bims-moremu 2026-05-24 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2026–05–24
38 papers selected by
Anna Vainshtein, Craft Science Inc.

The epigenetic landscape of skeletal muscle in response to exercise and aging.
Gene Expression Analysis on Single Myofibers from Mouse Edl and Soleus Muscles.
Exercise-induced muscle injury in Duchenne muscular dystrophy: impaired mitophagy and altered PINK1-PARKIN pathway in mdx mice.
Nuclear Speckles Regulate Splicing During Muscle Stem Cell Activation and Aging.
The cellular ecosystem of skeletal muscle regeneration: molecular mechanisms, pathological disorders, and potential therapeutic strategies.
Targeting FoxO1/3a, NF-κB, and mTOR signaling attenuates muscle atrophy in sepsis.
Deficiency of muscular dystrophy-related gene JAG2 causes NOTCH signaling dysfunction in muscle stem cells.
RNA-binding protein hnRNPK: a multifunctional regulator of skeletal muscle biology and disease.
Insights into the heterogeneous muscle lipidome of dysferlin-deficient mice: effects of age, muscle type, and sex.
Shaping the microvascular network: insights into skeletal muscle angiogenesis.
Loss of calcium-dependent phospholipase A2 contributes to multi-omic changes in mouse denervated skeletal muscle.
Repeated heat exposure upregulates skeletal muscle aquaporin-4 expression in male mice.
The perijunctional zone is a molecularly distinct muscle subdomain altered in Duchenne muscular dystrophy.
Transcriptional programs diverge in aging mouse and human skeletal muscle.
Tensin2 deficiency transiently accelerates early-phase regenerative myofiber growth following cardiotoxin-induced injury in mice.
Skeletal muscle dysfunction in COPD: miRNAs, myokines and exercise.
Ferroptosis as a Nexus in Skeletal Muscle Pathophysiology: From Molecular Networks to Precision Medicine.
Thyroid hormones as permissive regulators of skeletal muscle protein accretion and oxidative capacity: Implications for resistance and endurance training.
Restoration of neuromuscular function by mitochondrial transplantation in injured mouse skeletal muscle.
Voluntary wheel running attenuates peptidoglycan-polysaccharide-induced inflammation and preserves skeletal muscle remodeling in male C57BL/6J mice.
Heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) maintains muscle progenitor identity by stabilizing the Ppp1r1b-lncRNA-PRC2 complex.
Influence of the adaptation of lactate accumulation rate through physical training on muscle mass regulation.
Multi-Omic, Multi-Tissue Responses to Acute Exercise in Sedentary Adults: Findings from the Molecular Transducers of Physical Activity Consortium.
Increasing intramuscular fluid volume increases passive tension in mammalian skeletal muscle.
HSF1 modulates lipid metabolism and ferroptosis in sarcopenia: a novel diagnostic biomarker and therapeutic target.
Research into Resistance Training Response Heterogeneity: a Summary of the 2025 Conference at the University of Jyväskylä.
Menstrual Cycle Phase Does Not Influence Training-Induced Muscle Hypertrophy or Strength: A Randomized Controlled Trial.
EPAS1 is associated with human muscle fiber composition and endurance phenotypes.
Subunit composition of the KATP channels that modulate contractility of skeletal muscle during fatigue.
New Ways to Keep Muscle as You Age: Ozempic, similar drugs and aging take off muscle. New therapies could retain it.
Decoding cellular communication networks and signaling pathways in bone, skeletal muscle, and bone-muscle crosstalk through spatial transcriptomics in a young male mouse.
MicroRNA Quantification on Fast and Slow-Twitch Skeletal Muscles of Mouse.
Cachexia-induced alterations of miR-27a-3p drive cell-type specific effects in FAPs and tumor cells that coincide with muscle wasting.
DDRGK1 regulates muscle development by maintaining mitochondrial calcium homeostasis and oxidative phosphorylation via stabilizing IP3R.
Regulation of Satellite Cells and Myogenesis in Response to Eccentric Resistance Exercise in Hypoxic Conditions in Healthy Young Men.
In vivo base editing via single myotrophic adeno-associated viruses in dystrophic mouse muscle and satellite cells.
Temporal Proteomic Profiling Reveals Tissue-Specific and Coordinated Metabolic Reprogramming in Skeletal Muscle and Liver during Prolonged Fasting.
Beyond Birth Control: How Oral Contraceptives Impact Skeletal Muscle Health - a Systematic Review and Meta-Analysis.

