bims-moremu Biomed News
on Molecular regulators of muscle mass
Issue of 2025–07–13
43 papers selected by
Anna Vainshtein, Craft Science Inc.
  1. Duchenne Muscular Dystrophy Patient iPSCs-Derived Skeletal Muscle Organoids Exhibit a Developmental Delay in Myogenic Progenitor Maturation.
  2. A mechanistic basis of fast myofiber vulnerability to neuromuscular diseases.
  3. Sustained accumulation of molecular clock suppressors Period 1 and Period 2 promotes C2C12 myotube atrophy through an autocrine-mediated mechanism with relevance to androgen deprivation-induced limb muscle mass loss.
  4. Late-Stage Skeletal Muscle Transcriptome in Duchenne Muscular Dystrophy Shows a BMP4-Induced Molecular Signature.
  5. The tumor suppressor pRb and its relative p130 are required to maintain murine adult skeletal muscle homeostasis.
  6. From Development to Regeneration: Insights into Flight Muscle Adaptations from Bat Muscle Cell Lines.
  7. HIF1α mediates circadian regulation of skeletal muscle metabolism and substrate preference in response to time-of-day exercise.
  8. EIF4A3 Promotes Muscle Atrophy and Aging by Inhibiting the FAK Pathway Through NEDD9 mRNA Destabilization.
  9. Frontiers in Nondrug Treatment of Sarcopenia: A Review of Pathological Mechanisms and the Latest Treatment Strategies.
  10. Endurance training promotes chromatin closure and timely repression of the post-exercise immediate early stress response.
  11. Impaired Autophagic Flux in Skeletal Muscle of Plectin-Related Epidermolysis Bullosa Simplex With Muscular Dystrophy.
  12. Down-regulation of human-specific lncRNA TMEM9B-AS1 in skeletal muscle of people with type 2 diabetes affects ribosomal biogenesis.
  13. Combined angiogenic and hypertrophic gene therapy enhances skeletal muscle growth.
  14. Transcriptional Diversity in Response to Aging Across Skeletal Muscles.
  15. Multiomics and cellular senescence profiling of aging human skeletal muscle uncovers Maraviroc as a senotherapeutic approach for sarcopenia.
  16. Diabetes and exercise remodel the myonuclear transcriptome in a fibre type-dependent manner.
  17. Age and sex-specific changes in mitochondrial quality control in skeletal and cardiac muscle.
  18. Nucleolar FRG2 lncRNAs inhibit rRNA transcription and cytoplasmic translation, linking FSHD to dysregulation of muscle-specific protein synthesis.
  19. High-Quality Weight Loss in Obesity: Importance of Skeletal Muscle.
  20. Macrophage-derived Spp1 promotes intramuscular fat in dystrophic muscle.
  21. Mechanisms of skeletal muscle atrophy in type 2 diabetes mellitus.
  22. Targeting Dio3 to enhance mitophagy and ameliorate skeletal muscle wasting in sepsis.
  23. The proteoglycan decorin does not influence adiposity, glucose tolerance, or aerobic exercise capacity in mice.
  24. Impact of Adipose Tissue and Lipids on Skeletal Muscle in Sarcopenia.
  25. Scutellarein attenuates cancer cachexia-induced muscle atrophy via targeted inhibition of the JAK/STAT pathway.
  26. The human genetic variant rs6190 unveils Foxc1 and Arid5a as novel prometabolic targets of the glucocorticoid receptor in muscle.
  27. Exploring motor unit and neuromuscular junction dysfunction in aging and sarcopenia: insights from electromyography in systematic review.
  28. Non-Invasive Ultrasound Treatment Enhances the Release of Skeletal Muscle-Derived Extracellular Vesicles in Mice.
  29. Skeletal Muscle-Specific Deletion of E3 Ligase Asb2 Enhances Muscle Mass and Strength.
  30. Decreased Expression and Secretion of the Myokine Fndc5/Irisin by Cisplatin Treatment in Mouse Skeletal Muscle.
  31. Aerobic exercise ameliorates skeletal muscle atrophy in atic knockout zebrafish through the oxidative phosphorylation pathway.
  32. Soyasapogenol B prevents sarcopenia by increasing skeletal muscle mass and function through the Sirt1/PGC-1α and PI3K pathway.
  33. Aging induces sarcopenia by disrupting the crosstalk between the skeletal muscle microenvironment and myofibers.
  34. High-fat diet ablates an insulin-responsive pool of GLUT4 glucose transporters in skeletal muscle.
  35. Single cell RNA sequencing analysis of mice hindlimb muscles identifies transcriptional heterogeneity in aging and physical frailty.
  36. Exercise as a geroprotector: focusing on epigenetic aging.
  37. Applying lessons from limb muscle disuse and ageing to better understand ventilator-induced diaphragm dysfunction.
  38. Dynamic balance of myoplasmic energetics and redox state in a fast-twitch oxidative glycolytic skeletal muscle fiber.
  39. Early-life exercise extends healthspan but not lifespan in mice.
  40. An Optimized Ex Vivo Protocol for Quantitative Electrophysiological Assessment of Neuromuscular Junctions and Skeletal Muscle Function Using the Aurora System.
  41. Muscle growth by sarcomere divisions.
  42. Muscle AMP deaminase activity was lower in Neandertals than in modern humans.
  43. Unlimited adaptations of muscle fibres to exercise; are you kidding me?
  1. Cells. 2025 Jul 07. pii: 1033. [Epub ahead of print]14(13):
    Duchenne Muscular Dystrophy Patient iPSCs-Derived Skeletal Muscle Organoids Exhibit a Developmental Delay in Myogenic Progenitor Maturation.
    Urs Kindler, Lampros Mavrommatis, Franziska Käppler, Dalya Gebrehiwet Hiluf, Stefanie Heilmann-Heimbach, Katrin Marcus, Thomas Günther Pomorski, Matthias Vorgerd, Beate Brand-Saberi, Holm Zaehres.
       BACKGROUND: Duchenne muscular dystrophy (DMD), which affects 1 in 3500 to 5000 newborn boys worldwide, is characterized by progressive skeletal muscle weakness and degeneration. The reduced muscle regeneration capacity presented by patients is associated with increased fibrosis. Satellite cells (SCs) are skeletal muscle stem cells that play an important role in adult muscle maintenance and regeneration. The absence or mutation of dystrophin in DMD is hypothesized to impair SC asymmetric division, leading to cell cycle arrest.
    METHODS: To overcome the limited availability of biopsies from DMD patients, we used our 3D skeletal muscle organoid (SMO) system, which delivers a stable population of myogenic progenitors (MPs) in dormant, activated, and committed stages, to perform SMO cultures using three DMD patient-derived iPSC lines.
    RESULTS: The results of scRNA-seq analysis of three DMD SMO cultures versus two healthy, non-isogenic, SMO cultures indicate reduced MP populations with constant activation and differentiation, trending toward embryonic and immature myotubes. Mapping our data onto the human myogenic reference atlas, together with primary SC scRNA-seq data, indicated a more immature developmental stage of DMD organoid-derived MPs. DMD fibro-adipogenic progenitors (FAPs) appear to be activated in SMOs.
    CONCLUSIONS: Our organoid system provides a promising model for studying muscular dystrophies in vitro, especially in the case of early developmental onset, and a methodology for overcoming the bottleneck of limited patient material for skeletal muscle disease modeling.
    Keywords:  Duchenne muscular dystrophy; FAPs; human-induced pluripotent stem cells; myogenesis; myogenic progenitors; organoids; satellite cells; scRNA-seq; skeletal muscle
    DOI:  https://doi.org/10.3390/cells14131033
  2. Cell Rep. 2025 Jul 08. pii: S2211-1247(25)00730-2. [Epub ahead of print]44(7): 115959
    A mechanistic basis of fast myofiber vulnerability to neuromuscular diseases.
    Matthieu Dos Santos, Svetlana Bezprozvannaya, John R McAnally, Chunyu Cai, Ning Liu, Eric N Olson.
      Neuromuscular diseases such as amyotrophic lateral sclerosis and sarcopenia cause muscle atrophy, which preferentially affects fast-twitch glycolytic myofibers. The mechanisms underlying the susceptibility of fast myofibers to disease remain unclear. To investigate this, we analyzed the transcriptional profiles of myonuclei from denervated muscle fibers. We found that the fast muscle gene program and the transcription factor Maf were repressed upon denervation. Overexpression of Maf in mice prevented loss of muscle mass caused by denervation by repressing atrophic genes and restoring fast gene expression. Similar repression of fast genes and Maf was observed in muscles from mice and humans with amyotrophic lateral sclerosis. Notably, Maf overexpression in human skeletal muscle cells in vitro prevented muscle atrophy and activated the expression of fast muscle genes. Our findings highlight a key role for Maf in maintaining muscle mass and could offer a promising therapeutic strategy to preserve muscle function during disease, aging, and injury.
    Keywords:  Amyotrophic lateral sclerosis; CP: Cell biology; Maf; denervation; fast-twitch genes; glycolytic myofibers; muscle atrophy; myosin heavy chain; neuromuscular disease; single-nucleus ATAC-seq; single-nucleus RNA-seq
    DOI:  https://doi.org/10.1016/j.celrep.2025.115959
  3. Function (Oxf). 2025 Jul 09. pii: zqaf030. [Epub ahead of print]
    Sustained accumulation of molecular clock suppressors Period 1 and Period 2 promotes C2C12 myotube atrophy through an autocrine-mediated mechanism with relevance to androgen deprivation-induced limb muscle mass loss.
    Grant R Laskin, Jennifer L Steiner, Wayne A Ayers-Creech, Michael L Rossetti, Kirsten R Dunlap, Cynthia Vied, Choogon Lee, Nicholas P Greene, Dennis K Fix, Orlando Laitano, Kislay Parvatiyar, Bradley S Gordon.
      Low testosterone in males (hypogonadism) is associated with limb muscle mass loss, yet the underlying mechanisms of muscle mass loss remain largely unknown. We previously showed androgen deprivation disrupted limb muscle molecular clock function, and the disruption coincided with elevated levels of the primary molecular clock suppressor, Period 2 (Per2). The purposes herein were to determine if PER2 overexpression leads to muscle atrophy and if preventing PER2 accumulation blunts limb muscle mass loss in response to androgen deprivation. Here, we identify Per2 as a negative regulator of muscle size. Overexpression of Per2 in differentiated C2C12 myotubes reduced myotube diameter, while deletion of Per2 in male mice partially preserved tibialis anterior (TA) mass following castration. The muscle-sparing effect of Per2 deletion in vivo was specific to the TA despite evidence of molecular clock disruption and mass loss in other muscles. Subsequently, we show overexpression of the other primary clock suppressor, Period 1 (Per1) also reduced myotube diameter in differentiated C2C12 myotubes. Mechanistically, both Per1 and Per2 overexpression in vitro induced muscle atrophy in part by an autocrine-mediated mechanism likely involving inflammation as their overexpression induced an inflammatory gene expression signature and increased cytokine/chemokine secretion. Moreover, incubation of C2C12 myotubes in the media conditioned from Per1 or Per2 overexpressing myotubes reduced myotube diameter. Several inflammatory genes identified in vitro were also altered in the limb muscles in response to androgen deprivation. These findings identify a previously unrecognized role for Per1/2 in regulating skeletal muscle mass with implications for muscle loss during hypogonadism.
