuating cachexia-associated inflammation, metabolic dysregulation, and tissue loss. Notably, emerging multimodal approaches integrating NF-κB modulation with metabolic support, chemotherapy, and behavioral interventions demonstrate synergistic benefits. This review integrates current mechanistic insights and therapeutic advances, highlighting NF-κB as a central pathogenic axis and a compelling target for translational intervention in cancer cachexia.
    Keywords:  NF-κB signaling; adipose tissue remodeling; cancer cachexia; muscle wasting; systemic inflammation; therapeutic targeting
    DOI:  https://doi.org/10.3390/cancers18040557
  47. Am J Hum Genet. 2026 Feb 20. pii: S0002-9297(26)00060-1. [Epub ahead of print]
    Enhanced muscle uptake of chemically optimized miR-23b antisense oligonucleotides as lead compounds for myotonic dystrophy type 1.
    Irene González-Martínez, Estefanía Cerro-Herreros, Marc Carrascosa-Sàez, Andrea García-Rey, Diego Piqueras-Losilla, Anna Colom-Rodrigo, Nerea Moreno, Mouli Chakraborty, Aline Huguet-Lachon, Anchel González-Barriga, Neia Naldaiz-Gastesi, Martxel Dehesa, Ana Díaz-Maqueda, Nuria Barquero, Miguel A Varela, Adolfo López de Munain, Ramon Eritja, Geneviève Gourdon, Arturo López-Castel, Manuel Pérez-Alonso, Beatriz Llamusi, Rubén Artero.
      Myotonic dystrophy type 1 (DM1) is a multisystemic disorder caused by CTG repeat expansions in DM1 protein kinase (DMPK). Mutant transcripts containing expanded CUG repeats form ribonuclear foci that sequester muscleblind-like (MBNL) splicing regulator proteins, key regulators of RNA splicing and metabolism. This functional depletion leads to widespread mis-splicing and persistence of fetal transcript profiles, which underlie muscle weakness, myotonia, and muscle atrophy. In addition, miR-23b is upregulated in DM1 muscle and further represses MBNL1 translation, amplifying molecular defects. We developed chemically optimized microRNA (miRNA)-targeting antisense oligonucleotides (antimiRs) to inhibit miR-23b and restore functional MBNL1 levels. Using a multi-step screening process, we evaluated antimiRs with varying sequences, lengths, chemical modifications, and lipid conjugations. A key optimization was a 3'-oleic acid conjugation combined with specific chemical modifications, which enhanced muscle uptake and efficacy. Lead candidates showed strong activity in preclinical models (human skeletal actin [HSA]LR and DMSXL mice and human myoblasts), increasing MBNL1 levels, correcting mis-splicing, improving muscle strength, and reducing myotonia. They also exhibited efficient biodistribution to skeletal muscle, a critical DM1-affected tissue. In vitro toxicology indicated a favorable safety profile with minimal immune or renal toxicity. The antimiR mechanism was conserved in rat and pig fibroblasts. Overall, two lead antimiRs emerged as promising therapeutic candidates for DM1, with improved pharmacokinetics, tissue targeting, and safety, supporting the potential of microRNA-based approaches to correct key molecular defects in this disorder.
    Keywords:  MBNL; antisense oligonucleotides; muscle uptake; myotonic dystrophy; oleic acid conjugate
    DOI:  https://doi.org/10.1016/j.ajhg.2026.01.016
  48. Ageing Res Rev. 2026 Feb 19. pii: S1568-1637(26)00057-7. [Epub ahead of print] 103065
    Age-related sarcopenia and the gut microbiome: mechanistic insights into the gut-muscle axis and potential microbiome based therapeutic interventions.
    Sophie L Allen, Leigh Breen, Janet M Lord, Niharika A Duggal.
