bims-moremu Biomed News
on Molecular regulators of muscle mass
Issue of 2025–10–05
39 papers selected by
Anna Vainshtein, Craft Science Inc.
  1. Atlas of Lysosomal Aging Reveals a Molecular Clock of Storage Disorder-Associated Metabolites.
  2. In Vivo Electroporation of Plasmid DNA into the Skeletal Muscle of Dystrophic Mouse Models.
  3. In-vitro human myogenesis model reveals novel mRNA alternative splicing isoforms.
  4. Ampk alpha2 T172 Activation Dictates Exercise Performance and Energy Transduction in Skeletal Muscle.
  5. Synergistic muscle activation impacts muscle spindles projecting to mouse trigeminal mesencephalic nucleus.
  6. CSE/H2S/SESN2 Signalling Mediates the Protective Effect of Exercise Against Immobilization-Induced Muscle Atrophy in Mice.
  7. Miro1 Mediates Skeletal Muscle Insulin Resistance in Type 2 Diabetes.
  8. Analysis of Dystrophin-Associated Glycoproteins: Focus on Expression and Glycosylation of Dystroglycan in Skeletal Muscle.
  9. ATP1B4 as a candidate upstream regulator of muscle atrophy in diabetic sarcopenia via PI3K/AKT/mTOR-mediated autophagy.
  10. Immunoproteasome Inhibition Positively Impacts the Gut-Muscle Axis in Duchenne Muscular Dystrophy.
  11. Lipidomic Sample Preparation to Detect Phosphatidylcholine Alterations in Skeletal Muscle.
  12. MiR-126-5p Derived From Bone Marrow Mesenchymal Stem Cell Exosomes Promotes Skeletal Muscle Regeneration by Regulating FBXO32/MyoD Signaling.
  13. Proteomic profiling of the extracellular matrix in skeletal muscle.
  14. Development of Electric Field Stimulation (EFS)-Mediated Skeletal Muscle Training with iPSCs.
  15. The central clock drives metabolic rhythms in muscle stem cells.
  16. Cachexia progression differs among mouse models of metastatic triple-negative breast cancer.
  17. Muscular USP2 is dispensable for MASLD-associated disorders in the liver and skeletal muscle in mice.
  18. Multidimensional Modeling to Maximize Adaptations to eXercise: The M3AX Trial Rationale and Study Design.
  19. Temporal dynamics and functional implications of MiRNAs in denervation-induced skeletal muscle atrophy.
  20. Spatiotemporal analysis of dystrophin expression during muscle repair.
  21. Isolation of Immune Cells from Skeletal Muscles for Flow Cytometry.
  22. Stage-specific and cell-autonomous functions of Delta-like 1 in skeletal muscle stem cells and myogenesis.
  23. Effects of habitual endurance and resistance exercise on insulin action in primary human skeletal muscle stem cells.
  24. Reduced Muscle Force in Dystrophic DMDΔ52 Pigs Is Incompletely Restored by Systemic Transcript Reframing (DMDΔ51-52).
  25. α-Parvin Promotes Glucose Uptake and Metabolism in Skeletal Muscle with Minimal Influence on Hepatic Insulin Sensitivity.
  26. Sex-specific protective effects of angiotensin II type 1 receptor knockdown on disuse muscle atrophy in the rat soleus muscle.
  27. Impacts of sarcopenia and resistance exercise training on mitochondrial quality control proteins.
  28. Effects of low-intensity pulsed ultrasound on muscle mass and Fndc5 mRNA expression in aged male mice.
  29. Targeting IL-6/STAT3 signaling to mitigate sarcopenia: Insights from immuno-metabolic crosstalk in NSCLC.
  30. Muscle-derived miR-126 regulates TDP-43 axonal local synthesis and NMJ integrity in ALS models.
  31. Activin receptor type IIA/IIB blockade increases muscle mass and strength, but compromises glycemic control in mice.
  32. Impaired myogenesis in limb girdle muscular dystrophy type 2B.
  33. Regulation of NSL by TAF4A is critical for genome stability and quiescence of muscle stem cells.
  34. Isolation and Culture of Primary Myoblasts from Humans and Mice.
  35. Muscle homing peptide modified liposomes loaded with EGCG improved skeletal muscle dysfunction by inhibiting inflammation in aging mice.
  36. Breast cancer cell-conditioned media inhibit growth and reduce basal and insulin-stimulated glucose uptake by inhibiting Rac1 activation in rat myotubes.
  37. Increased Skeletal Muscle Oxidative Capacity Augments the Myokine Response to Whole Body Vibration.
  38. GLP-1 receptor agonists and sarcopenia: Weight loss at a cost? A brief narrative review.
  39. Effects of inhibition of Janus kinase signalling during controlled mechanical ventilation on the rate of skeletal muscle protein synthesis.
  1. bioRxiv. 2025 Sep 26. pii: 2025.09.25.678303. [Epub ahead of print]
    Atlas of Lysosomal Aging Reveals a Molecular Clock of Storage Disorder-Associated Metabolites.
    Anna M Puszynska, Thao P Nguyen, Andrew L Cangelosi, Andrea Armani, Justin M Roberts, Kristin A Singh, James C Cameron, Tenzin Tseyang, Grace Y Liu, Steven Lai, Hans-Georg Sprenger, Jason Yang, William N Colgan, Jibril F Kedir, Kathrin M Kajderowicz, Theodore K Esantsi, Yuancheng Ryan Lu, Millenia Waite, Tenzin Kunchok, Caroline A Lewis, Fabian Schulte, George W Bell, David M Sabatini, Jonathan S Weissman.
      Lysosomal dysfunction is a well-recognized feature of aging, yet its systematic molecular investigation remains limited. Here, we employ a suite of tools for rapid lysosomal isolation to construct a multi-tissue atlas of the metabolite changes that murine lysosomes undergo during aging. Aged lysosomes in brain, heart, muscle and adipose accumulate glycerophosphodiesters and cystine, metabolites that are causally linked to juvenile lysosomal storage disorders like Batten disease. Levels of these metabolites increase linearly with age, preceding organismal decline. Caloric restriction, a lifespan-extending intervention, mitigates these changes in the heart but not the brain. Our findings link lysosomal storage disorders to aging-related dysfunction, uncover a metabolic lysosomal "aging clock," and open avenues for the mechanistic investigation of how lysosomal functions deteriorate during aging and in age-associated diseases.
    One-Sentence Summary: Aging in mice is tracked by a lysosomal "clock", where glycerophosphodiesters and cystine - metabolites causally linked to juvenile lysosomal storage disorders - gradually accumulate in lysosomes of the brain, heart, skeletal muscle and adipose tissue.
    DOI:  https://doi.org/10.1101/2025.09.25.678303
  2. Methods Mol Biol. 2026 ;2975 239-249
    In Vivo Electroporation of Plasmid DNA into the Skeletal Muscle of Dystrophic Mouse Models.
    Miguel A Lopez Perez, Gianni N Giarrano, Noah L Weisleder.
      Gene transfer into living, adult skeletal muscle in experimental animals is a powerful tool for investigating the fundamental molecular mechanisms of neuromuscular disease progression. This methodology has been leveraged in the development of potential therapeutics for Duchenne muscular dystrophy (DMD), limb girdle muscular dystrophies (LGMD), and other skeletal muscle maladies. There are several modalities for gene transfer into skeletal muscle, including the use of viral vectors, nucleic acid encapsulation, and the development of transgenic mouse models. However, there are distinct advantages to the use of electroporation to deliver plasmid DNA in the preclinical setting. Electroporation applies an electric current to biological tissues that produce small, transient pores in the plasma membrane of cells. At high concentrations, plasmid DNA or other nucleic acid constructs can enter through these membrane disruptions and become enclosed within the cell after membrane resealing. This allows for rapid modification of gene expression or gene editing in target cells. Thus, electroporation represents a tractable and efficient method for tissue-specific gene delivery into the muscles of many mouse models, including those for DMD and other muscular dystrophies. In the specific approach detailed here, transdermal electric pulses applied to the hindlimb permeabilize the sarcolemmal membrane in vivo, allowing for plasmid DNA transfection of adult myofibers in dystrophic mice. We delineate the methodology for in vivo electroporation of the flexor digitorum brevis muscle for efficient plasmid gene transfer in dystrophic and wild-type mouse models.
    Keywords:  Electroporation; Electrotransfer; Gene delivery; Gene transfer; In vivo transfection; Muscular dystrophy; Plasmid DNA; Transdermal
    DOI:  https://doi.org/10.1007/978-1-0716-4811-7_15
  3. Sci Rep. 2025 Oct 01. 15(1): 34273
    In-vitro human myogenesis model reveals novel mRNA alternative splicing isoforms.
    Stefano Donega, Nirad Banskota, Jen-Hao Yang, Martina Rossi, Yulan Piao, Dimitrios Tsitsipatis, Jinshui Fan, Supriyo De, Charlotte A Peterson, Mary M McDermott, Myriam Gorospe, Luigi Ferrucci.
      
    Keywords:  AI-neural network; In-vitro muscle model; Myogenesis; Splicing; mRNA
    DOI:  https://doi.org/10.1038/s41598-025-16523-2
  4. bioRxiv. 2025 Sep 22. pii: 2025.09.22.677805. [Epub ahead of print]
    Ampk alpha2 T172 Activation Dictates Exercise Performance and Energy Transduction in Skeletal Muscle.
    Ryan N Montalvo, Xiaolu Li, Gina Many, Tyler J Sagendorf, Qing Yu, Wenqing Shen, Nishikant Wase, A Robert Burgardt, Marina A Gritsenko, Matthew J Gaffrey, A Hemangi Bhonsle, Yuntian Guan, Xuansong Mao, Mei Zhang, Wei-Jun Qian, Zhen Yan.
      AMPK (5'-AMP-activated protein kinase) is an energetic sensor for metabolic regulation and integration. Here, we employed CRISPR/Cas9 to generate non-activatable Ampkα knock-in (KI) mice with mutation of threonine 172 phosphorylation site to alanine, 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 multi-omic 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. Importantly, there is a significant overlap of skeletal muscle proteomic changes in Ampkα2 T172A KI mice with that of type 2 diabetic patients. 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/10.1101/2025.09.22.677805
  5. J Neurophysiol. 2025 Oct 03.
    Synergistic muscle activation impacts muscle spindles projecting to mouse trigeminal mesencephalic nucleus.
    Evrim O Yılmaz, Bernhard Englitz, Can A Yucesoy.