    DOI:  https://doi.org/10.1093/function/zqaf030
  4. J Cachexia Sarcopenia Muscle. 2025 Aug;16(4): e70005
    Late-Stage Skeletal Muscle Transcriptome in Duchenne Muscular Dystrophy Shows a BMP4-Induced Molecular Signature.
    Hanna Sothers, Xianzhen Hu, David K Crossman, Ying Si, Matthew S Alexander, Merry-Lynn N McDonald, Peter H King, Michael A Lopez.
       BACKGROUND: Duchenne muscular dystrophy (DMD) is a fatal X-linked recessive disease due to loss-of-function variants in the DYSTROPHIN gene. DMD-related skeletal muscle wasting is typified by an aberrant immune response involving upregulation of the TGFβ family of cytokines, like TGFβ1 and BMP4. We previously demonstrated that bone morphogenetic protein 4 (BMP4) is increased in DMD and BMP4 stimulation induces a 20-fold upregulation of Smad8 transcription in muscle cells. However, the role of BMP4 in late-stage DMD skeletal muscle is unknown. We hypothesized that BMP4 signalling is a driver of aberrant gene expression in late-stage human DMD skeletal muscle detectable by a transcriptomic signature.
    METHODS: Transcriptomes from skeletal muscle biopsies of late-stage DMD versus non-DMD controls and C2C12 muscle cells with or without BMP4 stimulation were generated using RNA-Seq. We tested transcriptional differences at the single transcript level in skeletal muscle biopsy samples from three patients with DMD and compared them to three non-DMD. They were then analyzed by Ingenuity Pathway Analysis, weighted gene coexpression network analyses (WGCNA) and Gene Set Enrichment Analysis (GSEA). Key hub and high-fold change genes overlapping in the DMD and BMP4 muscle transcriptomes were validated in additional primary and bulk skeletal muscle samples.
    RESULTS: A total of 3048 transcripts in the human muscle and 5291 transcripts in C2C12 muscle cells were differentially expressed. WGCNA identified an overlapping molecular signature of 1027 genes dysregulated in DMD muscle that were induced in BMP4-stimulated C2C12 muscle cells. SERPING1 and Aff3 were identified as the top hub genes. Highly upregulated DMD muscle transcripts that overlapped with BMP4-stimulated C2C12 muscle cells included ADAM12, SERPING1, SMAD8 and SFRP4. DMD skeletal muscle analysis showed aberrant upregulation of TGFβ signalling, extracellular matrix remodelling and collagen biosynthesis pathways, in contrast to inhibited mitochondrial and metabolic pathways.
    CONCLUSIONS: In summary, the DMD transcriptome was characterized by dysregulation of immune function, ECM remodelling and muscle bioenergetic metabolism. We additionally define a late-stage DMD skeletal muscle transcriptome that overlaps with a BMP4-induced molecular signature in C2C12 muscle cells. This supports BMP4/Smad8 pathway as a disease-driving regulator of transcriptomic changes in late-stage DMD skeletal muscle. Further exploration of this cross-species transcriptomic signature may expand our understanding of the evolution of dystrophic signalling pathways and the associated gene networks, which could be evaluated for therapeutic development.
    Keywords:   BMP4 ; SMAD8 ; TGFβ1 ; Duchenne muscular dystrophy
    DOI:  https://doi.org/10.1002/jcsm.70005
  5. Oncogene. 2025 Jul 10.
    The tumor suppressor pRb and its relative p130 are required to maintain murine adult skeletal muscle homeostasis.
    Zhe Jiang, Brittany L Baechler, Huiqin Li, Heta Lad, Giovanni Ciavarra, Yaacov Ben-David, Steven J Burden, Joe Quadrilatero, Eldad Zacksenhaus.
      The retinoblastoma tumor suppressor pRB is required for skeletal myogenesis but its role in maintenance of post-mitotic skeletal muscle and the contribution, if any, of its relatives, p107 and p130, are largely unknown. Here, we show that targeted deletion of murine Rb in proliferating myoblasts during myogenesis, using a Pax7-Cre deleter line, leads to muscle fiber degeneration, short myotubes with elongated, large nuclei, reduced late muscle marker expression, and fetal death. These defects are recapitulated in primary myoblasts derived from Pax7-Cre:Rbf/f mice, can be ameliorated by inhibition of autophagy in vitro, and are exacerbated in Pax7-Cre:Rbf/f:p107-/- but not Pax7-Cre:Rbf/f:p130-/- double mutant fetuses. In contrast, deletion of Rb on a wildtype or p107-/- background in post-mitotic muscle, via an Mlc1f-Cre deleter line, has no apparent impact on skeletal muscle homeostasis. However, approximately 10% of Mlc1f-Cre:Rbf/f:p130-/- mice, with combined deletion of Rb and p130, exhibit reduced size, wobbly, waddling gait, along with muscle degeneration and dramatic reduction in skeletal muscle mass. The remaining Mlc1f-Cre:Rbf/f:p130-/- mice had near normal posture and muscle mass, but certain muscle areas show extensive central nuclei, while whole muscles express elevated levels of Pax7 and autophagic markers, suggestive of excessive muscle degeneration and regeneration. These mice also display muscle fiber type redistribution accompanied by reduced PGC-1α expression. Thus, continuous pRB and p130 expression is required to maintain skeletal muscle homeostasis and prevent adult muscle degeneration. Moreover, genetic modifiers-yet to be defined-affect the balance between muscle atrophy and regeneration.
    DOI:  https://doi.org/10.1038/s41388-025-03487-w
  6. bioRxiv. 2025 Jul 03. pii: 2025.07.01.662643. [Epub ahead of print]
    From Development to Regeneration: Insights into Flight Muscle Adaptations from Bat Muscle Cell Lines.
    Fengyan Deng, Valentina Peña, Pedro Morales-Sosa, Andrea Bernal-Rivera, Bowen Yang, Shengping Huang, Sonia Ghosh, Maria Katt, Luciana Castellano, Cindy Maddera, Zulin Yu, Nicolas Rohner, Chongbei Zhao, Jasmin Camacho.
      Skeletal muscle regeneration depends on muscle stem cells, which give rise to myoblasts that drive muscle growth, repair, and maintenance. In bats-the only mammals capable of powered flight-these processes must also sustain contractile performance under extreme mechanical and metabolic stress. However, the cellular and molecular mechanisms underlying bat muscle physiology remain largely unknown. To enable mechanistic investigation of these traits (Graphical Abstract), we established the first myoblast cell lines from the pectoralis muscle of Pteronotus mesoamericanus , a highly maneuverable aerial insectivore. Using both spontaneous immortalization and exogenous hTERT/CDK4 overexpression, we generated two stable cell lines that retain proliferative capacity and differentiate into contractile myotubes. These cells exhibit frequent spontaneous contractions, suggesting robust functional integrity at the neuromuscular junction. In parallel, we performed transcriptomic and metabolic profiling of native pectoralis tissue to define molecular programs supporting muscle specialization. Gene expression analyses revealed enriched pathways for muscle metabolism, development, and regeneration, highlighting the supporting roles in tissue maintenance and repair. Consistent with this profile, the flight muscle is triglyceride-rich, which serves as an important fuel source for energetically demanding processes, including muscle contraction and cellular recovery. Integration of transcriptomic and metabolic data identified three key metabolic modules-glucose utilization, lipid handling, and nutrient signaling-that likely coordinate ATP production and support metabolic flexibility. Together, these complementary tools and datasets provide the first in vitro platform for investigating bat muscle research, enabling direct exploration of muscle regeneration, metabolic resilience, and evolutionary physiology.
    DOI:  https://doi.org/10.1101/2025.07.01.662643
  7. Proc Natl Acad Sci U S A. 2025 Jul 15. 122(28): e2504080122
    HIF1α mediates circadian regulation of skeletal muscle metabolism and substrate preference in response to time-of-day exercise.
    Amy M Ehrlich, Kirstin A MacGregor, Stephen P Ashcroft, Lewin Small, Ali Altıntaş, Alexander V Chibalin, Matthias Anagho-Mattanovich, Ben Stocks, Thomas Moritz, Jonas T Treebak, Juleen R Zierath.
      The regulation of metabolism in peripheral tissues is intricately linked to circadian rhythms, with hypoxia-inducible factor-1α (HIF1α) implicated in modulating time-of-day-specific exercise responses. To investigate this relationship, we generated a skeletal muscle-specific HIF1α knockout (KO) mouse model and performed extensive metabolic phenotyping and transcriptomic profiling under both basal conditions and following acute exercise during early rest (ZT3) and active (ZT15) phases. Our findings reveal that HIF1α drives a more robust transcriptional and glycolytic response to exercise at ZT3, promoting glucose oxidation and mannose-6-phosphate production while potentially sparing fatty acid oxidation. In the absence of HIF1α, skeletal muscle metabolism shifts toward oxidative pathways at ZT3, with notable alterations in glucose fate. These results establish HIF1α as an important regulator of time-of-day-specific metabolic adaptations, integrating circadian and energetic signals to optimize substrate utilization. This work highlights the broader significance of HIF1α in coordinating circadian influences on metabolic health and exercise performance.
    Keywords:  circadian; energy metabolism; exercise; metabolism; transcription factor
    DOI:  https://doi.org/10.1073/pnas.2504080122
  8. J Cachexia Sarcopenia Muscle. 2025 Aug;16(4): e70010
    EIF4A3 Promotes Muscle Atrophy and Aging by Inhibiting the FAK Pathway Through NEDD9 mRNA Destabilization.
    Qian Li, Xiaohang Yin, Wensi Wan, Yi Zhou, Siqi Wang, Yuwei Yan, Jingying Chen, Xinyi Ren, Junli Gao, Yuying Chen, Yanan Zhang, Caiyue Cui, Emeli Chatterjee, Guoping Li, Ming Wu, Yan Zhang, Dongchao Lu, Tingting Yang, Yongjun Zheng, Jin Li.
       BACKGROUND: Muscle atrophy has a poor prognosis, caused by various factors. Identifying a shared treatment target could address an unmet clinical need. The exon junction complex (EJC), a protein complex assembly that binds to RNA, facilitates post-transcriptional regulation by participating in mRNA splicing, mRNA export, translation and nonsense-mediated mRNA decay. This study aims to investigate the role of the EJC in muscle atrophy.
    METHODS: Single-cell transcriptome analysis and western blot were employed to analyse EJC expression in muscle atrophy. Overexpression of EJC helicase EIF4A3, as well as counteracting endogenous EIF4A3, was manipulated using lentiviral and adeno-associated virus 8 (AAV8) at both in vitro and in vivo levels. Imaging, RT-qPCR and immunoblot were utilized to identify phenotypes associated with muscle atrophy and aging. RNA-seq, RIP-seq, RT-qPCR and RIP-PCR were conducted to determine the targets of EIF4A3. A pharmacological approach that activates the downstream pathways in EIF4A3 knockdown muscle was employed to elucidate the molecular mechanisms of EIF4A3 in muscle atrophy.