FEBS J. 2026 May 18.

The epigenetic landscape of skeletal muscle in response to exercise and aging.

Sabrina Champsi, David A Hood.

  Skeletal muscle exhibits a remarkable level of plasticity that enables it to adapt to exercise training, as well as the deleterious effects of aging. Fundamental to this malleability are epigenetic processes, which collectively enhance chromatin remodeling and subsequently alter DNA availability for gene expression. A growing body of evidence has demonstrated that acute exercise is a powerful inducer of epigenetic remodeling, capable of stimulating gene-specific alterations, which transcriptionally activate exercise-responsive genes. These epigenetic processes, including DNA methylation and various histone modifications, are highly responsive to exercise-induced signaling cascades and mitochondrially-related metabolites, together indicating that exercise can modulate the nuclear and mitochondrial epigenome as a mechanism to regulate gene expression. However, aging is characterized by a unique epigenetic signature, which likely supports the alterations in gene expression observed with age. Yet, the effects of exercise on epigenetic regulation with age remain underexplored. To investigate the intersectionality of these two phenotypes and highlight significant gaps within the literature, this review aimed to discuss the different types of epigenetic modifications that have been reported within skeletal muscle and how they are altered with acute and chronic exercise. Furthermore, we aimed to analyze mitochondrial epigenetics and their role in mediating alterations in mitochondrial-nuclear crosstalk observed with exercise and age. Elucidating age-dependent adaptations in the epigenome and the differential effects of exercise in these populations will help uncover the complexity of gene regulation with age, and importantly, reveal how exercise can regulate many of these processes to improve muscle health.

Keywords:  aging; epigenetics; exercise; mitochondria; skeletal muscle

DOI:  https://doi.org/10.1111/febs.70591
Methods Mol Biol. 2026 ;3010 131-141

Gene Expression Analysis on Single Myofibers from Mouse Edl and Soleus Muscles.

Amairani Cancino-Bello, Mauricio Hernández-Somilleda, Estela G García-González, J Manuel Hernández-Hernández.

  Skeletal muscle is composed of different myofiber types with specific transcriptomic, proteomic, and metabolic identities. As such, skeletal muscle represents a valuable model to study cell differentiation and gene expression regulation. However, many molecular analyses of skeletal muscle are performed on whole muscle, with the caveat that many different cell types that constitute this organ contribute to the experimental results. Here, we describe a method to efficiently isolate individual myofibers from two muscle types and provide a guide to perform quantitative gene expression analysis of representative myosin heavy chain genes.

Keywords:  Eene expression; Extensor digitorum longus; Myh4; Myh7; Myofibers isolation; Skeletal muscle; Soleus; qPCR

DOI:  https://doi.org/10.1007/978-1-0716-5126-1_14
Brain Dev. 2026 May 17. pii: S0387-7604(26)00048-3. [Epub ahead of print]48(3): 104547

Exercise-induced muscle injury in Duchenne muscular dystrophy: impaired mitophagy and altered PINK1-PARKIN pathway in mdx mice.

Junxia Li, Qing Zhao, Hongyan He, Xueqin Song.