      Ageing is associated with a loss of skeletal muscle mass, strength and function, termed sarcopenia. The presence of sarcopenia is known to be problematic leading to an increased risk of falls, fractures and mortality. Age-related changes in the gut microbiome, characterized by reduced diversity and altered metabolite production, may compromise intestinal barrier function, leading to increased permeability. These age-associated changes in the gut microbiome led to changes in circulating microbial metabolites and toxins, such as a decrease in short-chain fatty acids, an increase in lipopolysaccharides and an imbalance in bile acid production. Together these alterations may contribute to the development of sarcopenia through impairments in muscle protein turnover. Currently, lifestyle-based approaches e.g., exercise and diet, alongside the use of pre-, pro- and post-biotics have been proposed as strategies to target the gut-muscle axis and combat the risk of sarcopenia in the expanding ageing population. However, little evidence is available to support their use within clinical settings. Several new strategies including the nutraceutical Urolithin A and faecal microbiome transplants (FMT) have been suggested to treat age-related sarcopenia. This review provides insight into the potential interactions of the gut microbiome and skeletal muscle with ageing and sarcopenia development, alongside potential new and existing countermeasures.
    Keywords:  bile acids; gut-muscle axis; microbiome; muscle; short chain fatty acids
    DOI:  https://doi.org/10.1016/j.arr.2026.103065
  49. Am J Physiol Cell Physiol. 2026 Feb 21.
    High Fat Diet and Obesity Each Increase Tumor Cell Proliferation and Muscle Wasting in Experimental Cancer Cachexia.
    Brittany R Counts, Andrea Bonetto, Ho Lam Chan, Ernie D Au, Yanlin Jiang, Marion E Couch, Denis C Guttridge, Michael C Ostrowski, Leonidas G Koniaris, Teresa A Zimmers.
      High fat diet (HFD) and associated obesity are suggested to predispose to cancer development, complicate cancer treatment, and accelerate mortality. Paradoxically, obese patients with lung cancer are reported to live longer, suggesting that high body mass is protective. Given that cachexia-tumor-induced weight loss with adipose and muscle wasting-is prevalent in lung cancer, we speculated that obese patients might survive longer due to the protective effect of larger tissue reservoirs, slowing time to fatal wasting. Thus, we modeled this condition using lean and high fat diet (HFD)-induced obese mice with Lewis lung carcinoma (LLC) tumors versus non-tumor bearing controls. We also assessed the effects of feeding HFD to lean mice with and without LLC tumors. HFD and obese-HFD without tumors gained weight over the study, with obese HFD mice exhibiting low muscle mass with obesity at endpoint. Low fat diet (LFD)-fed lean mice with LLC tumors (LFD-LLC) showed no change in total body weight, but exhibited reduced skeletal muscle, heart, and fat pad mass along with hepatosplenomegaly at endpoint. HFD and pre-existing obesity both modified the response to Lewis lung carcinoma (LLC) tumors. HFD did not affect tumor-induced weight loss, fat loss, or tumor burden, but worsened loss of gastrocnemius, tibialis anterior, and heart muscle, prevented hepatosplenomegaly, and enhanced tumor cell proliferation and expression of the cachexia-inducing cytokine, Interleukin-6 (IL-6). Obese-HFD mice showed greater tumor burden versus LFD and the worst cachexia phenotypes, including greater weight loss and muscle loss than HFD or LFD. This worsened cachexia was associated with increased blood-born inflammatory cytokines, increased phosphorylated STAT3 in muscle, and increased IL-6 expression in muscle, spleen, and tumor. Obese-HFD was associated with the highest rate of tumor cell proliferation in vivo and serum from obese HFD mice increased LLC cell proliferation in vitro. Thus, HFD and pre-existing obesity each separately enhance inflammation, cachexia, and tumor growth. These distinct contributions of HFD and chronic adiposity are potential therapeutic targets to slow cachexia and tumor growth in cancer.
    Keywords:  Interleukin-6; cancer cachexia; high fat diet; obesity; skeletal muscle
    DOI:  https://doi.org/10.1152/ajpcell.00545.2025
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