    RESULTS: The core RNA helicase of the EJC, EIF4A3, showed increased expression in atrophied muscles and aging human muscle (+150.43%, n = 5 in young and aged human, age: 26.20 ± 6.760 vs. 73.60 ± 5.030, p < 0.001) and aged mice muscle (+74.54% in male, +61.28% in female: n = 6 in young and aged mice in male/female, age: 3 months vs. 20 months, p < 0.001). In vitro studies demonstrated that EIF4A3 overexpression promoted muscle atrophy and aging in myotubes (n = 6, p < 0.05), while EIF4A3 inhibition mitigated these effects (p < 0.05). In vivo phenotypic analysis indicated that overexpression of EIF4A3 in skeletal muscle promoted muscle atrophy (n = 10, p < 0.05) including reduced grip strength (-42.36%, p < 0.001), running capacity (-21.24%, p < 0.001), contraction force (-19.62%, p < 0.001), muscle weight (gastrocnemius muscle: -15.75%; p < 0.001; tibialis anterior muscle: -9.50%, p < 0.01), myofiber size (-11.59%, p < 0.001) and worsened molecular phenotypes (all p < 0.05). Knockdown of EIF4A3 protected against muscle atrophy induced by various stimuli, including denervation (n = 10, p < 0.05), immobilization (n = 10, p < 0.05) and angiotensin II (n = 6-10, p < 0.05) in mice. Mechanistically, Neural Precursor Cell Expressed, Developmentally Down-Regulated 9 (NEDD9) mRNA was identified as a direct target of EIF4A3. EIF4A3 promoted the decay of NEDD9 mRNA and inhibited the downstream focal adhesion kinase (FAK) and PI3K-Akt pathway, promoting muscle atrophy. Pharmacological activation of the NEDD9-FAK pathway abolished the pro-atrophy effects of EIF4A3.
    CONCLUSIONS: Our findings shed significant light on the pivotal function of the EJC in muscle atrophy, revealing novel mechanisms that contribute to EJC-related disorders. Providing a target for therapeutic interventions aimed at combating muscle atrophy.
    Keywords:  EIF4A3; FAK; NEDD9; exon junction complex (EJC); muscle atrophy
    DOI:  https://doi.org/10.1002/jcsm.70010
  9. Aging Med (Milton). 2025 Jun;8(3): 200-209
    Frontiers in Nondrug Treatment of Sarcopenia: A Review of Pathological Mechanisms and the Latest Treatment Strategies.
    Qi-Fei Kuang, Yu-Qing Ni, You-Shuo Liu.
      Sarcopenia refers to the progressive decline and wasting of skeletal muscle function, typically linked to aging or as a secondary effect of various conditions, including systemic inflammation, oxidative stress, and mitochondrial dysfunction. Recent scientific research underscores that skeletal muscle function is regulated by multiple factors. These include not only physical activity, environmental exposures, and genetic tendencies, but also nutritional deficiencies. Currently, pharmacological interventions for sarcopenia remain a matter of ongoing debate; the recommended strategies for promoting muscle health center on nutritional support therapy and physical exercise. This review offers an insightful examination of the molecular pathways and Pathophysiology contributing to skeletal muscle atrophy and highlights recent progress in employing nonpharmacological approaches (particularly, nutritional supplementation and physical exercise) for its prevention and management. To provide new scientific evidence and effective strategies for the prevention and treatment of sarcopenia, help to bolster the preservation of skeletal muscle function, and improve the quality of life and health of the elderly.
    Keywords:  aging; sarcopenia; treatment of sarcopenia
    DOI:  https://doi.org/10.1002/agm2.70011
  10. Mol Metab. 2025 Jul 05. pii: S2212-8778(25)00113-9. [Epub ahead of print] 102206
    Endurance training promotes chromatin closure and timely repression of the post-exercise immediate early stress response.
    Laura M de Smalen, Volkan Adak, Aurel B Leuchtmann, Konstantin Schneider-Heieck, Stefan A Steurer, Christoph Handschin.
       OBJECTIVE: Endurance training is known to elicit numerous changes in skeletal muscle to enhance performance and function. Many of these adaptations are controlled by the modulation of transcriptional programs in myonuclei. While previous studies have explored alterations in DNA methylation and histone modifications in response to exercise, the specific changes in chromatin restructuring and accessibility, a prerequisite for transcription, are still poorly understood.
    METHODS: A multi-omics analysis was performed: ATAC-sequencing was used to map chromatin accessibility in myonuclei isolated from endurance-trained and untrained mice at multiple time points (0h, 6h, and 72h) post-exercise. Gene expression was assessed via RNA-sequencing, and motif activity analysis identified regulatory factors involved in exercise-induced chromatin remodeling and transcriptomic response.
    RESULTS: Endurance training amplified rapid chromatin closing immediately after exercise, with trained muscle exhibiting a more pronounced loss of chromatin accessibility at 0h and 6h post-exercise compared to untrained muscle. These chromatin accessibility changes persisted longer in trained muscle, with significant retention until 72h post-exercise. Immediate early transcription factors, such as Fos and Jun, showed a training state-dependent shift in activation dynamics. Similarly, specific modulation of genes involved in metabolism, insulin response and angiogenesis was observed.
    CONCLUSIONS: Endurance training triggers rapid and persistent chromatin remodeling in muscle, contributing to the transcriptional response to exercise. Our findings suggest that training induces long-lasting epigenetic changes, potentially underpinning muscle memory and improved physiological resilience. These new insights into the molecular mechanisms of muscle adaptation help to understand the training response, and might become relevant in disease prevention.
    Keywords:  Chromatin Accessibility; Endurance Training; Exercise; Immediate Early Genes; Skeletal Muscle Plasticity
    DOI:  https://doi.org/10.1016/j.molmet.2025.102206
  11. J Cachexia Sarcopenia Muscle. 2025 Aug;16(4): e70001
    Impaired Autophagic Flux in Skeletal Muscle of Plectin-Related Epidermolysis Bullosa Simplex With Muscular Dystrophy.
    Michaela M Zrelski, Margret Eckhard, Petra Fichtinger, Sabrina Hösele, Andy Sombke, Leonid Mill, Monika Kustermann, Wolfgang M Schmidt, Fiona Norwood, Ursula Schlötzer-Schrehardt, Gerhard Wiche, Rolf Schröder, Lilli Winter.
       BACKGROUND: Plectin, a multifunctional cytolinker and intermediate filament stabilizing protein, is essential for muscle fibre integrity and function. Mutations in the human plectin gene (PLEC) cause autosomal recessive epidermolysis bullosa simplex with muscular dystrophy (EBS-MD). The disorganization and aggregation of desmin filaments in conjunction with degenerative changes of the myofibrillar apparatus are key features in the skeletal muscle pathology of EBS-MD. We performed a comprehensive analysis addressing protein homeostasis in this rare protein aggregation disease by using human EBS-MD tissue, plectin knock-out mice and plectin-deficient cells.
    METHODS: Protein degradation pathways were analysed in muscles from EBS-MD patients, muscle-specific conditional plectin knockout (MCK-Cre/cKO) mice, as well as in plectin-deficient (Plec-/-) myoblasts by electron and immunofluorescence microscopy. To obtain a comprehensive picture of autophagic processes, we evaluated the transcriptional regulation and expression levels of autophagic markers in plectin-deficient muscles and myoblasts (RNA-Seq, qRT-PCR, immunoblotting). Autophagic turnover was dynamically assessed by measuring baseline autophagy as well as specific inhibition and activation in mCherry-EGFP-LC3B-expressing Plec+/+ and Plec-/- myoblasts, and by monitoring primary Plec+/+ and Plec-/- myoblasts using organelle-specific dyes. Wild-type and MCK-Cre/cKO mice were treated with chloroquine or metformin to assess the effects of autophagy inhibition and activation in vivo.
    RESULTS: Our study identified the accumulation of degradative vacuoles as well as LC3- and SQSTM1-positive patches in EBS-MD patients, MCK-Cre/cKO mouse muscles and Plec-/- myoblasts. The transcriptional regulation of ~30% of autophagy-related genes was altered, and protein levels of downstream targets of the autophagosomal degradation machinery were elevated in MCK-Cre/cKO muscle lysates (e.g., LAMP2, BAG3 and SQSTM1 to ~160, ~150 and ~140% of controls, respectively; p < 0.05). Autophagosome turnover was compromised in mCherry-EGFP-LC3B-expressing Plec-/- myoblasts (~40% reduction in median red:green ratio, reduced puncta number, smaller puncta; p < 0.01). By labelling autophagic compartments with CYTO-ID dye or lysosomes with LYSO-ID, we found reduced signal intensities in primary Plec-/- cells (p < 0.001). Treatment with chloroquine led to drastic swelling of autophagic vacuoles in primary Plec+/+ myoblasts, while the swelling in Plec-/- cells was moderate, establishing a defect in their autophagic clearance. Chloroquine treatment of MCK-Cre/cKO mice corroborated that loss of plectin coincides with impaired autophagic clearance, while metformin amelioratively induced autophagic flux.
    CONCLUSIONS: Our work demonstrates that the characteristic protein aggregation pathology in EBS-MD is linked to an impaired autophagic flux. The obtained results open a new perspective on the understanding of the protein aggregation pathology in plectin-related disorders and provide a basis for further pharmacological intervention.
    Keywords:  autophagy; desmin; epidermolysis bullosa simplex with muscular dystrophy; myofibrillar myopathy; plectin; skeletal muscle
    DOI:  https://doi.org/10.1002/jcsm.70001
  12. Sci Adv. 2025 Jul 11. 11(28): eads4371
    Down-regulation of human-specific lncRNA TMEM9B-AS1 in skeletal muscle of people with type 2 diabetes affects ribosomal biogenesis.
    Ilke Sen, Jonathon A B Smith, Elena Caria, Iurii Orlov, Mladen Savikj, Aidan J Brady, Kristian Lian, Stian Ellefsen, Juleen R Zierath, Anna Krook.
      Long noncoding RNAs (lncRNAs) are important regulators of skeletal muscle physiology, with altered expression noted in several human diseases including type 2 diabetes. We report that TMEM9B-AS1, a previously uncharacterized lncRNA, is down-regulated in skeletal muscle of men with type 2 diabetes and skeletal muscle from individuals with sarcopenia. Silencing of TMEM9B-AS1 in primary human myotubes attenuated protein synthesis, concomitant with reduced phosphorylation of ribosomal protein S6. Moreover, we show that TMEM9B-AS1 plays a pivotal role in regulation of ribosomal biogenesis by facilitating messenger RNA stabilization of the transcription factor MYC through direct physical interaction with the RNA binding protein, insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1). Disrupted ribosomal biogenesis resulting from TMEM9B-AS1 silencing leads to decreased expression of muscle contractile and structural proteins important for maintenance of skeletal muscle mass and function. Collectively, our data reveal a role of TMEM9B-AS1 in skeletal muscle loss associated with metabolic disorders.