   OBJECTIVE: Duchenne muscular dystrophy (DMD) is a severe hereditary disorder characterized by dystrophin deficiency, leading to progressive muscle weakness. Mitochondrial dysfunction and impaired quality control, particularly via the PTEN-induced putative kinase 1 (PINK1)-E3 ubiquitin ligase PARK2 (PARKIN) mitophagy pathway, are implicated in DMD pathogenesis, but the impact of exercise remains unclear. This study investigated the effects of short-term high-intensity exercise on skeletal muscle pathology and mitophagy in mdx mice.
METHODS: Skeletal muscle from DMD patients and non-dystrophic controls (CTR) was analyzed for mitochondrial content and PINK1-PARKIN expression. Eight-week-old male mdx and C57 control mice underwent a 5-day rotarod exercise protocol. Muscle pathology was assessed using hematoxylin and eosin (HE), acid phosphatase (ACP), and succinate dehydrogenase (SDH) staining. Mitophagy was evaluated via immunofluorescence for microtubule-associated protein 1 light chain 3 (LC3), cytochrome c oxidase subunit IV (COXIV), and voltage-dependent anion channel (VDAC), as well as western blotting for PINK1 and PARKIN. Transmission electron microscopy (TEM) was used to visualize mitochondrial ultrastructure.
RESULTS: In DMD patients, skeletal muscle showed reduced mitochondrial content and dysregulated PINK1-PARKIN expression. In mdx mice, basal mitophagy markers were elevated. Short-term high-intensity exercise exacerbated muscle necrosis and inflammation in mdx mice while impairing the activation of PINK1-PARKIN-mediated mitophagy, contrasting with the adaptive response in wild-type mice.
CONCLUSION: Short-term high-intensity exercise exacerbates skeletal muscle pathology in mdx mice, which is associated with impaired activation of PINK1-PARKIN-mediated mitophagy, underscoring the critical role of mitochondrial quality control in DMD and the need for tailored exercise regimens.

Keywords:  Duchenne muscular dystrophy; Exercise; Mitophagy; Muscle injury; PINK1-PARKIN pathway

DOI:  https://doi.org/10.1016/j.braindev.2026.104547
bioRxiv. 2026 May 07. pii: 2026.05.04.722644. [Epub ahead of print]

Nuclear Speckles Regulate Splicing During Muscle Stem Cell Activation and Aging.

Steve D Guzman, Pamela Duran, Yu Xiao, Yuxuan Song, Joshua D Welch, Chuan He, Carlos A Aguilar.

Skeletal muscle contains a population of adult stem cells called satellite cells or muscle stem cells (MuSCs) that are responsible for regeneration after injury. MuSCs utilize gene expression programs to maintain quiescence and differentiate after injury and a key regulator of gene expression is splicing, which uniquely changes when transcripts interact with nuclear speckles (NS). NS are membrane-less biomolecular condensates that phase separate proteins, RNAs and chromatin, but how these organelles regulate molecular processes in MuSCs remains unknown. Herein, we build a comprehensive and systems-level understanding of NS influence on alternative splicing, transcriptional regulation and stem cell function before and after injury and in aging. We establish that NS increased in size and number in MuSCs following injury and influence MuSC activation dynamics. We generated a catalog of isoform-resolved splicing events and linked how RNA interactions with NS amplify splicing completion during the injury response. In old age, MuSCs lose NS, yet shifted towards longer, more completely spliced isoforms enriched for RNA binding protein motifs and multivalency. Our studies unveil evidence that RNA interactions with NS shape stem cell state and regenerative responses but are attenuated in old age.
HIGHLIGHTS: 3D super-resolution imaging of nuclear speckles in muscle stem cells before and after muscle injury shows intricate relationship with activationIsoform-resolved profiling of muscle stem cells shows increases in gene expression and splicing during injury responseMapping RNA interactions with nuclear speckles shows RNAs undergo strongest splicing when proximal to nuclear specklesOld aged muscle stem cells lose nuclear speckles and display aberrant splicing, with longer transcripts, more exons, and increased RNA binding protein motifs.

DOI: https://doi.org/10.64898/2026.05.04.722644
Stem Cell Res Ther. 2026 May 16.

The cellular ecosystem of skeletal muscle regeneration: molecular mechanisms, pathological disorders, and potential therapeutic strategies.

Jiahuan Gong, Hongyi Xu, Xinlei Yao, Yutong Wei, Xia Li, Yuntian Shen, Bingqian Chen, Hualin Sun.

  Skeletal muscle regeneration is a highly coordinated physiological process. It relies on the intricate collaboration of a complex cellular ecosystem. This ecosystem includes muscle stem cells, immune cells, stromal cells, vascular cells, neural cells, and the extracellular matrix. Research has recently expanded beyond focusing solely on satellite cells. It now delves into the multi-level regulatory networks within this ecosystem. These networks encompass key signaling pathways, such as Wnt/β-catenin, TGF-β, Hippo/YAP, and AMPK. They also include epigenetic regulation, cellular metabolic reprogramming, and extracellular vesicle-mediated intercellular communication. However, under pathological conditions, this regenerative program is severely impaired. This leads to failed repair, fibrosis, and fatty infiltration, ultimately resulting in loss of muscle function. This review aims to systematically outline recent advances in the field of skeletal muscle regeneration. First, from the perspective of the "cellular ecosystem," we will elaborate on the dynamic behaviors and regulatory mechanisms of various cell types during regeneration. Second, we will dissect the core mechanisms underlying regenerative failures in various pathological states. Third, we will comprehensively evaluate the most promising current intervention strategies. Finally, considering the limitations of current research, we will provide future perspectives. This review aims to systematically integrate existing knowledge and provide a clear roadmap for future research, ultimately offering a robust theoretical foundation and innovative insights for the development of clinical treatments targeting skeletal muscle regenerative disorders.