      Muscle spindles (MSs) are essential for conveying sensory information about changes in muscle fiber lengths. Epimuscular myofascial force transmission (EMFT) occurs through mechanical connections between muscular and connective tissues and yields strain variability along muscle fibers. As those connective tissues also surround the MSs, EMFT effects imply a direct interaction of motor action and mechanoreceptor response. However, the sensory implications of EMFT remain poorly understood, limiting our understanding of muscle control. We investigated the impact of synergistic muscle activity on MS feedback by recording neuronal activity from the trigeminal mesencephalic nucleus (Me5) in mice. Using a modernized protocol, we applied mechanical stimuli to identify MS afferents while preserving epimuscular connections between mastication muscles. For the first time in vivo, we identified MS afferents from the masseter and temporalis muscles projecting to Me5 in mice using electrophysiological recordings, partly confirmed by histological analysis. Their firing properties were comparable to those in larger animals. We then assessed how MSs respond to local length changes induced by intramuscular electrical stimulation of a synergistic muscle. Our results showed that activating the temporalis muscle significantly influenced MS activity in the masseter MSs (n = 44), while activating the masseter led to a non-significant change in the firing rate of temporalis MSs (n = 7). The findings suggest that synergistic muscle activity impacts MS feedback through a combination of neural and mechanical mechanisms, with mechanical factors likely dominant. We conclude that EMFT contributes to sensorimotor integration, making synergistic muscle activity an important determinant for MS feedback.
    Keywords:  epimuscular myofascial force transmission; muscle spindle; sensorimotor integration; skeletal muscle; trigeminal mesencephalic nucleus
    DOI:  https://doi.org/10.1152/jn.00196.2025
  6. J Cachexia Sarcopenia Muscle. 2025 Oct;16(5): e70083
    CSE/H2S/SESN2 Signalling Mediates the Protective Effect of Exercise Against Immobilization-Induced Muscle Atrophy in Mice.
    Xiuru Li, Yating Huang, Xuege Yang, Sujuan Liu, Yanmei Niu, Li Fu.
       BACKGROUND: Hydrogen sulphide (H2S), a gasotransmitter synthesized by cystathionine-γ-lyase (CSE), exhibits antioxidant properties and may mimic exercise-induced muscle protection. However, its mechanistic role in muscle atrophy and exercise intervention remains unclear.
    METHODS: Six-month-old male wild-type (WT) and SESN2 knockout (SESN2-/-) C57BL/6J mice were subjected to a 2-week hindlimb immobilization, followed by combined resistance and aerobic exercise or pharmacological intervention using the H2S donor NaHS (30 μmol/kg) or the CSE inhibitor DL-propargylglycine (PAG, 50 mg/kg). In vitro, C2C12 myotubes were treated with H2O2 and NaHS to assess oxidative stress injury. Muscle mass, cross-sectional area (CSA), collagen deposition and oxidative stress markers were evaluated via histology, Western blot and immunofluorescence.
    RESULTS: Compared with the immobilization (IM) group, mice receiving a 2-week combined exercise intervention (IM + EX) exhibited significantly increased gastrocnemius muscle mass/body weight (10.86 ± 0.62 vs. 8.56 ± 1.61, p < 0.01), enlarged muscle fibre CSA (1628 ± 265 μm2 vs. 905.5 ± 88.52 μm2, p < 0.01) and reduced collagen deposition as indicated by Sirius red staining (collagen-positive area: 2.86% ± 1.12% vs. 7.06 ± 1.18%, p < 0.001). Pharmacological inhibition of CSE with PAG significantly attenuated these exercise-induced improvements (muscle mass/body weight: 10.22 ± 0.59, CSA: 1139 ± 96.21 μm2, collagen area: 5.04 ± 0.66%, all p < 0.05 vs. IM + EX). Conversely, administration of the H2S donor NaHS mimicked the protective effects of exercise, increasing muscle mass/body weight (8.94 ± 0.51), CSA (1474 ± 176.1 μm2) and reducing collagen accumulation (collagen area: 3.04 ± 0.74%, all p < 0.05 vs. IM). In vitro, NaHS treatment (30 μM) significantly reversed H2O2-induced reductions in myotube diameter (19.16 ± 0.91 μm vs. 15.61 ± 0.72 μm, p < 0.01) and improved fusion index (46.47 ± 1.51% vs. 35.28 ± 2.87%, p < 0.05). Western blot analysis showed that NaHS upregulated SESN2 and Nrf2 expression, as well as downstream antioxidant proteins HO-1 and NQO1 (p < 0.05), whereas SESN2 knockdown blocked these effects and abolished NaHS-mediated protection in myotubes. In SESN2-/- mice, NaHS failed to increase muscle mass/body weight (7.24 ± 1.3 vs. WT + NaHS 10.12 ± 0.38, p < 0.001), CSA (699.2 ± 21.51 μm2 vs. WT + NaHS 1189 ± 93.27 μm2, p < 0.001) or antioxidant capacity, confirming the essential role of SESN2 in mediating H2S-dependent muscle protection.
    CONCLUSIONS: H2S protects against disuse-induced muscle atrophy by enhancing antioxidant defences via the SESN2/Nrf2 signalling pathway. These findings identify H2S as a potential exercise-mimetic therapeutic strategy for preserving muscle mass and function.
    Keywords:  SESN2; cystathionine‐γ‐lyase; exercise; hydrogen sulphide; muscle atrophy; oxidative stress
    DOI:  https://doi.org/10.1002/jcsm.70083
  7. medRxiv. 2025 Aug 10. pii: 2025.08.06.25333143. [Epub ahead of print]
    Miro1 Mediates Skeletal Muscle Insulin Resistance in Type 2 Diabetes.
    Elizabeth C Heintz, Wagner S Dantas, Analisa L Taylor, Elizabeth R M Zunica, Kathryn P Belmont, Jacob T Mey, Robbie Beyl, Bolormaa Vandanmagsar, Hailey A Parry, Peter Ajayi, Brian Glancy, Christopher L Axelrod, John P Kirwan.
      Imbalanced skeletal muscle mitochondrial dynamics contributed to the onset and progression of type 2 diabetes (T2D) by mechanisms that remained incompletely understood. Here, we examined the role of mitochondrial Rho GTPase 1 (Miro1), an outer mitochondrial membrane enzyme, in the regulation of skeletal muscle insulin action and glucose homeostasis in T2D. Miro1 accumulated in the skeletal muscle of mice and humans with obesity and T2D, a phenomenon driven by impaired insulin-mediated interaction between AKT and Miro1 at the outer mitochondrial membrane. To determine whether Miro1 accumulation was reversible and functionally linked to metabolic improvements, we prospectively evaluated the impact of exercise training on skeletal muscle Miro1 expression, mitochondrial function, and insulin sensitivity in patients with T2D. Patients with T2D (N=24) were randomized to 12 weeks of standard care or exercise training. At baseline and after 12 weeks, we assessed changes in whole-body metabolic and mitochondrial function. Exercise training reduced skeletal muscle Miro1 accumulation (64.3% vs. -53.2% change from baseline; p=0.001) and enhanced mitochondrial oxidative capacity (-37.7% vs. 216.3% change from baseline; p=0.005) and insulin sensitivity (-18.5% vs. 80.0% change from baseline; p=0.007). To further establish a causal role for Miro1 in glucose homeostasis, we generated muscle-specific Miro1 loss- of-function models in mice and cells. Muscle-specific deletion of Miro1 improved insulin action and oxidative capacity in both models. Taken together, these findings supported a key regulatory role for skeletal muscle Miro1 in the pathophysiology of T2D.
    DOI:  https://doi.org/10.1101/2025.08.06.25333143
  8. Methods Mol Biol. 2026 ;2975 111-123
    Analysis of Dystrophin-Associated Glycoproteins: Focus on Expression and Glycosylation of Dystroglycan in Skeletal Muscle.
    Deborah Zygmunt, Patricia Lam, Paul T Martin.
      The dystrophin-associated glycoprotein (DAG) complex includes a number of important transmembrane and membrane-associated proteins that contribute to the maintenance of muscle membrane stability and to signaling through the muscle cell membrane. DAG expression and post-translational modifications can be altered in skeletal muscle from patients with Duchenne muscular dystrophy (DMD) and other forms of muscular dystrophy, making it essential to have robust protocols to assess these features. While good antibody and DNA probes exist to assess expression of most DAGs, quantitative analysis of glycosylation and protein expression for α dystroglycan (αDG) has been problematic. Here we provide protocols to describe proper functional glycosylation and expression of αDG using immunostaining and immunoblotting, demonstrating how such protocols can identify glycosylation defects that give rise to muscular dystrophy.
    Keywords:  Dystroglycan; Dystroglycanopathy; Glycosylation; Immunostaining; Matriglycan
    DOI:  https://doi.org/10.1007/978-1-0716-4811-7_7
  9. Int J Biochem Cell Biol. 2025 Sep 27. pii: S1357-2725(25)00137-2. [Epub ahead of print]189 106869
    ATP1B4 as a candidate upstream regulator of muscle atrophy in diabetic sarcopenia via PI3K/AKT/mTOR-mediated autophagy.
    Tingting Duan, Shumin Jia, Dan Zhou, Liqun Zhao.
       OBJECTIVE: This study aimed to elucidate the regulatory role of the muscle-specific gene ATP1B4 in skeletal muscle metabolism and mitophagy in diabetic sarcopenia (DS) rats.
    METHODS: Differentially expressed genes were screened from the GEO dataset GSE7014, and ATP1B4 was identified as a candidate gene associated with DS. A DS rat model was established via high-fat diet feeding and streptozotocin injection. ATP1B4 expression was modulated through lentiviral overexpression or knockdown. Additionally, PI3K/AKT/mTOR pathway activators (SC79, leucine) and inhibitors (LY294002, MK-2206) were administered. Protein expression of ATP1B4, phosphorylated PI3K/AKT/mTOR components, and autophagy markers (LC3-II, DRP1, ATG9, MFN2) was assessed via Western blotting, immunohistochemistry, and immunofluorescence. Skeletal muscle function and structure were evaluated using behavioral tests (treadmill and inclined plane) and histopathological staining (H&E, Masson, PAS).