    DOI:  https://doi.org/10.1126/sciadv.ads4371
  13. Am J Physiol Cell Physiol. 2025 Jul 07.
    Combined angiogenic and hypertrophic gene therapy enhances skeletal muscle growth.
    Aino Männistö, Kialiina Tonttila, Alfredo Ortega-Alonso, Harri Nurmi, Liina Uusitalo-Kylmälä, Karthik Amudhala Hemanthakumar, Erik Saikkala, Sami Myllykangas, Satu S Vertainen, Tuuli A Nissinen, Arja Pasternack, Olli Ritvos, Kari Kustaa Alitalo, Juha J Hulmi, Riikka Kivelä.
      Skeletal muscle atrophy in response to pathophysiological stimuli or disuse includes loss of muscle mass and strength. Targeting signaling pathways regulating muscle growth can counteract muscle loss, but also unwanted side-effects on muscle vascularization, oxidative metabolism and exercise tolerance have been reported. Here, we investigated if combined induction of angiogenesis and muscle hypertrophy can promote physiological muscle growth and improve muscle function to overcome the limitations of current hypertophic treatments. We used myostatin propeptide (Pro-MSTN) and vascular endothelial growth factor B (VEGF-B) gene therapies to increase muscle size and angiogenesis, respectively. Intramuscular and systemic adeno-associated viral vector (AAV) delivery was used to study their effects alone and in combination in healthy and diabetic mice. Single-cell RNA sequencing was used to investigate the effects on different cell types and on intercellular communication in the healthy mice. We demonstrate that in the healthy mice the i.m. delivery of VEGF-B rescued Pro-MSTN -induced capillary rarefaction and enhanced muscle growth in the combination group (VEGF-B+Pro-MSTN). The systemic combination treatment also improved body composition in the healthy mice and increased muscle mass and grip strength in the diabetic mouse model. The single-cell RNA sequencing data showed that among the non-myocytes, endothelial cells and pericytes responded the most to both treatments resulting in enhanced intercellular communication. Our findings demonstrate beneficial effects of the combined gene delivery of Pro-MSTN and VEGF-B on muscle growth and body composition. The results also decipher the contribution of various cell types and their crosstalk in skeletal muscle growth.
    Keywords:  Agrin; Myostatin; Single-cell RNAseq; VEGF-B; muscle atrophy
    DOI:  https://doi.org/10.1152/ajpcell.00966.2024
  14. Aging Cell. 2025 Jul 09. e70164
    Transcriptional Diversity in Response to Aging Across Skeletal Muscles.
    Can Liu, Dongbin Zheng, Rui Zhang, Hong Li, Xingyan Tong, Yujie Wu, Geng Zhang, Siyuan Wang, Hongyu Chen, Zhinong Ren, Ying Sun, Chengdong Wang, Desheng Li, Xuewei Li, Mingzhou Li, Long Jin.
      Aging leads to a gradual decline in muscle function, yet the mechanisms by which different skeletal muscles respond to aging remain unclear. Here, we constructed transcriptional maps of 11 skeletal muscles with extensive transcriptional diversity from young and old mice. Age-related changes in gene expression displayed distinct tissue-specific patterns, involving muscle diseases and metabolic processes. Notably, the mitochondrial-enriched soleus muscle exhibited superior resistance to aging compared to other skeletal muscles. Further, we generated a single-nuclei transcriptomic atlas on representative skeletal muscles, analyzing 73,170 nuclei. We found the age-related changes in the cellular composition of different skeletal muscles and the emergence of new cell states in aged mice. Among different types of myonuclei, type II myonuclei showed particular sensitivity to aging, with reduced metabolic activity of IIb myonuclei with age. We also found cell-specific changes occurring across nonmuscle nuclei populations, including adipocytes, fibro-adipogenic progenitors, and immune cells, accelerating muscle aging and associated pathologies. Intercellular communication analysis revealed more intensive intercellular interactions in aged skeletal muscles, particularly between myonuclei and other cell types. Specifically, we validated the regulatory role of the EGF/EGFR axis in age-related inflammatory processes. These findings provide insight into muscle biology and aging and highlight potential therapeutic targets for age-associated muscle disorders.
    Keywords:  EGF/EGFR; aging; myonuclei; skeletal muscles; transcriptional diversity
    DOI:  https://doi.org/10.1111/acel.70164
  15. Nat Commun. 2025 Jul 05. 16(1): 6207
    Multiomics and cellular senescence profiling of aging human skeletal muscle uncovers Maraviroc as a senotherapeutic approach for sarcopenia.
    Yang Li, Chuhan Li, Qin Zhou, Xingyuan Liu, Yulong Qiao, Ting Xie, Hao Sun, Michael Tim-Yun Ong, Huating Wang.
      Cellular senescence is a hallmark of organismal aging but how it drives aging in human tissues is not fully understood. Here we leverage single nucleus multiomics to profile senescence in mononucleated cells of human skeletal muscle and provide the first senescence atlas. We demonstrate the intra- and inter-populational transcriptomic and epigenomic heterogeneity and dynamics of cellular senescence. We also identify commonalities and variations in senescence-associated secretory phenotypes (SASPs) among the cells and elucidate SASP mediated cellular interactions and niche deregulation. Furthermore, we identify targetable SASPs and demonstrate the possibility of using Maraviroc as a pharmacological senotherapeutic for treating age-associated sarcopenia. Lastly, we define transcription factors that govern senescence state and SASP induction in aging muscle and elucidate the key function and mechanism of JUNB in SASP activation. Altogether, our findings demonstrate the prevalence and function of cellular senescence in skeletal muscle and identify a novel pharmacological intervention for sarcopenia.
    DOI:  https://doi.org/10.1038/s41467-025-61403-y
  16. J Physiol. 2025 Jul 05.
    Diabetes and exercise remodel the myonuclear transcriptome in a fibre type-dependent manner.
    Thomas Hobbs.
      
    Keywords:  fibre type; high‐intensity interval training; skeletal muscle; snRNA‐seq; transcriptome; type 2 diabetes mellitus
    DOI:  https://doi.org/10.1113/JP289363
  17. Front Aging. 2025 ;6 1606110
    Age and sex-specific changes in mitochondrial quality control in skeletal and cardiac muscle.
    Catherine B Springer-Sapp, Olayinka Ogbara, Maria Canellas Da Silva, AbryAnna Henderson, Yuan Liu, Steven J Prior, Sarah Kuzmiak-Glancy.
       Introduction: Skeletal and cardiac muscle mitochondria exist in a dynamic reticulum that is maintained by a balance of mitochondrial biogenesis, fusion, fission, and mitophagy. This balance is crucial for adequate ATP production, and alterations in skeletal muscle mitochondria have been implicated in aging-associated declines in mitochondrial function.
    Methods: We sought to determine whether age and biological sex affect mitochondrial content [Complex IV (CIV)], biogenesis (PGC-1ɑ), fusion (MFN2, OPA1), fission (DRP1, FIS1), and mitophagy (Parkin, Pink1) markers in skeletal and cardiac muscle by assessing protein expression in tibialis anterior (TA) and ventricular tissue from 16 young (≤6 months) and 16 old (≥20 months) male and female Sprague-Dawley rats.
    Results: In the TA, CIV expression was 40% lower in old vs. young rats (p < 0.001), indicating lower mitochondrial content, and coincided with higher expression of Parkin (+4-fold, p < 0.001). Further, MFN2 expression was higher (+2-fold, p < 0.005) and DRP1 expression was lower (-40%, p = 0.014) in older rats. In cardiac muscle, mitochondrial content was maintained in old vs. young rats, and this occurred concomitantly with higher expression of both PGC-1ɑ and Parkin. MFN2 and OPA1 expression were also 1.2-5-fold higher in older rats (p < 0.05 for all). Largely, protein expression did not differ between male and female rats, with the exception of Pink1 and FIS1 expression in the TA.
    Discussion: Collectively, older skeletal and cardiac muscle demonstrated higher expression of fusion and mitophagy proteins, which indicates age alters the balance of biogenesis, fission, fusion, and mitophagy. This may, in turn, affect the ability to provide ATP to these metabolically active tissues.
    Keywords:  biological sex; fission; fusion; mitophagy; muscle health
    DOI:  https://doi.org/10.3389/fragi.2025.1606110
  18. Nucleic Acids Res. 2025 Jul 08. pii: gkaf643. [Epub ahead of print]53(13):
    Nucleolar FRG2 lncRNAs inhibit rRNA transcription and cytoplasmic translation, linking FSHD to dysregulation of muscle-specific protein synthesis.
    Valentina Salsi, Francesca Losi, Bruno Fosso, Marco Ferrarini, Sara Pini, Marcello Manfredi, Gaetano Vattemi, Tiziana Mongini, Lorenzo Maggi, Graziano Pesole, Anthony K Henras, Paul D Kaufman, Brian McStay, Rossella Tupler.
      Facioscapulohumeral muscular dystrophy (FSHD) is a hereditary myopathy linked to deletions of the tandemly arrayed D4Z4 macrosatellite at human chromosome 4q35. These deletions cause local chromatin changes and anomalous expression of nearby transcripts FRG2A, DBET, and D4Z4. We discovered that FRG2A is part of a family of long noncoding RNAs (lncRNAs) expressed in skeletal muscle cells, with levels varying among patients. FRG2A localizes in the nucleolus and associates with repetitive DNA at ribosomal DNA (rDNA) loci and centromeres. Elevated FRG2A expression in FSHD cells alters the three-dimensional architecture of heterochromatin at the nucleolar periphery and reduces rDNA transcription and translation rates, resulting in decreased synthesis of skeletal muscle proteins. We also show that myoblasts from FSHD patients display reduced synthesis of skeletal muscle proteins during differentiation. Our results support a disease model in which nucleolar accumulation of D4Z4-driven lncRNA impairs protein synthesis and contributes to muscle wasting.
    DOI:  https://doi.org/10.1093/nar/gkaf643
  19. Diabetes. 2025 Jul 08. pii: dbi250003. [Epub ahead of print]
    High-Quality Weight Loss in Obesity: Importance of Skeletal Muscle.
    Mary-Ellen Harper, Robert R M Dent, Ruth McPherson.
       ARTICLE HIGHLIGHTS: High-quality weight loss, i.e., a high proportion of fat to skeletal muscle lost during the treatment of obesity, is advantageous for metabolic and physical health. Precise and accurate determinations of skeletal muscle mass in clinical settings are often challenging. In prevention of excessive loss of skeletal muscle during weight loss, advantages include minimization of metabolic adaptation that makes it difficult to sustain weight loss, improved glucose homeostasis and metabolic flexibility, and better mobility and strength. Effective approaches to preserving skeletal muscle include sufficient dietary protein and inclusion of exercise (especially resistance exercise) during weight loss; new pharmacological approaches are under development.
    DOI:  https://doi.org/10.2337/dbi25-0003
  20. JCI Insight. 2025 Jul 08. pii: e181946. [Epub ahead of print]10(13):
    Macrophage-derived Spp1 promotes intramuscular fat in dystrophic muscle.