Keywords:  Cellular Ecosystem; Regenerative Failure; Regulatory Networks; Skeletal Muscle Regeneration; Therapeutic Strategies

DOI:  https://doi.org/10.1186/s13287-026-05060-y
Sci Rep. 2026 May 21.

Targeting FoxO1/3a, NF-κB, and mTOR signaling attenuates muscle atrophy in sepsis.

Donglin Fu, Min Zhou, Yingxiao Zhang, Pan Cheng, Yue Shu, Qian Xiao, Meng Zhang.

Sepsis frequently leads to skeletal muscle atrophy, but its molecular mechanisms remain unclear. Using a mouse model of cecal ligation and puncture and LPS-treated C2C12 myotubes, we found that sepsis activates autophagy, the ubiquitin-proteasome system (UPS), and calpain pathways, resulting in muscle wasting and functional decline. These changes were linked to upregulated FoxO1/3a and NF-κB signaling and suppressed mTOR activity. Pharmacological inhibition or genetic deletion of key components in these pathways, especially MuRF1, mitigated muscle atrophy and preserved function. Our findings reveal that sepsis-induced muscle loss is driven by coordinated activation of proteolytic systems regulated by the FoxO1/3a, NF-κB, and mTOR signaling pathway, offering potential therapeutic targets.

DOI: https://doi.org/10.1038/s41598-026-52665-7
J Clin Invest. 2026 May 19. pii: e198639. [Epub ahead of print]

Deficiency of muscular dystrophy-related gene JAG2 causes NOTCH signaling dysfunction in muscle stem cells.

Minoru Tanaka, Nam Chul Kim, Isabelle Draper, Hannah R Littel, Mekala Gunasekaran, Johnnie Turner, Natalya M Wells, Qasim Mujteba, Yoko Asakura, Peter B Kang, Atsushi Asakura.

  We previously identified a muscular dystrophy caused by biallelic variants in JAG2, whose protein product Jagged2 JAGGED2 (JAG2) is a canonical Notch NOTCH ligand. However, the disease mechanism remains unclear, particularly with respect to muscle stem cell (MuSC) function and muscle regeneration. We examined the consequences of JAG2 deficiency and modeled pathogenic JAG2 variants in vitro and in vivo, the latter in mouse and fly models and with particular attention to the MuSC-muscle endothelial cell (MuEC) niche. We found that both Jag2 deficiency and overexpression of pathogenic JAG2 variants impaired NOTCHNotch signaling and myogenic self-renewal and differentiation. Hypomorphic Jag2 mutant (Jag2sm) mice display depleted MuSCs, corresponding with impaired muscle regeneration in those mice. Co-culture experiments and the examination of cell-type-specific Jag2 conditional knockout mice demonstrated that MuEC-specific Jag2 knockout resulted in reduced MuSC self-renewal, while MuSC-specific Jag2 knockout resulted in reduced myogenic differentiation. Human reference JAG2, but not human pathogenic variants of JAG2, rescued the deficiency of Serrate (Ser), the Drosophila ortholog of JAG2. Therefore, pathogenic variants in JAG2 impair muscle development and regeneration through disrupted cell-autonomous cis-inhibition and non-autonomous trans-activation involving NOTCHNotch signaling dysfunction. Our findings indicate that optimizing JAG2-mediated NOTCHNotch signaling is a potential therapeutic approach for JAG2-related muscular dystrophy.

Keywords:  Adult stem cells; Development; Mouse models; Muscle biology; Neuromuscular disease

DOI:  https://doi.org/10.1172/JCI198639
Biochem Soc Trans. 2026 May 27. 54(5): 571-584

RNA-binding protein hnRNPK: a multifunctional regulator of skeletal muscle biology and disease.