    RESULTS: Bioinformatic analysis of the GSE7014 dataset identified ATP1B4 as a skeletal muscle-related differentially expressed gene enriched in extracellular matrix and metabolic pathways. In DS rats, ATP1B4 expression was upregulated, coinciding with suppression of PI3K/AKT/mTOR signaling and activation of mitophagy markers (LC3-II, DRP1, ATG9). Overexpression of ATP1B4 exacerbated hyperglycemia, muscle atrophy, collagen accumulation, and glycogen deposition, while knockdown reversed these effects. Activation of the PI3K/AKT/mTOR pathway improved muscle function and histological architecture, normalized autophagy, and reduced pathological features. However, co-overexpression of ATP1B4 eliminated the protective effects of pathway activation. Conversely, dual intervention with ATP1B4 knockdown and PI3K activation restored skeletal muscle integrity and autophagy flux. Importantly, ATP1B4 expression remained unchanged following pathway modulation, supporting its unidirectional upstream regulatory role in DS.
    CONCLUSION: ATP1B4 may aggravate diabetic sarcopenia by acting as an upstream suppressor of the PI3K/AKT/mTOR pathway.
    Keywords:  ATP1B4; Autophagy; Diabetic sarcopenia; Gastrocnemius muscle; PI3K/AKT/mTOR; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.biocel.2025.106869
  10. J Cachexia Sarcopenia Muscle. 2025 Oct;16(5): e70054
    Immunoproteasome Inhibition Positively Impacts the Gut-Muscle Axis in Duchenne Muscular Dystrophy.
    Andrea Farini, Francesco Strati, Monica Molinaro, Debora Mostosi, Sabrina Saccone, Luana Tripodi, Jacopo Troisi, Annamaria Landolfi, Chiara Amoroso, Barbara Cassani, Aitor Blanco-Míguez, Emma Leonetti, Davide Bazzani, Mattia Bolzan, Francesco Fortunato, Flavio Caprioli, Federica Facciotti, Yvan Torrente.
       BACKGROUND: Duchenne Muscular Dystrophy (DMD) features immune-muscle crosstalk, where muscle fibre degeneration enhances pro-inflammatory macrophage infiltration, worsening inflammation and impairing regeneration.
    METHODS: We investigated the impact of immunoproteasome (IP) inhibition on the gut-muscle axis in mdx mice, a well-established model of DMD. We employed microbiota perturbation models, including broad-spectrum antibiotic treatment (ABX) and faecal microbiota transplantation (FMT) from IP-inhibited mdx mice. IP inhibition effects were assessed by analysing gut microbiota composition, intestinal inflammation, muscle integrity and associated metabolic and inflammatory pathways.
    RESULTS: IP inhibitor ONX-0914 significantly impacted the intestinal inflammatory microenvironment and gut microbiota of mdx mice. ONX-0914 treatment increased gastrointestinal transit (increased wet/dry faecal weights, p = 0.0486 and p = 0.0112, respectively) and partially restored intestinal barrier integrity (reduced FITC-dextran leakage, p = 0.0449). JAM-A was significantly upregulated (p < 0.0001). Colonic CD206+ M2 macrophages increased, while CD68 + M1 cells partially decreased. ONX-0914 downregulated IP isoforms in macrophages (PSMB8: p = 0.0022; PSMB9: p = 0.0186) as well as FOXO-1 (p = 0.0380) and TNF-α (p = 0.0487). Antibiotic-induced microbiota depletion abrogated these effects. Metagenomic analysis revealed significant differences in microbiota composition between C57Bl controls and mdx mice (PERMANOVA p < 0.001), with ONX-0914 inducing enrichment of stachyose degradation pathways. Metabolomic analysis showed enrichment of bacterial metabolites, fatty acid and sugar metabolism pathways, with increased glutathione, galactose, glycerol, glyceraldehyde and TCA cycle intermediates. ONX-0914 improved mitochondrial activity in skeletal muscle, as increased expression of ETC complexes (mdx vs. mdx+ONX: Complex II, p = 0.0338; Complex IV, p = 0.0023) and TCA enzymes (mdx vs. FTMmdx+ONX: IDH p = 0.0258; FH p = 0.0366). This led to a shift towards oxidative muscle fibres and improved muscle morphology (increased fibre size, p < 0.0001 mdx vs. mdx+ONX and mdx vs. FTMmdx+ONX). Muscle performance was enhanced with reduced CPK levels (p = 0.0015 mdx vs. mdx+ONX) and fibrosis (decreased TGFβ: mdx vs. mdx+ONX, p = 0.0248; mdx vs. FTMmdx+ONX, p = 0.0279). ONX-0914 reduced CD68+ (mdx vs. mdx+ONX, p = 0.0024; mdx vs. FTMmdx+ONX, p < 0.0001) and increased CD206+ (mdx vs. FTMmdx+ONX: p = 0.0083) macrophages in muscle, downregulated inflammatory genes (mdx vs. mdx+ONX: ccl2 p = 0.0327, vcam-1p = 0.0378) and reduced pro-inflammatory proteins (MCP1, mdx vs. mdx+ONX, p = 0.0442). Inflammatory cytokines and endothelial vessel density in ONX-0914 treated mdx were restored to wild type mice. These data demonstrate that ONX-0914 enhances muscle function through microbiota-dependent mechanisms.
    CONCLUSIONS: Our study advances the understanding of the role of dysbiosis in DMD disease and identifies IP inhibition as a potential therapeutic strategy to modulate the dystrophic gut-muscle axis, offering new perspectives for microbiota-targeted therapies.
    Keywords:  Duchenne muscular dystrophy; immunoproteasome; macrophages; muscle metabolism
    DOI:  https://doi.org/10.1002/jcsm.70054
  11. Methods Mol Biol. 2026 ;2963 79-89
    Lipidomic Sample Preparation to Detect Phosphatidylcholine Alterations in Skeletal Muscle.
    William J Valentine, Suzumi M Tokuoka, Yoshihiro Kita, Hideo Shindou.
      Altered phospholipid compositions in skeletal muscle occur in muscular dystrophy and other pathological conditions; however, origins and relationships to the disease course are unclear. Liquid chromatography-mass spectrometry (LC-MS) technologies allow the determination of phospholipid compositions and alteration patterns in disease states. Here, we describe a basic protocol to prepare methanolic extracts from skeletal muscle, which may be analyzed by lipidomic LC-MS in order to detect compositional alterations in phosphatidylcholine, a major phospholipid species of skeletal muscle, as well as other phospholipid classes such as phosphatidylethanolamine. These analyses are useful to determine relative increases or decreases in individual phospholipid species between samples and capture changes in membrane compositions rather than the absolute quantities of lipids. LC-MS lipidomic analyses often yield large datasets containing hundreds of chromatographic peaks for each sample, and a ratiometric analysis strategy to determine the relative abundances of the major PC species is also briefly introduced.
    Keywords:  Lipidomic analyses; Muscular dystrophy; Phosphatidylcholine; Phospholipid compositions; Skeletal muscle
    DOI:  https://doi.org/10.1007/978-1-0716-4738-7_5
  12. Acta Physiol (Oxf). 2025 Nov;241(11): e70114
    MiR-126-5p Derived From Bone Marrow Mesenchymal Stem Cell Exosomes Promotes Skeletal Muscle Regeneration by Regulating FBXO32/MyoD Signaling.
    Yi Yan, Minxing Zheng, Xuanjing Wang, Tingting Fu, Jiahui Qi, Xiaofang Wei, Yaqin Sun, Jiayin Lu, Xiaomao Luo, Ying Wang, Haidong Wang.
       AIM: In the process of muscle growth and repair, microRNAs (miRNAs) serve as a critical factor in spatiotemporal regulation. Nevertheless, the molecular regulatory mechanisms underlying muscle regeneration remain largely unknown.
    METHODS: Exosomes from control and miR-126-knockdown BMSCs were isolated via ultracentrifugation. A mouse muscle injury model was established using 1.2% barium chloride in gastrocnemius muscles. Injured tissues received local injections of BMSC exosomes or AAV-miR-126. Gene expression was analyzed by qRT-PCR/Western blot. Tissue morphology and repair were assessed via H&E staining, while regeneration markers were evaluated through immunostaining.
    RESULTS: Here, we identified miR-126-5p in BMSC-derived exosomes as a positive regulator of muscle regeneration. These exosomes promoted the proliferation and maturation of myoblasts and facilitated the regeneration of skeletal muscle in male C57BL/6J mice. FBXO32 was confirmed as the downstream target of exosomal miR-126-5p to regulate skeletal muscle regeneration, and it ubiquitinated and degraded myogenic differentiation 1 (MyoD). Notably, miR-126-5p knockdown from BMSC-derived exosomes significantly inhibited proliferation and differentiation of Pax7+ SCs and muscle regeneration, whereas adeno-associated virus (AAV)-mediated overexpression of miR-126-5p accelerated these processes. Specifically, the BMSC-derived exosomes delivered miR-126-5p to skeletal muscle, thus decreasing the expression of FBXO32, in turn increasing MyoD expression, finally significantly promoting satellite cell differentiation and skeletal muscle regeneration.
    CONCLUSIONS: BMSC-derived exosomes could promote skeletal muscle injury repair through miR-126-5p, and thus miR-126-5p may act as a molecular therapeutic target of skeletal muscle diseases. Elucidating functional mechanisms of exosomes and miRNA is of great significance for developing new biotherapy strategies for skeletal muscle disease.
    Keywords:  bone marrow mesenchymal stem cell; exosome; miR‐126‐5p; regeneration; skeletal muscle
    DOI:  https://doi.org/10.1111/apha.70114
  13. Adv Clin Chem. 2025 ;pii: S0065-2423(25)00053-8. [Epub ahead of print]129 53-122
    Proteomic profiling of the extracellular matrix in skeletal muscle.
    Dieter Swandulla, Kay Ohlendieck.
      A dynamic extracellular matrix (ECM) surrounds individual cellular units and fills the intercellular space to provide physical support, structural organization and a medium for signaling mechanisms. This article focuses on the ECM in skeletal muscles, which exhibits a diverse and dynamic protein composition in the endomysium, perimysium and epimysium. The muscle matrisome plays a key role in providing tissue integrity during embryonic myogenesis, muscle repair and myofiber regeneration. Mass spectrometry-based proteomics has been instrumental in the systematic cataloguing of the muscle ECM, including collagens, glycoproteins, proteoglycans, matricellular proteins and adhesion complexes, and the elucidation of their pathophysiological role in neuromuscular disorders.