    Philip K Farahat, Chino Kumagai-Cresse, Raquel L Aragón, Feiyang Ma, Justin K Amakor, Alejandro Espinoza, Irina Kramerova, Robert J Jimenez, Bradley M Smith, Jesus Perez, Rachelle H Crosbie, Apoorva H Nagendra, Jackie McCourt-Towner, Gerald Coulis, Oluwatayo F Ikotun, April D Pyle, Matteo Pellegrini, Elizabeth M McNally, S Armando Villalta, Melissa J Spencer.
      Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disorder involving cycles of muscle degeneration and regeneration, leading to accumulation of intramuscular fibrosis and fat. Ablation of Osteopontin/Spp1 in a murine model of DMD (mdx) improves the dystrophic phenotype, but the source of Spp1 and its impact on target cells in dystrophic muscles remain unknown. In dystrophic muscles, macrophages are the predominate infiltrating leukocyte and express high levels of Spp1. We used macrophage-specific ablation combined with single-cell transcriptional profiling to uncover the impact of macrophage-derived Spp1 on cell-cell interactions in mdx muscles. Ablation of macrophage-specific Spp1 (cKO) correlated with reduction of 2 PDGFRa+ stromal cell populations, expressing Lifr+ and Procr+. Sorting and transcriptional profiling of these populations confirmed that they are enriched in adipogenesis genes and are highly related to fibroadipogenic precursors (FAPS). These adipogenic stromal cells (ASC) displayed more adipogenic potential in vitro compared with FAPS, likely due to a more differentiated state. Reduction of ASCs correlated with reduced intramuscular diaphragmatic fat and improved diaphragm function. These data suggest a role for myeloid-derived Spp1 in the differentiation of stromal cells towards an adipogenic fate, leading to accumulation of intramuscular fat in dystrophic muscles.
    Keywords:  Genetics; Monogenic diseases; Muscle; Muscle biology
    DOI:  https://doi.org/10.1172/jci.insight.181946
  21. Front Physiol. 2025 ;16 1607873
    Mechanisms of skeletal muscle atrophy in type 2 diabetes mellitus.
    Jingyi Yang, Yingdong Wang, Yuzhe Xu, Xinqi Jia, Fangping Lu.
       Introduction: ERS-induced apoptosis may play a pivotal role in diabetic skeletal muscle atrophy. However, the specific mechanisms by which ERS regulates skeletal muscle atrophy in diabetes remain unclear. The research examines the impact of endoplasmic reticulum stress (ERS) on skeletal muscle atrophy in type 2 diabetes mellitus (T2DM) mice.
    Methods: Leptin receptor-deficient Db/db mice (n = 7, 24-week-old, male) were employed as a type 2 diabetes model, while age-matched male C57BL/6J mice (n = 7) served as normal controls. Pathway enrichment analysis of differentially expressed genes was performed based on transcriptome sequencing data, focusing on apoptosis, ERS, and ubiquitin-proteasome pathways. Skeletal muscle morphology was assessed via anatomical observation, Laminin Staining, and immunoblotting analysis (WB). WB was used to detect ERS markers (ATF6, p-eIF2α, Bip, p-JNK, Chop), apoptosis-related proteins (Bcl2, Bax, Cleaved Caspase-3, CytC), p-Akt, and muscle atrophy marker Atrogin1.
    Results: Transcriptomic enrichment analysis confirmed specific activation of apoptosis, ERS, and ubiquitin-proteasome pathways. WB revealed upregulated ERS-related proteins, increased apoptotic proteins, decreased p-Akt expression, elevated Atrogin1 levels, and enhanced proteolytic activity. Db/db mice exhibited significant skeletal muscle atrophy, with Laminin Staining demonstrating reduced cross-sectional area (CSA) of muscle fibers.
    Discussion: These findings uncovers a dual regulatory mechanism underlying diabetic muscle atrophy. The diabetic skeletal muscle microenvironment exhibits elevated oxidative stress and significantly enhanced ER stress, which promotes direct muscle atrophy through ER stress sensor-mediated apoptosis. Concurrently, sustained ER stress suppresses Akt activity while upregulating the muscle-specific E3 ubiquitin ligase Atrogin1, thereby accelerating proteolysis and inducing indirect muscle wasting. These findings provide crucial mechanistic insights into diabetic skeletal myopathy, highlighting the ER stress signaling network as a promising therapeutic target for mitigating muscle atrophy in diabetes.
    Keywords:  apoptosis; endoplasmic reticulum stress; proteostasis; skeletal muscle atrophy; type 2 diabetes mellitus
    DOI:  https://doi.org/10.3389/fphys.2025.1607873
  22. Redox Biol. 2025 Jul 03. pii: S2213-2317(25)00264-2. [Epub ahead of print]85 103751
    Targeting Dio3 to enhance mitophagy and ameliorate skeletal muscle wasting in sepsis.
    Gang Wang, Ming Chen, Yuheng Zhang, Dacheng Wang, Tao Gao, Jianfeng Duan, Huimin Lu, Minhua Cheng, Yun Xu, Xiaoyao Li, Yan Wang, Ke Cao, Wenkui Yu.
      Recent studies highlight the role of skeletal muscle wasting in the sepsis-associated long-term mortality. Despite clinical recommendations for increased protein intake to counteract muscle wasting, the outcomes have been suboptimal, suggesting that anabolic resistance should be considered in addition to nutritional support. Emerging evidence suggests that impaired mitophagy hampers anabolic processes in skeletal muscle, exacerbating muscle wasting in sepsis. Furthermore, thyroid hormone (TH), which is essential for both anabolism and mitophagy, is locally inactivated by type 3 Deiodinase (Dio3) at the onset of sepsis, potentially disrupting mitophagy and contributing to anabolic resistance. Here we demonstrate that local hypothyroidism is a key factor impairing mitophagy in skeletal muscle during early sepsis, leading to metabolic disturbances and muscle wasting. Dio3 knockdown preserves muscle mass, and ameliorates metabolic dysfunction via mitophagy promotion in sepsis models. Mechanistically, the knockdown of Dio3 triggers an upregulation of NRK2, facilitating the restoration of NAD salvage synthesis. This enhancement of NAD levels subsequently activates Sirtuins deacetylase, which in turn decreases PINK1 acetylation, preventing its proteolytic processing by OMA1. Therefore, targeting Dio3 offers a promising therapeutic approach to counteract sepsis-induced muscle wasting.
    DOI:  https://doi.org/10.1016/j.redox.2025.103751
  23. Physiol Rep. 2025 Jul;13(13): e70424
    The proteoglycan decorin does not influence adiposity, glucose tolerance, or aerobic exercise capacity in mice.
    Casey L Egan, Atanaska Doncheva, Martin Pal, Sarah L Fox, Knut Tomas Dalen, Martin Whitham, Mark A Febbraio, Marit Hjorth.
      Physical activity is associated with improvements in insulin sensitivity and muscle function. The proteoglycan decorin is increased in skeletal muscle and plasma in response to exercise, but the biological implications are unknown. We investigated the effects of decorin deficiency on obesity, glucose tolerance, and exercise adaptation in C57BL/6J mice. Decorin deficiency did not influence adiposity, insulin- and glucose- tolerance, or energy metabolism in obese, high fat diet fed mice (Dcn-/- vs. Dcn+/+). Decorin is abundant in the skeletal muscle extracellular matrix, thus we further compared the skeletal muscle of Dcn-/- and Dcn+/+ littermates. There were no effects on muscle morphology or the expression of metabolic markers. Dcn-/- mice had normal exercise capacity measured as running distance on a treadmill. To study the effects of long-term exercise, mice were housed with access to running wheels. Overall, there were no major differences in voluntary wheel running or skeletal muscle metabolic markers, but Dcn-/- mice had a tendency for reduced running wheel activity compared to Dcn+/+ mice. This was accompanied by a smaller exercise effect on metabolic markers in muscle Dcn-/- mice. Our findings indicate that decorin does not have a major impact on glucose tolerance, metabolic adaptation, or aerobic exercise performance.
    Keywords:  decorin; exercise; extracellular matrix; myokines; obesity
    DOI:  https://doi.org/10.14814/phy2.70424
  24. J Cachexia Sarcopenia Muscle. 2025 ;16(4): e70000
    Impact of Adipose Tissue and Lipids on Skeletal Muscle in Sarcopenia.
    Soo Yeon Jang, Kyung Mook Choi.
       BACKGROUND: Although the decline in muscle mass, function and increased visceral obesity are attracting substantial attention in the ageing society, approved treatment modalities for sarcopenia/sarcopenic obesity (SO) remain limited. Elucidating effects and mechanisms of adipose tissue and lipids on skeletal muscle is important for identifying potential prevention and treatment targets for sarcopenia/SO.
    METHODS: In this narrative review, we aim to comprehensively summarize current knowledge on how adipose tissue and lipid metabolites influence skeletal muscle with detailed mechanistic explanations, especially in sarcopenia development. We also tried to explore future perspectives for optimal strategies for managing sarcopenia.
    RESULTS: Fatty infiltration in skeletal muscle can alter the structure, metabolism and signalling pathways of muscle, thereby worsening muscle function and physical performance. Intracellular lipid droplets could disrupt normal physiology within muscle cells, but it might be influenced not only by quantity but also by size, location and characteristics of lipid droplets. Intracellular lipid metabolites may induce lipotoxicity in cell signalling of muscle cells, but effects might differ by types or chemical structure. Highly trained athletes exhibit insulin sensitivity despite high levels of muscular fat, a phenomenon called the athlete's paradox. Lipid droplets within the skeletal muscle of athletes are small and are mainly located in the intermyofibrillar area, which is rich in fast-twitch, Type I fibres. In contrast, patients with Type 2 diabetes/obesity accumulate larger lipid droplets in the subsarcolemmal area, which is richer in Type II fibres. Ageing is intricately associated with mitochondrial dysfunction and the concomitant decline in mitochondrial biogenesis, all of which may lead to sarcopenia. SIRT1 and AMPK, two key energy sensors, are involved in mitochondrial biogenesis through regulation of PGC-1α. Modulation of PGC-1α levels in skeletal muscle may help protect against sarcopenia by preserving muscle integrity, enhancing muscle function, improving insulin sensitivity and reducing inflammation and oxidative stress. Excessive nutrient intake and obesity triggers mitochondrial dysfunction by inducing activation of the inflammatory response and increased production of reactive oxygen species. Skeletal muscle and adipose tissue are closely connected through mediators called adipokines and myokines, and it is important to understand the mechanisms of their interaction.
    CONCLUSIONS: Dysregulation of lipid metabolism and intramuscular fat accumulation leads to inflammation, oxidative stress, insulin resistance and mitochondrial dysfunction, resulting in reduced muscle mass and strength. Further research on associations between fat/lipids and muscle would be helpful to investigate optimal management strategies for sarcopenia/SO in the rapidly ageing world.