Kejin Ren, Kaili Zhou, Yijia An, Xiaofang Cheng, Tiantian Meng, Cencen Li, Haixia Xu, Pengpeng Zhang, Yongjie Xu.

  Heterogeneous nuclear ribonucleoprotein K (hnRNPK) is a highly conserved, multifunctional DNA/RNA-binding protein that regulates gene expression at both transcriptional and post-transcriptional levels. In skeletal muscle, hnRNPK is essential for development, regeneration, and homeostasis, influencing satellite cell activation, myoblast proliferation and differentiation, and myofiber maturation. Its dysregulation is linked to muscle atrophy, degenerative diseases, and impaired regeneration. This review summarizes current knowledge of hnRNPK's molecular structure, subcellular localization and dynamics, and interactions with nucleic acids and proteins. We highlight its roles in myogenic differentiation, gene expression control, signaling pathway cross-talk, and skeletal muscle development. We also discuss the potential of hnRNPK as a diagnostic biomarker and therapeutic target in muscle disorders, and outline key directions for future research to resolve outstanding questions about its complex regulatory functions. Together, these insights provide a framework for advancing muscle biology and improving the management of muscle-related diseases.

Keywords:  hnRNPK; muscle disease; regulation; skeletal muscle development

DOI:  https://doi.org/10.1042/BST20250557
Skelet Muscle. 2026 May 22.

Insights into the heterogeneous muscle lipidome of dysferlin-deficient mice: effects of age, muscle type, and sex.

Stacey N Keenan, Jackie Bayliss, Olivia Lee, Erin M Lloyd, Peter J Meikle, Miranda D Grounds, Matthew J Watt.

  Dysferlinopathy is an age-dependent muscular dystrophy caused by loss of the membrane-associated protein dysferlin. Disease severity increases with age and selectively affects specific muscle groups, yet the molecular basis for this vulnerability remains unclear. Since lipid remodeling is a hallmark of dysferlinopathy and aging, we investigated how age, sex, and muscle fiber type interact to shape the muscle lipidome in dysferlin-deficient mice. We performed omics-scale lipid profiling across 738 lipid species and 30 lipid classes in quadriceps and gastrocnemius (fast-twitch muscles exhibiting pronounced pathology), soleus (slow-twitch) and extensor digitorum longus (EDL; fast-twitch, relatively spared) muscles from male and female dysferlin-deficient (BLA/J) and wildtype C57BL/6J (WT) mice aged 3, 10, and 26 months. Normal aging was associated with broad lipid remodeling, however, in the absence of dysferlin markedly amplified this remodeling, leading to elevations in specific triglycerides, diglycerides, cholesterol esters, gangliosides, ceramides, and sphingomyelin compared to WT muscle. Interestingly, we observed minimal sex differences between dysferlin-deficient muscles. Fast-twitch muscles, particularly quadriceps and gastrocnemius, exhibited the most extensive lipid alterations, whereas the slow-twitch soleus muscle showed relative lipid stability even at advanced age. Thus, fast-glycolytic muscles are more susceptible to age- and dysferlin-dependent lipid dysregulation than slow oxidative muscle. The preferential vulnerability of fast-twitch muscles to muscle wasting in dysferlinopathy suggests that fiber-type-dependent lipid handling contributes to selective muscle degeneration. This work defines a comprehensive lipidomic signature of disease progression and provides a framework for understanding how aging, sex, and muscle phenotype interact in muscular dystrophy.

Keywords:  Dysferlin; Dysferlinopathy; Lipid metabolism; Lipidomics; Skeletal muscle

DOI:  https://doi.org/10.1186/s13395-026-00427-4
Open Biol. 2026 Apr 29. pii: 250183. [Epub ahead of print]16(5):

Shaping the microvascular network: insights into skeletal muscle angiogenesis.

Thomas Gustafsson, Emmanuel Nwadozi, Andrea Tryfonos, Tara L Haas.