    Keywords:  Extracellular matrix; Fibrosis; Mass spectrometry; Matrisome; Muscular dystrophy; Myofibrosis; Proteomics
    DOI:  https://doi.org/10.1016/bs.acc.2025.06.008
  14. Methods Mol Biol. 2026 ;2963 185-194
    Development of Electric Field Stimulation (EFS)-Mediated Skeletal Muscle Training with iPSCs.
    Tomoya Uchimura, Hidetoshi Sakurai.
      Functional analysis of skeletal muscle in vitro requires maturation and stimuli to induce excitation-contraction coupling as well as a quantitative method to analyze contraction. Electric field stimulation (EFS) has been traditionally used as a method to excite skeletal muscle in vitro and in vivo. A combination of human-induced pluripotent stem cell (hiPS) technology and EFS will lead to recapitulation of functional phenotypes of skeletal muscle diseases. Here, we describe the combinational technology using hiPS technology and EFS to induce the maturation of skeletal muscle and analyze contractile performance in vitro.
    Keywords:  Contraction; Electric field stimulation (EFS); Gel culture; Induced pluripotent cells; Skeletal muscle
    DOI:  https://doi.org/10.1007/978-1-0716-4738-7_13
  15. Cell Rep. 2025 Sep 30. pii: S2211-1247(25)01125-8. [Epub ahead of print]44(10): 116354
    The central clock drives metabolic rhythms in muscle stem cells.
    Valentina Sica, Jacob G Smith, Oleg Deryagin, Eva Andrés, Vera Lukesova, Mirijam Egg, Nina Cabezas-Wallscheid, Salvador Aznar Benitah, Antonio L Serrano, Eusebio Perdiguero, Pura Muñoz-Cánoves.
      Satellite cells (SCs), the skeletal muscle resident stem cells, maintain a state of quiescence yet exhibit robust circadian oscillations at the transcriptional level. How SC circadian rhythms are controlled is not well understood. Here, we use SC-specific reconstitution of the essential clock gene Bmal1 in mice to elucidate the role of the local SC clock and its interplay with the central clock in the brain. We find that 24-h rhythmicity of metabolic genes in SCs depends on central clock inputs, independent of the SC clock, and identify rhythmic feeding-fasting cycles as the key brain clock-dependent output controlling their oscillation. Functionally, central signals regulate SC metabolic state and SC-mediated muscle repair, and we identify intact autophagic function as a prerequisite for correct oscillation of metabolic transcripts. Overall, we show that the central clock acts dominantly via feeding-fasting cycles to control rhythmic gene expression and metabolic state in quiescent SCs.
    Keywords:  CP: Metabolism; CP: Stem cell research; autophagy; circadian clocks; circadian rhythms; inter-organ crosstalk; metabolism; muscle; quiescence; satellite cells; stem cells; time-restricted feeding
    DOI:  https://doi.org/10.1016/j.celrep.2025.116354
  16. Am J Physiol Cell Physiol. 2025 Oct 03.
    Cachexia progression differs among mouse models of metastatic triple-negative breast cancer.
    Alastair A E Saunders, Chris Karagiannis, Wayne X Du, Lauren S James, Rachel E Thomson, Robin L Anderson, Paul Gregorevic.
      Cancer-associated cachexia decreases quality of life, reduces therapy response, and diminishes survival prospects. Effective cachexia countermeasures remain a significant unmet need. Research into cancer cachexia has made extensive use of models of colon, lung and pancreatic cancers. However, while cachexia also affects people with metastatic breast cancer, the mechanisms underlying breast cancer-associated cachexia are relatively understudied. Thus, we sought to investigate orthotopic mouse models of metastatic breast cancer for the progression of cachexia, with a focus on muscle wasting given its role in the frailty that is a hallmark of the condition. Female Balb/c mice received an intramammary fat pad injection of 4T1.2 or EMT6.5 cells, and NSG mice received MDA-MB-231-HM (231-HM) cells, to induce primary breast tumors that were subsequently excised. The resultant metastatic burden after approximately 4 weeks led to variable loss of muscle mass (tibialis anterior: EMT6.5: -17.1%, 231-HM: -13.5%, 4T1.2: -9.5%) and fat mass (gonadal fat: EMT6.5: -75.1%, 231-HM: -62.5%, 4T1.2: -30.2%). Muscle protein synthesis markers were decreased in EMT6.5 tumor-bearing mice. Distinct increases in the abundance of mRNA for E3-ubiquitin ligase and autophagy-related genes were observed between models. Neuromuscular junction perturbations were observed in EMT6.5 and 4T1.2 tumor-bearing mice. Neutrophilia was noted in the muscles of EMT6.5 tumor-bearing mice. The findings show that muscle mass and function are reduced in mouse models of metastatic breast cancer. Further study of these models could provide useful insights with which to better understand the diversity of cachexia progression across different cancer types.
    Keywords:  Breast cancer; cachexia; metastasis; neuromuscular junction; neutrophil
    DOI:  https://doi.org/10.1152/ajpcell.00230.2025
  17. Biomed Res. 2025 ;46(5): 203-214
    Muscular USP2 is dispensable for MASLD-associated disorders in the liver and skeletal muscle in mice.
    Aya Iida, Masaki Fujimoto, Hiroshi Kitamura.
      We investigated the roles of muscular ubiquitin-specific protease (USP) 2 in the integrity of liver and muscle in metabolic dysfunction-associated steatotic liver disease (MASLD) using a mouse model. Choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) for 8 weeks caused apparent steatosis and fibrosis in the liver of C57BL/6N mice, whereas serum triglyceride and total cholesterol levels were reduced. Although CDAHFD promoted steatosis, inflammation, and fibrosis in the liver, it failed to affect the tissue mass of the gastrocnemius and soleus muscles. Muscle-specific Usp2 knockout (musUsp2KO) mice and control Usp2fl/fl mice exhibited the CDAHFD-induced changes in blood lipids, liver weight, and liver histology at a comparable level. Similarly, soleus muscle weight, diameter of muscle fibers, and physical activity were indistinguishable between musUsp2KO mice and Usp2fl/fl mice in CDAHFD-induced MASLD condition. Comprehensive RNA sequencing and subsequent RT-qPCR analyses indicated that USP2 deficiency potentiated C1qtnf3 expression in the muscle of MASLD mice. Accordingly, chemical inhibition of USP2 elevated C1qtnf3 mRNA in C2C12 myotubes. Application of recombinant C1QTNF3 stimulated mitochondrial biogenesis in C2C12 cells. Considering that USP2 mitigates mitochondrial oxidative stress, induction of C1QTNF3 might compensate for the depletion of USP2 in skeletal muscle.
    Keywords:  C1QTNF; MASH; MASLD; USP2; fatty liver; muscle atrophy
    DOI:  https://doi.org/10.2220/biomedres.46.203
  18. J Appl Physiol (1985). 2025 Sep 27.
    Multidimensional Modeling to Maximize Adaptations to eXercise: The M3AX Trial Rationale and Study Design.
    Zachary A Graham, Matthew P Bubak, Christiana J Raymond-Pope, Gary R Cutter, Jeremy S McAdam, S Craig Tuggle, Jacob A Siedlik, Luis G O de Sousa, Ed J Chappe, Kana Meece, Amritpal Kaur, Benny S R Ruiz, Sophia C Bamman, Katherine M Vanselow, Trevor W Perry, Jorge S Acosta-Arreguin, Natalie J Bohmke, Greg J Addison, J Michelle Bowers, Rachel L Wright, Lena D Fuentes, Jennifer E Smith, Karyn A Esser, Benjamin F Miller, Sue C Bodine, Marcas M Bamman.
      Age-related functional declines are thought to be caused by hallmark biological processes that manifest in physical, mental, and metabolic impairments compromising intrinsic capacity, healthspan and quality-of-life. Exercise is a multipotent treatment with promise to mitigate most aging hallmarks, but there is substantial variability in individual exercise responsiveness. This inter-individual response heterogeneity (IRH) was first extensively interrogated by Bouchard and colleagues in the context of endurance training. Our group has interrogated IRH in response to resistance training and combined training, and we have conducted trials in older adults examining dose titration and adjuvant treatments in attempts to boost response rates. Despite the work of many groups, the mechanisms underpinning IRH and effective mitigation strategies largely remain elusive. The National Institute on Aging (NIA) hosted a focused workshop in 2022 titled "Understanding heterogeneity of responses to, and optimizing clinical efficacy of, exercise training in old adults". This workshop spurred a dedicated NIA request for applications (RFA) with the major goal "to better understand factors underlying response variability to exercise training in older adults." We developed a two-phase Sequential Multiple Assignment Randomized Trial (SMART) in response to the RFA that will allow us to classify individual responsiveness to combined endurance and resistance training and interrogate potential mechanistic underpinnings (Phase I), followed by an approach to boost responsiveness (Phase II). Using deep in vivo, ex vivo, and molecular phenotyping, we will establish multidimensional biocircuitry of responsiveness and build predictive models, providing a basis for personalized exercise prescriptions.
    Keywords:  combined training; geroscience; heterogeneity; skeletal muscle
    DOI:  https://doi.org/10.1152/japplphysiol.00486.2025
  19. Mol Biol Rep. 2025 Sep 29. 52(1): 964
    Temporal dynamics and functional implications of MiRNAs in denervation-induced skeletal muscle atrophy.
    Wei Li, Yuntian Shen, Hua Liu, Fei Xue, Jitai Zhang, Jia Yi, Xia Li, Leilei Gong, Xinlei Yao, Hualin Sun, Bingqian Chen, Jianwei Zhu.
       BACKGROUND: Peripheral nerve injury often leads to muscle atrophy and compromised functional recovery. Growing evidence underscores the critical role of microRNAs (miRNAs) as key epigenetic regulators in this degenerative process. However, most current studies are limited to isolated time points, leaving a gap in the systematic understanding of the temporal dynamics of miRNA expression and their regulatory networks during the initiation of muscle atrophy.
    METHODS AND RESULTS: In this study, we employed small RNA sequencing to dynamically profile miRNA expression in the tibialis anterior muscle across a time series from 12 h to 28 days following denervation. Through differential expression analysis, functional enrichment, and construction of miRNA-mRNA interaction networks integrated with multi-dimensional bioinformatics approaches including GO and KEGG analyses, we identified 199 temporally differentially expressed miRNAs. A pronounced shift in miRNA expression was observed at day 3 post-injury. Functional annotation of target genes revealed an transition in regulatory emphasis from cytoskeletal remodeling toward energy metabolic imbalance. Within this core window of day 3, rno-miR-128-1-5p was found to regulate mitochondrial metabolism-related genes, and cooperated with rno-miR-296-3p in modulating tight junction pathways.