    Keywords:  adipose tissue; cachexia; fat mass; lipids; sarcopenia
    DOI:  https://doi.org/10.1002/jcsm.70000
  25. J Adv Res. 2025 Jul 04. pii: S2090-1232(25)00499-0. [Epub ahead of print]
    Scutellarein attenuates cancer cachexia-induced muscle atrophy via targeted inhibition of the JAK/STAT pathway.
    Heeju Ahn, Heeju Kim, Yeyoung Yoon, Minju Jeong, Sieun Lee, Peng Chen, Keke Wang, Sujung Park, Jae Hwan Kim, Jiyun Ahn, Qiantao Wang, Yoonhee Jin, Young Jin Jang, Sanguine Byun.
       INTRODUCTION: Cancer cachexia is a multifaceted metabolic syndrome characterized by severe loss of skeletal muscle and adipose tissue, diminishing both quality of life and survival in cancer patients. Despite its prevalence, effective treatments for cancer cachexia remain limited. The JAK/STAT signaling pathway has been identified as a key driver of muscle atrophy in cachexia.
    OBJECTIVES: This study aimed to investigate the therapeutic potential of scutellarein, a natural compound, as a JAK kinase inhibitor to prevent and mitigate cancer cachexia-induced muscle atrophy.
    METHODS: In vitro experiments were conducted using the mouse myoblast cell line C2C12 and human induced pluripotent stem cell (hiPSC)-derived skeletal muscle cells. Myotube atrophy was induced using IFN-γ/TNF-α and cancer cell-conditioned media. Two independent mouse models of cancer cachexia were utilized for in vivo analysis. Muscle tissues were examined through transcriptomic and molecular analyses, including RNA sequencing, PCR, and immunoblotting. Structure-activity relationship studies and molecular docking analyses were performed to investigate the binding interaction of scutellarein with JAK kinases.
    RESULTS: Through a chemical library screen, we identified scutellarein as a potent JAK kinase inhibitor. Scutellarein effectively mitigated myotube atrophy by inhibiting protein degradation and promoting protein synthesis in C2C12 and hiPSC-derived muscle cells. In two distinct mouse models of cancer cachexia, scutellarein treatment significantly reduced muscle wasting, improved muscle strength and function, and countered fat depletion. Transcriptomic and molecular analyses of muscle tissues further demonstrated that scutellarein inhibited activation of JAK/STAT pathways and restored suppression of myogenesis and mitochondrial biogenesis. Structure-activity relationship analyses further revealed critical hydroxyl group positions essential for JAK binding.
    CONCLUSION: Collectively, our findings suggest scutellarein as a promising candidate for the prevention and treatment of cancer cachexia, providing a novel therapeutic approach to address this critical unmet need in cancer care.
    Keywords:  Cancer cachexia; Janus kinase; Muscle atrophy; Scutellarein; Signal transducers and activators of transcription; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.jare.2025.07.001
  26. Sci Adv. 2025 Jul 11. 11(28): eadw2593
    The human genetic variant rs6190 unveils Foxc1 and Arid5a as novel prometabolic targets of the glucocorticoid receptor in muscle.
    Ashok Daniel Prabakaran, Fabian Montecino-Morales, Kevin McFarland, Thirupugal Govindarajan, Hima Bindu Durumutla, Hannah Latimer, Olukunle Akinborewa, Chiara Villa, Douglas P Millay, Mattia Quattrocelli.
      The mechanisms segregating positive from negative effects of the glucocorticoid receptor (GR) on metabolic health remain poorly elucidated. Here, we generated mice genocopying the human GR polymorphism rs6190, which was sufficient to increase muscle insulin sensitivity and blunt obesity-induced adverse effects on adiposity and exercise intolerance. We identified Foxc1 and Arid5A genes as prospective transactivation targets by the mutant GR in skeletal muscle. In the muscle, we further characterize Foxc1 as transcriptional activator of Insr and Irs1 in the canonical insulin signaling and Arid5a as transcriptional repressor of Cd36 and Fabp4 in the lipid uptake pathway. Moreover, Foxc1 and Arid5a programs in muscle were divergently changed by glucocorticoid regimens with opposite metabolic outcomes. Last, in the UK Biobank and All of Us datasets, the rs6190 variant correlated with prometabolic changes in BMI, lean mass, strength, and glucose control according to zygosity. Collectively, our study leveraged a human nuclear receptor coding variant to unveil epigenetic regulators of muscle metabolism.
    DOI:  https://doi.org/10.1126/sciadv.adw2593
  27. Geroscience. 2025 Jul 08.
    Exploring motor unit and neuromuscular junction dysfunction in aging and sarcopenia: insights from electromyography in systematic review.
    Can Cui, Yong Hu, Ronald Man Yeung Wong, Ning Zhang, Yuzhou Guan, Wing-Hoi Cheung.
      The neuromuscular junction (NMJ) is a vital interface between motor neurons and muscle fibers, and alterations in its structure and function can substantially influence the onset and progression of sarcopenia. Electromyography (EMG) is a critical tool to assess motor unit and NMJ function, providing insights into neuromuscular activation patterns and the integrity of motor unit communication. However, its implications for aging and muscle performance during sarcopenia have not been fully discussed. Therefore, we conducted a systematic review using the PubMed, Embase, and Web of Science databases by employing relevant keywords. A total of 53 articles were included. This review explored the various alterations in the NMJ associated with aging, their functional implications, and potential interventions to mitigate these effects, highlighting the structural and functional alterations of the NMJ during aging and sarcopenia. Key findings include early NMJ transmission instability, motor unit loss and compensatory remodeling, and impaired neuromuscular activation preceding overt muscle atrophy and weakness. Notably, biomarkers such as C-terminal agrin fragment and neurofilament light chain, along with EMG-derived parameters (e.g., jitter, jiggle, MUNE), are sensitive indicators of NMJ deterioration. Both physical inactivity and hormonal changes (e.g., menopause) accelerate NMJ decline, while interventions such as resistance and endurance training, nutritional supplementation, and emerging gene therapies demonstrate potential to preserve or restore NMJ structure and function. In conclusion, this systematic review underscores the importance of NMJ dysfunction in aging and sarcopenia, advocating further research into diagnostic biomarkers and therapeutic strategies to enhance NMJ integrity. The interplay between aging, exercise, and NMJ function is complex and requires a nuanced approach to rehabilitation and exercise strategies tailored to the aging population. Future directions should prioritize the development of sensitive biomarkers, mechanistic studies of NMJ degeneration, and rigorous evaluation of multimodal interventions to mitigate neuromuscular decline and promote healthy aging.
    Keywords:  Aging; Electromyography; Motor unit; Neuromuscular junction; Sarcopenia
    DOI:  https://doi.org/10.1007/s11357-025-01760-0
  28. FASEB J. 2025 Jul 15. 39(13): e70787
    Non-Invasive Ultrasound Treatment Enhances the Release of Skeletal Muscle-Derived Extracellular Vesicles in Mice.
    Atomu Yamaguchi, Xiaoqi Ma, Mikiko Uemura, Kento Tanida, Nozomi Nishimura, Jiaqi Tan, Gojiro Nakagami, Hiromi Sanada, Dongming Su, Kristopher Sarosiek, Hidemi Fujino, Noriaki Maeshige.
      Skeletal muscle, the largest secretory organ, regulates distant organs through the secretion of various factors. Among these are extracellular vesicles (EVs), which play a significant role in mediating communication between muscle and other tissues and hold therapeutic potential due to their target specificity and anti-inflammatory properties. Enhancing the release of EVs from skeletal muscle into the circulation is crucial for eliciting their diverse effects, including anti-inflammatory actions; however, effective strategies to increase the levels of muscle-derived EVs in the bloodstream have not yet been developed. While exercise is the most studied method to increase blood EV levels, its efficacy in enhancing skeletal muscle-derived EVs remains unclear. This study reveals that a brief, 5-min ultrasound (US) treatment of skeletal muscle robustly elevates circulating levels of muscle-derived EVs, introducing a novel, non-invasive stategy to modulate EV release. US-induced EVs showed altered miRNA profiles enriched with anti-inflammatory miRNAs that target pathways involved in inflammatory responses. Additionally, transient upregulation of reactive oxygen species and activation of the endoplasmic reticulum stress pathway were observed in US-treated muscle, suggesting a mechanism for enhanced EV release. Our findings establish US as the first non-invasive and rapid method to selectively enhance skeletal muscle-derived EV release into the circulation, highlighting its potential for therapeutic applications through its anti-inflammatory effect.
    Keywords:  anti‐inflammation; extracellular vesicles; skeletal muscle; ultrasound
    DOI:  https://doi.org/10.1096/fj.202501797R
  29. J Cachexia Sarcopenia Muscle. 2025 Aug;16(4): e70007
    Skeletal Muscle-Specific Deletion of E3 Ligase Asb2 Enhances Muscle Mass and Strength.
    Hye Rim Jang, Shi-Young Park, Yeonmi Lee, Dongjin Lee, Jongjun Lee, Yoonil Cho, Cheol Soo Choi, Hui-Young Lee.
       BACKGROUND: Maintaining skeletal muscle mass and strength is crucial to prevent sarcopenia during healthy ageing. Ankyrin repeat and suppressor of cytokine signalling box protein 2 (Asb2), an E3 ligase, has been implicated in regulating muscle mass; however, its roles on muscle strength remain unclear, with mixed findings from previous studies. Overexpression of Asb2 decreases muscle mass, whereas its knockdown delays myoblast differentiation and reduces contractile proteins. Given these contradictory findings, we aimed to clarify the role of Asb2 in muscle mass and strength using a skeletal muscle-specific Asb2 knockout (Asb2 MKO) mouse model. Additionally, we investigate the long-term effects of Asb2 on aged muscle, underlying mechanisms on muscle regulation and metabolic effects of Asb2 MKO mice to better understand its role in muscle function and age-related metabolic diseases.
    METHODS: Asb2 MKO mice were generated using Acta1-Cre recombinase. Body composition was quantified in male and female mice up to 18 months of age. Muscle strength, energy expenditure and glucose metabolism were evaluated using the grip strength test, mitochondrial oxygen consumption measurement, indirect calorimetry and glucose/insulin tolerance tests. Transcriptomic analyses and siRNA studies were performed to elucidate the mechanisms underlying the Asb2 deletion.
    RESULTS: The MKO mice were born healthy and exhibited selective Asb2 deletion in the skeletal muscle, leaving the cardiac muscle unaffected. This deletion led to an increase in the mass of various skeletal muscles (9%-23%, p < 0.05) and improved grip strength (~10%, p < 0.05), both of which were sustained throughout the ageing process. The MKO mice also revealed enhanced mitochondrial function, energy expenditure and whole-body insulin sensitivity. Transcriptomic data supported the muscle phenotype observed in the MKO mice. Notably, desmin, a protein critical for structural integrity and mitochondrial function, was identified as a target protein of the ASB2 E3 ligase.
    CONCLUSIONS: Skeletal muscle-specific deletion of Asb2 led to increased muscle mass and strength, potentially through preservation of desmin levels. These findings suggest that targeting Asb2 may enhance muscle growth and prevent age-related muscle decline, with potential benefits for metabolic health, particularly by improving mitochondrial function and insulin sensitivity.