  Angiogenesis, the formation of new blood vessels from pre-existing vasculature, is a complex and tightly regulated biological process that plays a fundamental role in both physiological and pathological tissue remodeling by facilitating the delivery of oxygen and nutrients. Over recent decades, extensive research has identified a wide array of factors that regulate the balance between endothelial cell quiescence and activation. This review discusses the cellular events and molecular mechanisms that regulate angiogenesis within skeletal muscle, considering dynamic interactions with the extracellular matrix and highlighting the critical involvement of multiple resident and infiltrating cell types-including myofibres, satellite cells, fibro-adipogenic progenitors, immune cells and pericytes. The current understanding of these regulatory networks is examined in both healthy muscle tissue as part of the phenotype changes that occur during exercise and in pathological conditions that affect skeletal muscle angiogenesis. Particular attention is given to introduce data of emerging high-resolution techniques, especially omics-based approaches such as single-cell RNA sequencing (scRNA-seq) of skeletal muscle tissue. These methodologies hold significant promise for elucidating cell-type-specific roles and intercellular interactions that drive angiogenic processes in both physiological and disease contexts. Despite substantial progress, the precise mechanisms governing angiogenesis in skeletal muscle remain only partially understood.

Keywords:  VEGF; angiogenesis; endothelial cells; skeletal muscle

DOI:  https://doi.org/10.1098/rsob.250183
Physiol Rep. 2026 May;14(10): e70906

Loss of calcium-dependent phospholipase A2 contributes to multi-omic changes in mouse denervated skeletal muscle.

Agnieszka Czyżowska-Froemling, Hongyang Xu, Kylene Harold, Jessica Thomason, Kara Kneuper, Elizabeth Duggan, Atul Pranay, Jie Zhu, Martin-Paul Agbaga, Constantin Georgescu, Victoria Tyrrell, Valerie O'Donnell, Ken Humphries, Holly Van Remmen, Jacob L Brown.

  Age-related loss of innervation in skeletal muscle is a key driver of sarcopenia. We investigated the role of calcium-dependent phospholipase A2 (cPLA2) in denervation-atrophy. cPLA2 mediates the release of polyunsaturated fatty acid substrates, and the oxidation of the free fatty acids generates oxylipins, which are bioactive signaling facilitators. We hypothesized that loss of cPLA2 would protect against muscle atrophy by altering hydroperoxide and oxylipin generation, thereby modifying the transcriptome and lipidome of denervated muscle to mitigate atrophy. We used a sciatic nerve transection model in wildtype and cPLA2 knockout (KO) mice to test this hypothesis. Surprisingly, oxylipin content was significantly higher in 4,10,11,13,14-HDoHE, 12-HEPE, 9,10-EpOME, and 12,13-EpOME in gastrocnemius muscle from mice with genetic deletion of cPLA2 compared to wildtype controls. We observed reductions in several glycolytic intermediates after denervation such as fructose-6-phosphate, glucose-6-phosphate, fructose-1,6-bisphosphate, and phosphoenol pyruvate. Both alpha-hydroxy-glutarate and glucose-6-phosphate were lower in muscle from mice lacking cPLA2. Transcriptomic analysis showed that G-protein coupled receptor signaling was differentially expressed when comparing wildtype and cPLA2 KO mice. In contrast to the protective effects previously reported with inhibition of cPLA2, we found that genetic deletion of cPLA2 did not mitigate denervation-induced muscle atrophy despite having lower hydroperoxide generation in gastrocnemius muscle.

Keywords:  atrophy; denervation; lipids; oxylipins; transcriptomics

DOI:  https://doi.org/10.14814/phy2.70906
Physiol Rep. 2026 May;14(10): e70926

Repeated heat exposure upregulates skeletal muscle aquaporin-4 expression in male mice.

Yuka Kudo, Nozomi Yazawa, Yui Shimizu, Atsumi Tomatsuri, Yuho Mizuseki, Kazuko Koshiba-Takeuchi, Taku Nedachi.

  Heat acclimation involves coordinated physiological adaptations, yet the role of skeletal muscle water channels remains insufficiently defined. We investigated how repeated heat exposure affects aquaporin-4 (AQP4) in skeletal muscle using both in vivo and in vitro models. Male C57BL/6NJ mice were exposed to daily passive heating (45°C for 30 min/day, 14 days). Repeated heat exposure reduced body-weight gain and markedly attenuated Hspa1a induction following an acute heat challenge, confirming systemic heat acclimation. Immunofluorescence analysis revealed an approximately 1.3-fold increase in AQP4 protein in fast-twitch muscles without changes in its subcellular localization. In vitro, C2C12 myocytes were subjected to repeated heat bouts (42°C, 3 h/day for 1-5 days). Heat-acclimated cells exhibited blunted Hspa1a induction in response to acute heat stress and progressively increased AQP4 protein levels (approximately 1.6-fold), indicating that heat stress directly promotes AQP4 upregulation in muscle cells. Together, these findings identify AQP4 as a heat-responsive component of skeletal muscle and suggest that AQP4 may contribute to peripheral osmotic regulation during heat acclimation.