    CONCLUSIONS: Our findings illustrate that a time-specific molecular regulatory network underpins the pathological progression of denervation-induced muscle atrophy. These insights offer novel targets for developing precise therapeutic strategies aligned with disease timeline.
    Keywords:  Energy metabolism; MiRNA; Muscle atrophy; Peripheral nerve injury
    DOI:  https://doi.org/10.1007/s11033-025-11057-2
  20. Skelet Muscle. 2025 Oct 02. 15(1): 27
    Spatiotemporal analysis of dystrophin expression during muscle repair.
    John C W Hildyard, Liberty E Roskrow, Dominic J Wells, Richard J Piercy.
       BACKGROUND: Dystrophin mRNA is produced from a very large genetic locus and transcription of a single mRNA requires approximately 16 h. This prolonged interval between initiation and completion results in unusual transcriptional behaviour: in skeletal muscle, myonuclei express dystrophin continuously and robustly, yet degrade mature transcripts shortly after completion. Consequently, most dystrophin mRNA is nascent, not mature. This implies expression is principally controlled post-transcriptionally, a mechanism that circumvents transcriptional delay, allowing rapid responses to change in demand. Dystrophin protein is however highly stable, with slow turnover: in healthy muscle, despite constant production of dystrophin mRNA, demand is low and the need for responsive expression is minimal. We reasoned this system instead exists to control dystrophin expression during rare periods of elevated but changing demand, such as during muscle development or repair, when newly formed fibres must establish sarcolemmal dystrophin rapidly.
    METHODS: We assessed dystrophin mRNA (both nascent and mature) and dystrophin protein in regenerating skeletal muscle following injury, using a combination of qPCR, immunofluorescence and in-situ hybridisation to determine timing and location of expression during the repair process.
    RESULTS: We reveal a complex program that suggests control at multiple levels: nascent transcription is detectable even prior to overt myoblast fusion, suggesting cells 'pay in advance' to minimise subsequent delay. During myotube differentiation and maturation, when sarcolemmal demands are high, initiation increases only modestly while mature transcript stability increases markedly to generate high numbers of mature dystrophin transcripts, a state that persists until repair is complete, when oversupply and degradation resumes.
    CONCLUSION: Our data demonstrate that dystrophin mRNA is indeed chiefly controlled by turnover, not initiation: degradation consequently represents a potential therapeutic target for maximising efficacy of even modest dystrophin restoration.
    DOI:  https://doi.org/10.1186/s13395-025-00398-y
  21. Methods Mol Biol. 2026 ;2975 165-172
    Isolation of Immune Cells from Skeletal Muscles for Flow Cytometry.
    Zachary M Howard, Jeovanna Lowe, Jill A Rafael-Fortney.
      Inflammation is a characteristic of skeletal muscle wound healing and of many muscle diseases. Analysis and isolation of the immune cell populations infiltrating skeletal muscles and their molecular signatures allow optimal use of anti-inflammatory treatments and identification of novel therapeutic targets. Here we describe a protocol for unbiased isolation of skeletal muscle immune cells. This technique allows for downstream assessment of immune cell populations or their isolation for downstream molecular or cellular assays from individual skeletal muscles during normal wound healing or disease.
    Keywords:  Diaphragm; Macrophages; Myeloid cells; Quadriceps; Skeletal muscles; T-cells
    DOI:  https://doi.org/10.1007/978-1-0716-4811-7_11
  22. Nat Commun. 2025 Sep 30. 16(1): 8667
    Stage-specific and cell-autonomous functions of Delta-like 1 in skeletal muscle stem cells and myogenesis.
    Ying Peng, Sara Scinto, Beatriz Castro, Haowei Xu, Kashyap Akkinapally, Stephanie N Oprescu, Feng Yue, Jingjuan Chen, Shihuan Kuang.
      NOTCH signaling plays multiple roles in muscle satellite cells (MuSCs), but the regulation of NOTCH signaling in MuSCs is poorly defined. Using conditional knockout (cKO) mice, here we explore the role of Delta-Like 1 (DLL1), a ligand of NOTCH receptors, in MuSCs and myogenesis. Dll1-cKO in embryonic myoblasts, but not post-differentiation myocytes, diminishes myogenic progenitors and myogenesis. Dll1-cKO in MuSCs of adult mice disrupts MuSCs homeostasis in non-injured muscles, leading to precocious differentiation, self-renewal deficiency, and regenerative failure upon injuries. These defects of Dll1-cKO myoblasts are cell intrinsic, as they cannot be rescued by cocultured wild-type myoblasts. Overexpression of full-length Dll1 leads to a truncated intracellular domain (DLL1ICD), which promotes differentiation and fusion of myoblasts. Thus, besides its widely accepted role in transactivating NOTCH in a neighboring cell, DLL1ICD also plays a cell-autonomous role in the Dll1-expressing cell. These cell-autonomous and non-autonomous roles together are essential for embryonic myogenesis and postnatal regeneration.
    DOI:  https://doi.org/10.1038/s41467-025-63631-8
  23. Physiol Rep. 2025 Oct;13(19): e70600
    Effects of habitual endurance and resistance exercise on insulin action in primary human skeletal muscle stem cells.
    Polina Krassovskaia, Filip Jevtovic, Donghai Zheng, John Noone, Reichelle X Yeo, Maria F Pino, Cynthia L Stowe, Shannon S Emilson, Nicolas Musi, Kim M Huffman, Caitlin Hebert, Sophia Bowen, Simona Zarini, Eric Ravussin, Nicholas T Broskey, William E Krauss, Bryan C Bergman, Lauren Sparks, Joseph A Houmard.
      Endurance-oriented exercise typically enhances insulin action in skeletal muscle; however, relatively little is known about the impact of resistance exercise. In the present study, insulin action was determined in primary human skeletal muscle stem cells (HSkMCs) isolated from habitual endurance and resistance exercisers and sedentary controls (N = 8-9/group). Insulin action was assessed by insulin-stimulated glycogen synthesis and glucose oxidation using 14C-labeled glucose and insulin signal transduction measured as phosphorylation of Akt (Ser473) and AS160 (Thr640). No differences were detected in basal and insulin-stimulated glycogen synthesis, glucose oxidation, and insulin signal transduction between the endurance and resistance exercisers. When HSkMCs were challenged by a fatty-acid treatment which induced insulin resistance, no differential protection was detected with either exercise training modality. When data from the habitual endurance and resistance exercise groups were combined (EX) and compared to sedentary controls, HSkMC from EX exhibited greater rates of insulin-stimulated glycogen synthesis. However, Akt and AS160 phosphorylation were similar between EX and sedentary individuals. Exercise training provided no protection against fatty-acid-induced insulin resistance across any measure of insulin action. These data suggest that habitual exercise, including resistance training, improves insulin action in skeletal muscle but may not offer intrinsic protection against fatty-acid-induced insulin resistance.
    Keywords:  exercise; insulin action; insulin signaling; primary myotubes; skeletal muscle
    DOI:  https://doi.org/10.14814/phy2.70600
  24. J Cachexia Sarcopenia Muscle. 2025 ;16(5): e70084
    Reduced Muscle Force in Dystrophic DMDΔ52 Pigs Is Incompletely Restored by Systemic Transcript Reframing (DMDΔ51-52).
    Michaela Blasi, Hristiyan Hristov, Jan B Stöckl, Martin Kraetzl, Sonja Fiedler, Elisabeth Kemter, Mayuko Kurome, Barbara Kessler, Josep M Cambra, Valeri Zakhartchenko, Maggie C Walter, Christian Kupatt, Nikolai Klymiuk, Thomas Fröhlich, Andreas Blutke, Michael Stirm, Florian Jaudas, Eckhard Wolf.
       BACKGROUND: Duchenne muscular dystrophy (DMD) is a fatal X-linked disease caused by mutations in the DMD gene, leading to dystrophin deficiency and progressive degeneration of skeletal and cardiac muscles. Pigs lacking DMD exon 52 (DMDΔ52) are a clinically severe model for DMD, mimicking molecular, functional and pathological hallmarks of the human disease. Dystrophin expression can be restored by additionally deleting exon 51 (DMDΔ51-52), which reframes DMD transcripts and alleviates pathological alterations. DMDΔ51-52 pigs model Becker muscular dystrophy (BMD), a milder and slower-progressing form of muscle degeneration.
    METHODS: The Aurora Swine Isometric Footplate Test Apparatus was used to quantify functional parameters of the hind limb dorsiflexor muscle group of 3.5-month-old DMD pigs (n = 5), BMD pigs (n = 3) and wild-type (WT) littermate controls (n = 3). In addition, histopathological and proteomic studies of the functionally tested muscles were performed.
    RESULTS: After twitch stimulation, DMD muscle achieved 62.4% (p < 0.05) and BMD muscle 67.1% (p < 0.05) of the absolute peak force of WT muscle, indicating partial but not complete restoration of muscle force by DMDΔ51-52 transcript reframing. After normalization to the cube root of body mass, the values were 70.9% for DMD muscle (p = 0.05) and 65.8% for BMD muscle (p < 0.05). DMD muscle showed a reduced rate of contraction (p < 0.01); the rate of relaxation was decreased in both DMD (p < 0.01) and BMD (p < 0.05) compared with WT muscle. After tetanic stimulation, DMD muscle reached 54.7% (p < 0.001) and BMD muscle 80.4% (p = 0.08) of WT muscle force. Normalized values were 62.7% (DMD; p < 0.01) and 79.3% (BMD; p = 0.08). The rate of contraction was reduced in both DMD (p < 0.001) and BMD muscle (p < 0.01), whereas the return to the resting state was prolonged (p < 0.001) only in DMD vs. WT muscle. Histopathology and proteomics revealed no significant differences between BMD and WT muscles, whereas severe alterations were observed in DMD pigs.
    CONCLUSIONS: Our study pioneers the quantitative assessment of skeletal muscle function in dystrophic pigs. It demonstrates that systemic exon 51 skipping in DMD caused by loss of DMD exon 52 partially restores muscle function but does not achieve WT levels. These findings highlight the value of dynamic muscle force measurements as a sensitive tool to evaluate the efficacy of therapeutic interventions in the porcine DMD model.