    Keywords:   Asb2 ; ageing; desmin; mitochondrial function; skeletal muscle mass
    DOI:  https://doi.org/10.1002/jcsm.70007
  30. Calcif Tissue Int. 2025 Jul 09. 116(1): 96
    Decreased Expression and Secretion of the Myokine Fndc5/Irisin by Cisplatin Treatment in Mouse Skeletal Muscle.
    Yu Miyauchi, Shinki Soga, Hayato Nanri, Shiori Yonamine, Takayuki Ogiwara, Miho Kiyama, Risako Kon, Nobutomo Ikarashi, Yoshihiko Chiba, Tomoo Hosoe, Hiroyasu Sakai.
      The systemic administration of cisplatin has been shown to substantially reduce skeletal muscle mass. This is a serious concern, as muscle loss is correlated with increased mortality in patients with cancer. Cisplatin also contributes to cognitive decline, but the exact mechanism thereof remains unclear. In this study, we focused on fibronectin type III domain-containing 5 (Fndc5), a gene that produces irisin, a myokine that is important for brain health. Male C57BL/6J mice (8-9 weeks old) were injected with cisplatin or saline for 4 consecutive days. Twenty-four h after final injection of cisplatin, quadriceps muscles were isolated. C2C12 myotubes were treated with cisplatin with/without AICAR. In male C57BL/6J mice treated with cisplatin, a reduced expression of the key regulator PGC-1α was observed, along with reduced levels of Fndc5/irisin mRNA and protein in the mice quadriceps muscles. Similar findings were seen in cisplatin-treated C2C12 myotube cells, where the activation of PGC-1α with AICAR partially offset these effects. These results suggest that cisplatin inhibits the synthesis of Fndc5/irisin and may contribute to the metabolic changes and cognitive decline observed in patients with cancer who receive this treatment.
    Keywords:  Anticancer drugs; Cisplatin; Irisin; Muscle atrophy; PGC-1α; Side effects
    DOI:  https://doi.org/10.1007/s00223-025-01406-5
  31. Free Radic Biol Med. 2025 Jul 05. pii: S0891-5849(25)00811-1. [Epub ahead of print]
    Aerobic exercise ameliorates skeletal muscle atrophy in atic knockout zebrafish through the oxidative phosphorylation pathway.
    Zheng Peng, Tianle Yang, Siting Xu, Boyu Yang, Zhilong Zhang, Meng Ding, Wenzhi Gu, Lan Zheng.
      The mechanisms linking purine metabolism disorders to skeletal muscle pathology are unclear. This study constructed a CRISPR/Cas9-mediated zebrafish atic knockout model and a siRNA-interfered C2C12 myoblast cell model. We revealed a novel mechanism by which ATIC (5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase) deletion drove the atrophy of skeletal muscle through the downregulation of the oxidative phosphorylation of mitochondria (OXPHOS) pathway. It was found that atic/Atic knockout/knockdown led to the interruption of purine de novo synthesis, abnormal 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) accumulation, and blockage of inosine monophosphate (IMP) synthesis, which in turn triggered mitochondrial structural damage, dysfunction of complex I-V function, and a burst of reactive oxygen species (ROS), and ultimately triggered muscle atrophy through activation of the ubiquitin-proteasome system. The progressive aerobic intervention revealed that 8 weeks of training significantly restored skeletal muscle function in zebrafish atic-/- mutants, and the mechanism was related to the enhancement of mitochondrial biogenesis, up-regulation of the core complex expression of the OXPHOS pathway, and the improvement of ROS scavenging ability. These findings reveal that ATIC deficiency disrupts mitochondrial function through purine metabolism dysregulation, linking aberrant AICAR accumulation to OXPHOS impairment, which provides a theoretical basis for the early warning of muscular toxicity of targeted purine metabolizing drugs and lays a molecular foundation for the exercise rehabilitation strategy of metabolic myopathies.
    Keywords:  ATIC; CRISPR-Cas9; aerobic exercise; muscle; oxidative phosphorylation pathway
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.07.007
  32. Biomed Pharmacother. 2025 Jul 05. pii: S0753-3322(25)00510-4. [Epub ahead of print]189 118316
    Soyasapogenol B prevents sarcopenia by increasing skeletal muscle mass and function through the Sirt1/PGC-1α and PI3K pathway.
    Byeong Min Ahn, Yuran Noh, Justin Jaesuk Lee, Jung Han Yoon Park, Ki Won Lee, Young Jin Jang.
      Sarcopenia, caused by aging, is characterized by the reduction of muscle mass and function. In this study, we investigated the effects of soyasapogenol B on skeletal muscle and the underlying mechanisms to determine its potential as a prevention for sarcopenia. Soyasapogenol B, a natural triterpenoid found in soybeans, has biological effects that inhibit cancer, inflammation, and obesity; however, its effects on skeletal muscle remain unclear and require further investigation. C57/BL6 mice were fed soyasapogenol B for 8 weeks, after which skeletal muscle mass, function, and protein analysis for muscle synthesis and exercise mimetics were evaluated. The mechanism of skeletal muscle improvement by soyasapogenol B was identified through in vitro experiments. Soyasapogenol B increased the weight of the quadriceps and gastrocnemius muscles, grip strength, and running endurance. It also enhanced oxidative muscle fiber switching, mitochondrial enzyme complex, and mitochondria biogenesis through the Sirt1/PGC-1α pathway. Soyasapogenol B increased myogenic differentiation and protein synthesis, through the PI3K pathway. The upregulation of mitochondrial biogenesis and myogenic differentiation by soyasapogenol B was attenuated by treatment with EX-527, a SIRT1 inhibitor, and LY294002, a PI3K inhibitor. Molecular docking analyses showed that soyasapogenol B has the potential to directly bind to Sirt1. In conclusion, soyasapogenol B increased skeletal muscle mass, skeletal muscle strength and endurance by activating the Sirt1 and PI3K pathways. Thus, by promoting protein synthesis and mitochondrial biogenesis, soyasapogenol B could be a potential prevention option for sarcopenia.
    Keywords:  PI3K pathway; Sarcopenia; Sirt1/PGC-1α pathway; Soyasapogenol B; mitochondrial biogenesis
    DOI:  https://doi.org/10.1016/j.biopha.2025.118316
  33. J Adv Res. 2025 Jul 03. pii: S2090-1232(25)00502-8. [Epub ahead of print]
    Aging induces sarcopenia by disrupting the crosstalk between the skeletal muscle microenvironment and myofibers.
    Ning Wang, Aojie Zheng, Youzhen Yan, Tailai He, Xuan Wu, Menglin Xian, Jingyuan Luo, Changjun Li, Jie Wei, Yilun Wang, Chao Zeng, Guanghua Lei.
       BACKGROUND: Sarcopenia is a degenerative muscular disease associated with aging, characterized by a reduction in muscle mass and strength. This disease poses a significant global health challenge, owing to its high prevalence and association with adverse outcomes such as increased frailty, impaired physical function, and elevated mortality risk. A deeper understanding of its underlying mechanisms is urgently warranted for the development of effective therapeutic interventions.
    AIM OF REVIEW: Skeletal muscle is a heterogeneous tissue composed of various cellular components, including myofibers and other muscle-resident cells such as satellite cells, neurons and immune cells. Myofibers serve as the fundamental units determining muscle mass and strength, while muscle-resident cells establish the skeletal muscle microenvironment (SMME), which plays a significant role in maintaining skeletal muscle health. This review aimed to systematically dissect the crosstalk between myofibers and the SMME, and develop potential therapeutic interventions by highlighting novel insights into the pathogenesis of sarcopenia.
    KEY SCIENTIFIC CONCEPTS OF REVIEW: This review provides a comprehensive overview of the age-related changes in various SMME components, with a specific focus on the disrupted interactions between them and myofibers during aging.
    Keywords:  Aging; Crosstalk; Myofiber; Sarcopenia; Skeletal muscle microenvironment
    DOI:  https://doi.org/10.1016/j.jare.2025.07.004
  34. bioRxiv. 2025 Jul 03. pii: 2025.06.29.662135. [Epub ahead of print]
    High-fat diet ablates an insulin-responsive pool of GLUT4 glucose transporters in skeletal muscle.
    Youjia Hu, Stacey N Brown, Ali Nasiri, Don T Li, Haiyan Wang, Gregory D Cartee, Gerald I Shulman, Jonathan S Bogan.
      To stimulate glucose uptake in muscle, insulin mobilizes GLUT4 glucose transporters to the cell surface. During fasting, GLUT4 and the transmembrane aminopeptidase IRAP are trapped in intracellular, insulin-responsive vesicles bound by TUG, AS160, and Usp25m proteins. Here we show that Usp25m, a protease, is required for the bulk of insulin-stimulated TUG cleavage and consequent vesicle mobilization and glucose uptake. Efficient TUG cleavage also requires AS160. In mice with diet-induced insulin resistance, Usp25m abundance is reduced, IRAP is mislocalized during fasting, and TUG cleavage is impaired; effects of Usp25m and TUG deletion to alter insulin-stimulated and fasting glucose uptake, respectively, are ablated. We conclude that skeletal muscle insulin resistance results in part from altered membrane trafficking of GLUT4 and IRAP during fasting. This alteration depletes the pool of insulin-responsive vesicles marked by TUG and Usp25m. Mistargeting of GLUT4 and IRAP may contribute to distinct aspects of the metabolic syndrome in humans.
    DOI:  https://doi.org/10.1101/2025.06.29.662135
  35. Sci Rep. 2025 Jul 10. 15(1): 24828
    Single cell RNA sequencing analysis of mice hindlimb muscles identifies transcriptional heterogeneity in aging and physical frailty.
    Minwen Jie, Tong Feng, Fengjuan Hu, Xuelian Sun, Shuli Jia, Yanrong Lu, Birong Dong, Hao Jiang.
      Frailty, a geriatric syndrome, is characterized by the age-related deterioration of physical capabilities and multiple organ systems. However, its age-associated and age-independent mechanisms remain vague, impeding prevention and clinical intervention. Here, the physical frailty status of young and old mice estimated using the frailty phenotype and frailty index values was used to divide mice into non-frail young/old (NF-Y/NF-O) and frail old (F-O) groups. Age-associated and age-independent transcriptional changes in frailty were investigated using single-cell RNA sequencing to profile transcriptomes in various cell types in limb muscles. We investigated the ratio of cell types, transcriptional regulation networks, and cell-cell communications in 15 major cell types in mice during relatively healthy aging (RHA), age-associated frailty (AAF), and age-independent frailty (AIF). Each group of RHA, AAF or AIF genes exhibited one major expression pattern and transcriptional regulation network. Besides its unique pattern, genes in the AAF group faintly exhibited the two major patterns seen in the AIF and RHA groups. B cells and satellite cells in both the AIF and AAF groups showed the most down-regulated and up-regulated differentially expressed genes, respectively. The transcriptional pattern of B cells, which showed stronger transcriptional changes than satellite cells in the AIF process, was validated by sorting B cells and performing SMART-sequencing. Thus, by analyzing these molecular events at the single-cell level, our study revealed the specific expression patterns and transcriptional heterogeneities of candidate cell types involved in relatively healthy aging and physical frailty, laying a foundation to characterize the detailed mechanisms and presenting possible therapeutic strategies for physical frailty.