    Keywords:  Becker muscular dystrophy; Duchenne muscular dystrophy; dystrophin; muscle force; pig model
    DOI:  https://doi.org/10.1002/jcsm.70084
  25. bioRxiv. 2025 Sep 23. pii: 2025.09.22.676818. [Epub ahead of print]
    α-Parvin Promotes Glucose Uptake and Metabolism in Skeletal Muscle with Minimal Influence on Hepatic Insulin Sensitivity.
    Fabian Bock, David A Cappel, Xinyu Dong, John W Deaver, Dan S Lark, Luciano Cozzani, Deanna P Bracy, Louise Lantier, Kakali Ghoshal, Allison Do, Richard L Printz, Owen P McGuinness, David H Wasserman, Ambra Pozzi, Roy Zent, Nathan C Winn.
      Skeletal muscle and liver insulin resistance are early features in the sequelae of type 2 diabetes. Integrins are extracellular matrix receptors expressed on skeletal muscle cells and hepatocytes and have been implicated in modulating obesity-associated insulin resistance. Integrins regulate cell function through intracellular proteins including the ILK-PINCH-Parvin (IPP) complex. ILK promotes skeletal muscle and liver insulin resistance in diet-induced obesity in mice but the role of Parvin is unexplored. Here we demonstrate that hepatocyte specific deletion of α-Parvin had only minimal influence on endogenous glucose production or whole-body insulin sensitivity. In contrast, deletion of α-Parvin in skeletal muscle caused a striking reduction in muscle glucose uptake during an insulin clamp in lean mice which was not exacerbated by diet-induced obesity. Insulin-mediated GLUT4 membrane recruitment was impaired in mutant muscles which displayed significant morphological abnormalities due to actin cytoskeleton dysfunction. Consistent with severe muscular dysfunction, mitochondrial oxidative capacity and aerobic exercise capacity were blunted in muscle α-Parvin-null mice. Thus, α-Parvin has a minor role in liver insulin action but is required for insulin-stimulated glucose uptake in skeletal muscle due to its role in actin cytoskeleton regulation. These data suggest that individual IPP complex proteins link cell structure to metabolism via distinct mechanisms in a tissue-specific fashion.
    DOI:  https://doi.org/10.1101/2025.09.22.676818
  26. J Appl Physiol (1985). 2025 Sep 27.
    Sex-specific protective effects of angiotensin II type 1 receptor knockdown on disuse muscle atrophy in the rat soleus muscle.
    Toshinori Yoshihara, Mizuki Takaragawa, Shohei Dobashi, Hisashi Naito.
      Skeletal muscle disuse leads to atrophy. Accumulating evidence suggests that angiotensin II type 1 receptor (AT1R) contributes to sex-dependent catabolic signaling. However, the direct role of AT1R in skeletal muscle is unclear. This study investigated whether selective suppression of AT1R expression in the rat soleus muscle via adeno-associated virus serotype 9 (AAV9)-mediated short hairpin RNA (shRNA) delivery could mitigate hindlimb unloading (HU)-induced muscle atrophy, and whether this effect differed between male and female rats. Male and female rats received intramuscular injections of AAV9 vectors encoding AT1R-targeted shRNA into the soleus muscle. After 7 d of HU, AT1R gene copy number (digital PCR), receptor abundance (ligand binding assay), muscle fiber cross-sectional area (CSA), and downstream molecular markers (including phosphorylated Smad2/3 and Smad1/5/8, HDAC4 expression, and the atrogenes, Fbxo32 and Trim63) were assessed. Female rats exhibited substantially higher AT1R gene copy numbers, which were selectively reduced by AAV9-shRNA. Ligand binding confirmed reduced receptor abundance in both sexes. CSA loss attenuation was observed exclusively in females, particularly in type I fibers. In female animals, AT1R knockdown substantially increased Smad1/5/8 phosphorylation and decreased HDAC4 expression. The AT1R copy number was positively correlated with Fbxo32 and Trim63 expression, independent of AAV dose. AT1R plays a sex-specific role in disuse-induced muscle atrophy, as muscle-specific AT1R knockdown conferred selective protection in female rats. The effect appears to be mediated via Smad1/5/8-HDAC4 signaling rather than oxidative stress or autophagy. This study provides mechanistic support for sex-informed therapeutic strategies targeting the muscle-localized renin-angiotensin system.
    Keywords:  AAV9; Angiotensin II type 1 receptor; disuse atrophy; sex differences; skeletal muscle
    DOI:  https://doi.org/10.1152/japplphysiol.00731.2025
  27. J Frailty Aging. 2025 Oct 01. pii: S2260-1341(25)00083-0. [Epub ahead of print]14(6): 100090
    Impacts of sarcopenia and resistance exercise training on mitochondrial quality control proteins.
    Catherine B Springer-Sapp, Olayinka O Ogbara, Odessa Addison, Sarah Kuzmiak-Glancy, Steven J Prior.
       BACKGROUND: The progression of sarcopenia with aging may be related to mitochondrial dysfunction due in part to altered mitochondrial dynamics (fusion, fission, mitophagy, and biogenesis). Previous work has identified altered expression of proteins associated with these processes in with aging, but whether further changes occur in sarcopenia remains unclear.
    OBJECTIVES: The purpose of this study was to assess protein expression of markers of mitochondrial fusion (Mfn2, Opa1), fission (Drp1, Fis1), mitophagy (Parkin), biogenesis (PGC-1α), and content (Complex IV: CIV) in sarcopenic and non-sarcopenic older adults. We also determined whether resistance training affected skeletal muscle mitochondrial content and expression of mitochondrial quality control proteins in sarcopenic older adults.
    DESIGN: Longitudinal exercise training study, with cross-sectional baseline comparison.
    SETTING AND PARTICIPANTS: Ten older adults with mild-moderate sarcopenia, plus ten non-sarcopenic, matched older adults from Maryland, USA.
    INTERVENTION: Twelve-week resistance training.
    MEASUREMENTS: Strength, sarcopenic index (ALM/BMI: appendicular lean mass divided by body mass index), body composition, and mitochondrial morphology and protein expression in vastus lateralis muscle.
    RESULTS: No differences in protein expression were observed between sarcopenic and non-sarcopenic participants at baseline; however, ALM/BMI was inversely related to CIV expression (r = -0.55, P = 0.013) across all subjects. Similarly, lean body mass and ALM correlated inversely with expression of the fusion protein Opa1-S (r = -0.55 - -0.51, P ≤ 0.022). Resistance training increased strength in sarcopenic older adults by 13 % (P = 0.02), but this group's expression of mitochondrial quality control proteins was mostly unaltered.
    CONCLUSIONS: The presence of sarcopenia identified by ALM/BMI was not associated with changes in protein expression that are consistent with impaired mitochondrial dynamics beyond those changes that might occur with aging alone. While short-term resistance training increased strength in older adults with sarcopenia, this was not accompanied by changes in protein expression, with the possible exception of fusion protein Mfn2.
    Keywords:  Age; Fission; Fusion; Mitophagy; Muscle health
    DOI:  https://doi.org/10.1016/j.tjfa.2025.100090
  28. Biogerontology. 2025 Oct 03. 26(5): 187
    Effects of low-intensity pulsed ultrasound on muscle mass and Fndc5 mRNA expression in aged male mice.
    Yoshitsugu Kojima.
      Sarcopenia, the progressive loss of skeletal muscle mass and function with aging, is a growing public health concern. Conventional treatments such as exercise, pharmacological agents, and nutritional support offer limited efficacy, especially in older populations with reduced mobility or comorbidities. This study aimed to evaluate low-intensity pulsed ultrasound (LIPUS) as a novel, non-invasive therapeutic approach for age-related muscle atrophy. LIPUS was applied to the right hindlimbs of young (12-week), middle-aged (60-week), and aged (95-week) mice for 8 weeks. Muscle weights and mRNA expression levels were analyzed. In aged mice, LIPUS significantly increased gastrocnemius muscle mass and upregulated Fndc5 and Opa1 mRNA, genes associated with mitochondrial function and muscle regeneration. These findings suggest that LIPUS may serve as a safe, non-invasive intervention to counteract sarcopenia by promoting muscle growth and mitochondrial gene activation in aged skeletal muscle.
    Keywords:   Fndc5 ; Irisin; Low-intensity pulsed ultrasound; Muscle mass; Sarcopenia
    DOI:  https://doi.org/10.1007/s10522-025-10331-x
  29. Biochem Biophys Res Commun. 2025 Sep 30. pii: S0006-291X(25)01443-3. [Epub ahead of print]786 152727
    Targeting IL-6/STAT3 signaling to mitigate sarcopenia: Insights from immuno-metabolic crosstalk in NSCLC.
    Gautam Kumar, Shweta Khandibharad, Shailza Singh.
      Non-small cell lung cancer (NSCLC) is the most prevalent subtype of lung cancer and a leading cause of cancer-related mortality worldwide. Literature evidences indicates a strong association between systemic inflammation, driven by cytokines such as Interleukin-6 (IL-6), and the development of NSCLC-associated sarcopenia. However, the immuno-metabolic underpinnings that link tumor-derived IL-6 signaling to skeletal muscle degradation remain incompletely understood. We developed a comprehensive immuno-metabolic mathematical model to investigate how IL-6 signaling influences branched-chain amino acids (BCAA) metabolism and redox homeostasis in the context of NSCLC-induced sarcopenia by understanding two key causes of sarcopenia which are malnutrition and redox homeostasis. Our model proposes that IL-6 alters tumor metabolism by activating the STAT3 pathway. Elevated IL-6 impairs protein synthesis, proteolysis, and muscle atrophy by interfering with insulin signaling, inhibiting mTORC1 activation, and increasing oxidative stress. Additionally, it reveals a central role for IL-6-driven metabolic rewiring, particularly BCAA utilization and redox imbalance, in promoting NSCLC-induced sarcopenia. These findings underscore the dual impact of IL-6 on tumor progression and systemic muscle degradation, and provide a framework for evaluating therapeutic strategies that target IL-6/STAT3 signaling and amino acid metabolism via STAT3 and acetyl-CoA cross talk to mitigate NSCLC-induced sarcopenia.
    Keywords:  IL-6; Immunometabolism; Muscle degradation; NSCLC; Sarcopenia
    DOI:  https://doi.org/10.1016/j.bbrc.2025.152727
  30. Nat Neurosci. 2025 Oct 03.
    Muscle-derived miR-126 regulates TDP-43 axonal local synthesis and NMJ integrity in ALS models.