    Keywords:  Age-associated frailty; Age-independent frailty; Frailty; Relatively healthy aging; Single-cell RNA-seq
    DOI:  https://doi.org/10.1038/s41598-025-10421-3
  36. Aging (Albany NY). 2025 Jul 08. 17
    Exercise as a geroprotector: focusing on epigenetic aging.
    Takuji Kawamura, Mitsuru Higuchi, Zsolt Radak, Yasuyuki Taki.
      Emerging evidence suggests that physical activity, exercise, and physical fitness may delay or reverse epigenetic aging, with implications for the extension of healthspan. This Perspective review defines essential exercise-related terminology and synthesizes findings from both human and animal studies examining the relationships between these factors and DNA methylation-based epigenetic clocks. While observational studies have demonstrated inverse relationships between cardiorespiratory fitness and epigenetic age acceleration, interventional studies further suggest that structured exercise training can induce epigenomic rejuvenation, particularly in blood and skeletal muscle. However, these effects exhibit considerable interindividual and organ-specific variability, underscoring the need for future research to elucidate causal mechanisms and organ-specific responses in order to optimize the application of exercise as a geroprotective intervention.
    Keywords:  epigenetic clock; exercise; geroprotector; physical activity; physical fitness
    DOI:  https://doi.org/10.18632/aging.206278
  37. Exp Physiol. 2025 Jul 10.
    Applying lessons from limb muscle disuse and ageing to better understand ventilator-induced diaphragm dysfunction.
    P H C Mesquita, J L Halle, J D Fuqua, B F Miller.
      Mechanical ventilation (MV) is a life-saving intervention applied to critically ill patients. A common consequence of MV is ventilator-induced diaphragm dysfunction (VIDD), which is characterized by significant diaphragm atrophy and reduced contractile function. Older patients who receive MV are more likely to develop VIDD, have worse recovery, and higher mortality rates compared to younger adults. Despite the greater susceptibility of older adults to develop VIDD and lower survival rates compared to young adults, studies investigating the effects of ageing on VIDD and the recovery from MV are scarce. The field of limb skeletal muscle disuse has extensively shown that compared to adult limb muscles, aged limb muscles respond differently and have blunted recovery after disuse. This review summarizes the literature on the effects of MV on the diaphragm, discussing the available data on the effects of ageing and the recovery process after MV. We also provide an overview of the effects of ageing and the recovery of limb muscle from periods of disuse. We conclude with recommendations for future studies to apply lessons learned from the field of limb muscle disuse to the field of MV and VIDD.
    Keywords:  VIDD; proteostasis; recovery; unloading
    DOI:  https://doi.org/10.1113/EP092707
  38. bioRxiv. 2025 Jul 05. pii: 2025.07.03.662956. [Epub ahead of print]
    Dynamic balance of myoplasmic energetics and redox state in a fast-twitch oxidative glycolytic skeletal muscle fiber.
    Jana Disch, Jeroen A L Jeneson, Daniel A Beard, Oliver Röhrle, Thomas Klotz.
      In order to investigate the mechanisms governing energy and redox balance in skeletal muscle, we developed a computational model describing the coupled biochemical reaction network of glycolysis and mitochondrial oxidative phosphorylation (OxPhos) in fast-twitch oxidative glycolytic (FOG) muscle fibers. The model was identified against dynamic in vivo recordings of Phosphocreatine (PCr), inorganic Phosphate (Pi), and pH in rodent hindlimb muscle and verified against independent data from in vivo experiments and muscle biopsies. Step response testing revealed that mass action kinetics in combination with feedback control were sufficient to accomplish myoplasmic ATP homeostasis over a 100-fold range of ATP turnover rates. This vital emergent property of the metabolic model was associated with dynamic behaviour of intermediary metabolite concentrations similar to a second-order underdamped system that remains to be verified. The simulations additionally predicted that the lactate dehydrogenase (LDH) reaction makes substantial contributions to redox balance across the physiological range of ATP demands in this myofiber phenotype, while its role in slowing cellular acidification is minimal. Yet, LDH knock-out simulations revealed that oxidative recycling of myoplasmic NADH in and by itself sufficed to maintain redox balance over ATP turnover rates in the range of mitochondrial ATP synthesis. We conclude that aerobic lactate production in working muscles is a byproduct of the metabolic flexibility of FOG myofibers afforded by expression of high levels of LDH and OxPhos enzymes to support continual myoplasmic redox balance and ATP synthesis under conditions of high-intensity mechanical work. In the future, the presented simulation framework may be used to further enhance the understanding of how experimental observations in muscle emerge from the integrative behaviour of the metabolic network for carbohydrate metabolism in FOG myofibers.
    DOI:  https://doi.org/10.1101/2025.07.03.662956
  39. Nat Commun. 2025 Jul 09. 16(1): 6328
    Early-life exercise extends healthspan but not lifespan in mice.
    Mengya Feng, Min Li, Jing Lou, Guiling Wu, Tian Gao, Fangqin Wu, Yanzhen Tan, Nini Zhang, Yong Zhao, Lin Zhao, Jia Li, Changhong Shi, Xing Zhang, Jiankang Liu, Feng Gao.
      It is well-known that physical activity exerts health benefits, yet the potential impacts of early-life regular exercise on later-life health and lifespan remains poorly understood. Here, we demonstrate that 3 months of early-life exercise in mice results in lasting health benefits, extending healthspan, but not lifespan. C57BL/6J mice underwent swimming exercise from 1 to 4 months of age, followed by detraining for the remainder of their lives. While early-life exercise did not extend the overall lifespan, it significantly improved healthspan in both male and female mice, as evidenced by enhanced systemic metabolism, cardiovascular function, and muscle strength, as well as reduced systemic inflammation and frailty in aged mice. Multiple-organ transcriptome analyses identified enhanced fatty acid metabolism in skeletal muscles as a major feature in aged mice that underwent early-life exercise. These findings reveal the enduring long-term health benefits of early-life exercise, highlighting its pivotal role in improving healthspan.
    DOI:  https://doi.org/10.1038/s41467-025-61443-4
  40. Bio Protoc. 2025 Jun 20. 15(12): e5353
    An Optimized Ex Vivo Protocol for Quantitative Electrophysiological Assessment of Neuromuscular Junctions and Skeletal Muscle Function Using the Aurora System.
    Can Cui, Zhengyuan Bao, Simon Kwoon-Ho Chow, Qianjin Wang, Senlin Chai, Zhihong Xu, Qing Jiang, Wing Hoi Cheung.
      The neuromuscular junction (NMJ) is critical for muscle function, and its dysfunction underlies conditions such as sarcopenia and motor neuron diseases. Current protocols for assessing NMJ function often lack standardized stimulation parameters, limiting reproducibility. This study presents an optimized ex vivo method to evaluate skeletal muscle and NMJ function using the Aurora Scientific system, incorporating validated stimulation protocols for both nerve and muscle to ensure consistency. Key steps include tissue preparation in a low-calcium, high-magnesium solution to preserve NMJ integrity, determination of optimal muscle length, and sequential stimulation protocols to quantify neurotransmission failure and intratetanic fatigue. By integrating rigorous standardization, this approach enhances reproducibility and precision, providing a robust framework for investigating NMJ pathophysiology in aging and disease models. Key features • Dual stimulation modes enable direct muscle and indirect nerve stimulation to isolate NMJ-specific dysfunction. • Optimized stimulation parameters for nerve (5 mA, 0.8 ms pulse width) and muscle (300 mA, 0.2 ms pulse width) on mouse model. • Preservation of NMJ integrity through dissection in low-calcium, high-magnesium artificial cerebrospinal fluid (aCSF) and synthetic interstitial fluid (SIF). • Quantitative analysis of neurotransmission failure and intratetanic fatigue using standardized equations. This protocol is used in: Ageing Cell (2024), DOI: 10.1111/acel.14156.
    Keywords:  Ex vivo muscle function; Intratetanic fatigue; Neuromuscular junction; Neurotransmission failure; Optimal stimulation parameters; Sarcopenia models
    DOI:  https://doi.org/10.21769/BioProtoc.5353
  41. Sci Adv. 2025 Jul 11. 11(28): eadw9445
    Muscle growth by sarcomere divisions.
    Clement Rodier, Ian D Estabrook, Eunice HoYee Chan, Gavin Rice, Vincent Loreau, Stefan Raunser, Dirk Görlich, Benjamin M Friedrich, Frank Schnorrer.
      The sarcomere is the elementary contractile unit of muscles. Adult muscle cells are large and chain thousands of sarcomeres into long periodic myofibrils that attach to the skeleton. During development, muscle cells must increase in length to maintain the mechanical connection to the growing skeleton. How muscles add new sarcomeres to facilitate muscle growth is unknown. Using live imaging and high-throughput image analysis, we have now tracked the sarcomere components during the developmental growth of Drosophila muscle and found that individual sarcomeres divide along the myofibril tension axis into daughter sarcomeres. This way, new sarcomeres can be inserted into contractile and mechanically intact myofibrils. We propose that sarcomere division is triggered by tension and local sarcomere damage originating from skeletal growth and muscle contractions. Sarcomere divisions repair damaged sarcomeres, ensure their mechanical integrity, and synchronize sarcomere addition with skeletal growth during animal development.
    DOI:  https://doi.org/10.1126/sciadv.adw9445
  42. Nat Commun. 2025 Jul 10. 16(1): 6371
    Muscle AMP deaminase activity was lower in Neandertals than in modern humans.
    Dominik Macak, Shin-Yu Lee, Tomas Nyman, Henry Ampah-Korsah, Emilia Strandback, Svante Pääbo, Hugo Zeberg.
      The enzyme AMPD1 is expressed in skeletal muscle and is involved in ATP production. All available Neandertal genomes carry a lysine-to-isoleucine substitution at position 287 in AMPD1. This variant, which occurs at an allele frequency of 0-8% outside Africa, was introduced to modern humans by gene flow from Neandertals. Here, we show that the catalytic activity of the purified Neandertal AMPD1 is ~25% lower than the ancestral enzyme, and when introduced in mice, it reduces AMPD activity in muscle extracts by ~80%. Among present-day Europeans, another AMPD1 variant encoding a stop codon occurs at an allele frequency of 9-14%. Individuals heterozygous for this variant are less likely to be top-performing athletes in various sports, but otherwise reduced AMPD1 activity is well tolerated in present-day humans. While being conserved among vertebrates, AMPD1 seems to have become less functionally important among Neandertals and modern humans.
    DOI:  https://doi.org/10.1038/s41467-025-61605-4
  43. Exp Physiol. 2025 Jul 05.
    Unlimited adaptations of muscle fibres to exercise; are you kidding me?
    Hans Degens, Paul Hendrickse.
      
    DOI:  https://doi.org/10.1113/EP092983
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