    Ariel Ionescu, Lior Ankol, Anand Ganapathy Subramaniam, Topaz Altman, Iddo Magen, Yahel Cohen, Yehuda Danino, Tal Gradus-Pery, Yoav Niv, Ori Bar Avi, Danielle Geller, Amjd Ibraheem, Ruilei Cheng, Noam Steinberg, Leenor Alfahel, Pauline Duc, Zeynep Ergul-Ulger, Doruk Arslan, Ersin Tan, Florence Rage, Nilo Riva, Angello Quattrini, Can Ebru Bekircan-Kurt, Adrian Israelson, Amir Dori, Eran Hornstein, Eran Perlson.
      Amyotrophic lateral sclerosis (ALS) is characterized by neuromuscular junction (NMJ) disruption and neurodegeneration. Recent findings highlight a pivotal role for TAR DNA-binding protein 43 (TDP-43) in forming axonal pathological condensates and facilitating NMJ disruption through inhibition of local protein synthesis. However, the mechanisms that drive local TDP-43 accumulation remain unknown. Here we identify that the TDP-43 axonal accumulation in peripheral nerves of SOD1 patients and mice stems from its aberrant local synthesis. This is a non-cell-autonomous process driven by muscle-derived miR-126a-5p extracellular vesicles (EVs). Inhibiting muscle secretion of miR-126a-5p prompts presynaptic TDP-43 synthesis and accumulation, which disrupts axonal translation and causes NMJ degeneration. Introducing miR-126 to SOD1G93A mice, primary co-cultures and human induced pluripotent stem cell (iPSC)-derived co-cultures with ALS mutations exhibits neuroprotective effects and delays motor decline. These findings identify a transcellular communication axis between muscles and motor neurons that regulates axonal local synthesis and NMJ maintenance, offering insights into ALS onset and progression.
    DOI:  https://doi.org/10.1038/s41593-025-02062-6
  31. Mol Metab. 2025 Sep 27. pii: S2212-8778(25)00168-1. [Epub ahead of print] 102261
    Activin receptor type IIA/IIB blockade increases muscle mass and strength, but compromises glycemic control in mice.
    Michala Carlsson, Emma Frank, Joan M Màrmol, Mona Sadek Ali, Steffen H Raun, Edmund Battey, Nicoline Resen Andersen, Andrea Irazoki, Camilla Lund, Carlos Henríquez-Olguin, Martina Kubec Højfeldt, Pauline Blomquist, Frederik Duch Bromer, Gabriele Mocciaro, Andreas Lodber, Christian Brix Folsted Andersen, Marco Eijken, Andreas Mæchel Fritzen, Jonas Roland Knudsen, Erik A Richter, Lykke Sylow.
       PURPOSE: Blocking the Activin receptor type IIA and B (ActRIIA/IIB) has clinical potential to increase muscle mass and improve glycemic control in obesity, cancer, and aging. However, the impact of blocking ActRIIA/IIB on strength, metabolic regulation, and insulin action remains unclear.
    METHODS: Here, we investigated the effect of short- (10mg kg-1 bw, once, 40h) or long-term (10mg kg-1 bw, twice weekly, 21 days) antibody treatment targeting ActRIIA/IIB (αActRIIA/IIB) in lean and diet-induced obese mice and engineered human muscle tissue.
    RESULTS: Short-term ActRIIA/IIB administration in lean mice increased insulin-stimulated glucose uptake in skeletal muscle by 76-105%. Despite this, ActRIIA/IIB-treated mice exhibited 33% elevated blood glucose and glucose intolerance. Long-term αActRIIA/IIB treatment increased muscle mass (+20%) and reduced fat mass (-8%) in obese mice but failed to enhance insulin-stimulated glucose uptake in muscle or adipose tissue. Instead, it induced glucose intolerance, cardiac hypertrophy with glycogen accumulation, and elevated hepatic triacylglycerol and glucose output in response to pyruvate. Concomitantly, long-term ActRIIA/IIB treatment increased strength (30%) in mouse soleus muscle and prevented activin A-induced loss of tissue strength in engineered human muscle tissue. Surprisingly, long-term ActRIIA/IIB treatment lowered volitional running (-250%).
    CONCLUSION: Our findings demonstrate that, in accordance with human studies, ActRIIA/IIB blockade holds promise for increasing muscle mass, strength, and muscle insulin sensitivity. However, contrary to the improved glycemic control in humans, ActRIIA/IIB blockade in mice causes severe glucose intolerance and lowers voluntary physical activity. Our study underscores the complex metabolic and functional consequences of ActRIIA/IIB blockade, and highlight species differences on glycemic control, which warrant further investigation.
    Keywords:  Activin receptor; Bimagrumab; Insulin resistance; Obesity; glycemic regulation; muscle mass
    DOI:  https://doi.org/10.1016/j.molmet.2025.102261
  32. Sci Rep. 2025 Sep 30. 15(1): 33948
    Impaired myogenesis in limb girdle muscular dystrophy type 2B.
    Lucas Santos Souza, Renata Ishiba, Antonio Fernando Ribeiro-Junior, Isabela Aquino Zogbi, Dounia Bouragba, Anne Bigot, Vincent Mouly, Mariz Vainzof.
      The skeletal muscle tissue has a remarkable capacity of growth and regeneration. Fusion of myoblasts and myotubes elongation are fundamental processes in muscle development. Previous studies have depicted impaired myogenic processes in animal models and myoblast from human patients with muscle diseases. Here, we evaluated the myogenesis in patients with Limb-girdle Muscle Dystrophy 2B (LGMD2B). Aiming to explain why dysferlin-deficient muscle cells lose its myogenic potential, we used immortalized myoblasts from LGMD2B patients and a cellular DYSF knocking-out model. Myotubes from patients were smaller and containing less myonuclei than control myotubes. Main muscle regulatory factors expression were not altered in these cells. The analysis of the expression of newly described genes associated with muscle fusion and growth, such as MYMK, MYMX, PALMD, SHISA2, COL25A, didn´t show any difference with controls, which is a novel finding. It was also observed that dysferlin deficiency doesn't alter the expression of FAM65B and HDAC6 genes, components of a proposed protein complex that needs to be formed to allow muscle differentiation. Interestingly, morphometric analysis of DYSF knock-out myotubes induced by CRISPR/Cas9 also revealed reduced myogenic capacity with formation of smaller myotubes. These findings suggest that the absence of DYSF itself is sufficient to impair muscle formation in vitro, and that downstream gene and protein expression related to muscle development might depend on the presence and proper function of dysferlin.
    DOI:  https://doi.org/10.1038/s41598-025-10205-9
  33. Nat Commun. 2025 Sep 30. 16(1): 8726
    Regulation of NSL by TAF4A is critical for genome stability and quiescence of muscle stem cells.
    Angelina M Georgieva, Krishna Sreenivasan, Dong Ding, Clementine Villeneuve, Sara A Wickström, Stefan Günther, Carsten Kuenne, Ulrich Gärtner, Xinyue Guo, Yonggang Zhou, Xuejun Yuan, Thomas Braun.
      Acetylation of lamin A/C by the non-specific lethal complex, containing MOF and KANSL2, is instrumental for maintaining nuclear architecture and genome stability, but the mechanisms controlling expression of its components in different cell types are poorly characterized. Here, we show that TAF4A, primarily known as a subunit of TFIID, forms a complex with the heterotrimeric transcription factor NF-Y and is critical for cell type-specific regulation of Kansl2 in muscle stem cells. Inactivation of Taf4a reduces expression of Kansl2 and alters post-translational modification of lamin A/C, thereby decreasing nuclear stiffness, which disrupts the nuclear architecture and results in severe genomic instability. Reduced expression of Kansl2 in Taf4a-mutant muscle stem cells changes expression of numerous genes involved in chromatin regulation. The subsequent loss of heterochromatin, in combination with pronounced genomic instability, activates muscle stem cells but impairs their proliferation, which depletes the stem cell pool and abolishes skeletal muscle regeneration. We conclude that TAF4A-NF-Y-dependent transcription regulation safeguards heterochromatin and genome stability of muscle stem cells via the non-specific lethal complex.
    DOI:  https://doi.org/10.1038/s41467-025-64402-1
  34. Methods Mol Biol. 2026 ;2975 151-163
    Isolation and Culture of Primary Myoblasts from Humans and Mice.
    Felipe de Souza Leite, Emanuela Gussoni.
      Primary myoblasts are generated from committed stem cells, responsible for repairing skeletal muscle fibers upon injury. They are a valuable resource for scientific research in muscle disease and drug screening and hold promise for cell-based therapies. However, skeletal muscle biopsies contain a plethora of non-myogenic cells, exacerbated in diseased muscle tissues. Thus, purification methods of the myogenic cell population are necessary. This protocol describes techniques for dissociating cells from human and mouse skeletal muscle biopsies and enrichment for a highly myogenic population using magnetic isolation for mouse muscles and by fluorescence-activated cell sorting (FACS) using cell surface antibodies for humans. We also describe methods to expand myoblasts in culture and assess myogenicity.
    Keywords:  Cell culture; Fluorescence-activated cell sorting (FACS); Magnetic enrichment; Skeletal muscle; Tissue dissociation
    DOI:  https://doi.org/10.1007/978-1-0716-4811-7_10
  35. Mater Today Bio. 2025 Dec;35 102265
    Muscle homing peptide modified liposomes loaded with EGCG improved skeletal muscle dysfunction by inhibiting inflammation in aging mice.
    Zongyu Huang, Jianjie Xie, Nana Gao, Huicong Feng, Biaobiao Wang, He Tian, Chao Wu, Chang Liu.
      Skeletal muscle aging frequently leads to a reduction in muscle mass and strength, significantly compromising the quality of life in elderly individuals. Skeletal muscle dysfunction during aging is widely recognized to be closely linked to chronic inflammation, oxidative stress and mitochondrial dysfunction. In this study, we confirmed the successful synthesis of M12 (muscle homing peptide)-modified EGCG (Epigallocatechin gallate) liposomes and validated their specific targeting to skeletal muscle through immunofluorescence analysis and in vivo imaging in small animal models. Both in vivo and in vitro experiments demonstrated that M12EGLP effectively suppressed the expression of inflammatory markers such as TNF-α and IL-6, thereby alleviating oxidative stress and restoring mitochondrial function in skeletal muscle. These effects ultimately contributed to the improvement of skeletal muscle dysfunction in aging mice. We have developed M12-modified EGCG liposomes (M12EGLP), a targeted drug delivery system capable of specifically accumulating in skeletal muscle, thereby enhancing the bioavailability and therapeutic potential of EGCG. M12EGLP enhances the exercise capacity of aging mice by reducing skeletal muscle inflammation, which subsequently alleviates oxidative stress and improves mitochondrial function. Therefore, as a novel and targeted drug delivery system, M12EGLP may provide a promising therapeutic strategy for the clinical management of age-related skeletal muscle dysfunction.
    Keywords:  Aging; Epigallocatechin gallate; Inflammation; Liposome; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.mtbio.2025.102265
  36. J Physiol. 2025 Oct 03.
    Breast cancer cell-conditioned media inhibit growth and reduce basal and insulin-stimulated glucose uptake by inhibiting Rac1 activation in rat myotubes.
    Mona Sadek Ali, Stine Bitsch-Olsen, Emma Frank, Scott Sebastian Birch Themsen, Edmund Battey, Mirela Perla, Steffen Henning Raun, Steven de Jong, Lykke Sylow.
      Metabolic disorders are common in women with breast cancer, raising mortality and recurrence rates, but their causes remain poorly understood. Given the importance of skeletal muscle metabolism in glucose homeostasis, we investigated the effect of breast cancer cell-conditioned media on insulin-stimulated glucose uptake in muscle. Rat L6 myotubes overexpressing myc-tagged GLUT4 were incubated with 40% conditioned media from tumourigenic MCF7 or BT474, or non-tumourigenic control MCF10A breast cells. Mass-spectrometry-based proteomics was applied to detect molecular rewiring in response to breast cancer in the muscle. Expression of myogenesis and inflammation markers, GLUT4 translocation, [3H]2-deoxyglucose uptake, and intramyocellular insulin signalling were determined. Breast cancer cell-conditioned media induced proteomic changes in pathways linked to sarcomere organisation, actin filament binding and vesicle trafficking. Myogenic differentiation was disrupted, marked by a 50% increase in Mki67 mRNA and trend (P = 0.087) towards reduced myosin heavy chain expression, as shown by immunofluorescence. Additionally, breast cancer cell-conditioned media activated inflammation via nuclear factor-κB and interleukin-6 signalling and reduced myotube width by 70% (P = 0.0524). Myotubes treated with breast cancer cell-conditioned media had a reduced basal and insulin-stimulated GLUT4 translocation and glucose uptake. Insulin signalling via the Rho GTPase Rac1 was reduced by 40%, while absolute Akt-TBC1D4 phosphorylation was unaffected. Conditioned media from MCF7 and BT474 breast cancer cells altered skeletal muscle proteome, induced inflammation, lowered growth markers, reduced glucose uptake, inhibited GLUT4 translocation and blocked insulin-stimulated Rac1 activation. These findings indicate that the rewiring of skeletal muscle could play a role in metabolic dysfunction in patients with breast cancer. KEY POINTS: Metabolic disorders in breast cancer increase mortality and cancer recurrence. Here, we show that incubation with breast cancer cell-conditioned media (CM) alters the proteome in rat skeletal muscle cells. In addition, breast cancer CM activates NF-κB and type 1 interferon pathways, inhibiting muscle growth. Moreover, breast cancer CM inhibits basal and insulin-mediated GLUT4 translocation and glucose uptake, likely by blocking insulin-stimulated Rac1, but not Akt-TBC1D4 activation. These results underscore a potential mechanistic link between breast cancer and metabolic disorders and suggest that skeletal muscle rewiring may play a role.
    Keywords:  breast cancer; glucose metabolism; insulin signalling; muscle growth; skeletal muscle
    DOI:  https://doi.org/10.1113/JP288099
  37. Med Sci Sports Exerc. 2025 Sep 30.
    Increased Skeletal Muscle Oxidative Capacity Augments the Myokine Response to Whole Body Vibration.
    Morgan N Broniec, Kimberly Norland, Jacob Looney, Reva Crandall, Jeffrey Thomas, Xiaoling Wang, Ryan A Harris.
       INTRODUCTION: The role of skeletal muscle health on preventing and ameliorating chronic disease is emerging. The improvements in skeletal muscle metabolism are likely mediated by myokines, such as myostatin, IL-6, and decorin. Whether or not basal skeletal muscle health contributes to the myokine response to Whole body vibration (WBV), an exercise mimetic, has yet to be elucidated.
    METHODS: Data from Sixty-three young adults (32.5± 0.7 years, 57.1% female, 42.9% non-Hispanic Black) were included from a longitudinal twin cohort study. Skeletal muscle oxidative capacity (SMOC) was determined using near-infrared spectroscopy by measuring the rate of skeletal muscle oxygen consumption after stimulation and was represented as a rate constant averaged over three trials (AvgRC). The acute WBV protocol consisted of 10 cycles of 1 min of vibration exercise followed by 30s of standing rest. Blood was collected at baseline (PRE), immediately post, and 1h, 3h, and 24h post WBV and myokine concentrations of IL-6, myostatin, and decorin were measured at each of these timepoints. Participants were divided into two groups by SMOC: low skeletal muscle oxidative capacity (AvgRC < 1.82) and high skeletal muscle oxidative capacity (AvgRC > 2.13).
    RESULTS: Participant characteristics including age, BMI, body fat percentage, handgrip, and skeletal muscle index (SMI) were similar between groups. SMOC was positively associated with myostatin at baseline (ß= 564.6, SE=232.4, p=0.045) and 24H following WBV (ß= 661.0, SE=189.4, p=0.029). In addition, a significantly higher overall myostatin (p=0.026) and IL-6 response (p=0.001) to WBV was observed in in the high skeletal muscle oxidative capacity group when compared to the low skeletal muscle oxidative capacity group.
    CONCLUSIONS: Higher skeletal muscle oxidative capacity is associated with a greater myostatin and IL-6 response to acute WBV. These data suggest that a higher SMOC at baseline may positively impact the myokine response to WBV, independent of adiposity, and demonstrates the importance of skeletal muscle health on preventing and ameliorating chronic disease.
    Keywords:  IL-6; MUSCLE HEALTH; MYOSTATIN; OBESITY; WHOLE BODY VIBRATION
    DOI:  https://doi.org/10.1249/MSS.0000000000003854
  38. Diabetes Res Clin Pract. 2025 Sep 27. pii: S0168-8227(25)00938-6. [Epub ahead of print]229 112924
    GLP-1 receptor agonists and sarcopenia: Weight loss at a cost? A brief narrative review.
    Dimitrios Pantazopoulos, Evanthia Gouveri, Dimitrios Papazoglou, Nikolaos Papanas.
      Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual agonists targeting both GLP-1 and glucose-dependent insulinotropic polypeptide receptors (GLP-1/GIP RAs) are established therapies for type 2 diabetes mellitus (T2DM) and obesity. However, there is evidence that treatment with these agents may lead to significant loss of muscle mass, potentially resulting in sarcopenia or sarcopenic obesity. This brief narrative review explores the complex relationship between GLP-1 based therapies and muscle health. Some studies have linked GLP-1 RAs and dual GLP-1/GIP RAs with significant reductions in lean mass, and sarcopenia. However, preclinical evidence suggests that these agents can attenuate skeletal muscle atrophy, improve muscle function, and enhance mitochondrial health. Moreover, limited clinical data indicate a potential role in preserving muscle mass under certain conditions. Management includes optimised diet, targeted exercise, and novel pharmacological interventions, such as blockade of growth differentiation factor-8 (GDF8) and activin A (ActA). These measures hold potential to preserve muscle mass and to improve patient outcomes. Further research is warranted to clarify these mechanisms and to evaluate combination therapies aimed at preventing sarcopenia in patients receiving GLP-1 RAs.
    Keywords:  GLP-1 RAs; GLP-1/GIP RAs; Sarcopenia; T2DM; Weight loss
    DOI:  https://doi.org/10.1016/j.diabres.2025.112924
  39. J Physiol. 2025 Oct 03.
    Effects of inhibition of Janus kinase signalling during controlled mechanical ventilation on the rate of skeletal muscle protein synthesis.
    William J Evans, Mahalakshmi Shankaran, Lars Larsson, Nicola Cacciani, Yvette Hedström, James L Kirkland, Tamar Tchkonia, Hussein Mohammed, Tyler Field, Marc K Hellerstein.
      We employed a unique murine intensive care unit (ICU) model allowing long-term studies of the ICU condition (immobilization, paralysis, sedation and mechanical ventilation). This model resulted in a substantial loss of myofibrillar protein and muscle size. We hypothesized that an inhibitor of Janus kinase (JAK) activation of transcription 3 (STAT3 (signal transducer and activator of transcription 3)) phosphorylation would help to preserve muscle mass by stimulating the rate of protein synthesis. Sprague-Dawley rats were divided into a control group (CON, n = 5) and two groups exposed to the ICU condition for 8 days. One group was treated with a JAK/STAT3 inhibitor (JST, n = 5) and one without a JST (immobilized group, n = 3) inhibitor. To measure the fractional synthesis rate (FSR) of proteins across the muscle proteome, 2H2O was administered as an intraparitoneal (IP) bolus followed by continuous infusion of 8% 2H2O to maintain body water enrichment. Soleus, extensor digitorum longus (EDL), tibialis anterior (TA), gastrocnemius and diaphragm were obtained from all animals. Liquid chromatography-mass spectrometry (LC/MS-MS) analysis was used to measure protein FSR. Compared to CON myofibrillar protein FSR was decreased 39%-73%, with the decrease in gastrocnemius > soleus > TA > diaphragm > EDL. Sarcoplasmic protein FSR was decreased 38%-69%, with the decrease in gastrocnemius > TA > EDL > soleus > diaphragm. Mitochondrial protein FSR was decreased 34%-52%, with the decrease in TA > soleus > gastrocnemius > EDL > diaphragm. The decreases in protein flux rates by ontology corresponded broadly with function and fibre types. Immobilization resulted in profound and tissue-specific decreases in protein FSR, with JAK/STAT3 showing a significant effect to preserve FSR, muscle mass and body weight. KEY POINTS: Mechanical silencing of skeletal muscle resulted in a large lowering of protein fractional synthesis rate (FSR) in all muscles measured, the extent of which was muscle- and fibre specific. All muscle protein ontologies were affected. A Janus kinase (JAK)/STAT inhibitor had a positive effect on body mass, muscle size and protein FSR.
    Keywords:  critical illness myopathy; immobilization; proteome fluxes
    DOI:  https://doi.org/10.1113/JP288982
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