Keywords:  aquaporins; heat acclimation; heat exposure; skeletal muscle

DOI:  https://doi.org/10.14814/phy2.70926
Nat Commun. 2026 May 21.

The perijunctional zone is a molecularly distinct muscle subdomain altered in Duchenne muscular dystrophy.

Seth G Haddix, Chuansheng Zhang, Yanhong Liu, Juan Oses-Prieto, Alma L Burlingame, Matthew N Rasband.

The neuromuscular junction (NMJ) is a well-established model for synapse development, structure, and function. Surrounding the NMJ is a narrow perijunctional zone (PJZ), enriched in muscle-specific voltage-gated sodium channels that prevent synaptic fatigue. Despite this role, the PJZ remains poorly characterized. To determine its molecular composition, we engineered mice to express the biotin ligase TurboID fused to the cell adhesion molecule neurofascin (Nfasc), and that localizes to the PJZ through ankyrin scaffolding proteins. Using proximity proteomics, we identify numerous PJZ-associated proteins, including Perilipin 4 (Plin4), that are highly enriched and clustered at the PJZ. We also perform proximity proteomics on the PJZ of mdx mice, a model of Duchenne muscular dystrophy. We find broad changes in PJZ composition, including significantly reduced PJZ Plin4. Although Plin4 is linked to lipid droplet storage and autosomal dominant myopathy, Plin4 knockout mice exhibit no obvious neuromuscular phenotype or changes in lipid droplet distribution, suggesting a gain-of-function disease mechanism. These findings establish the PJZ as a molecularly distinct subdomain of skeletal muscle and provide insight into its potential roles in neuromuscular function and disease.

DOI: https://doi.org/10.1038/s41467-026-73525-y
Aging (Albany NY). 2026 May 18. 18(1): 575-592

Transcriptional programs diverge in aging mouse and human skeletal muscle.

Charles D Hwang, Siti Rahmayanti, Yori Endo, Seamus P Caragher, Luisa Weber, Jessica Mroueh, Simone Marini, Indranil Sinha.

  Animal models provide a crucial scientific substrate for medical innovation, yet findings in these models do not always translate directly to humans. Although murine models are extensively employed to study skeletal muscle aging, the extent to which they diverge from the human aging process remains poorly understood. This study examined transcriptional changes with aging in mouse and human skeletal muscle. RNA bulk-sequencing was performed on gastrocnemius muscles from young and old C57BL/6 mice and compared to transcriptomic data from young and old healthy human vastus lateralis muscles obtained from the GESTALT study (NIA/NIH) via the Gene Expression Omnibus database. Cross-species comparison revealed substantial divergence in age-associated transcriptional profiles, with fewer than 5% of significant GO and KEGG terms shared between species. Hypoxia signaling, VEGFA, and inflammatory pathways showed concordant downregulation with aging in both species; however, angiogenesis, neurogenesis, and myogenesis demonstrated opposing or non-significant trends. These findings caution against direct extrapolation of murine aging transcriptomics to human skeletal muscle biology, though select conserved pathways may represent viable cross-species targets for future investigation.

Keywords:  aging; angiogenesis; hypoxia; regeneration; skeletal muscle

DOI:  https://doi.org/10.18632/aging.206382
Exp Anim. 2026 May 20.

Tensin2 deficiency transiently accelerates early-phase regenerative myofiber growth following cardiotoxin-induced injury in mice.

Marina Miyaki, Yusuke Komiya, Minori Nakada, Kensei Noguchi, Issei Yokoyama, Takahiro Suzuki, Koichi Ojima, Keizo Arihara, Nobuya Sasaki.

  Tensin2 (TNS2) is a focal adhesion-associated protein that can negatively regulate insulin/insulin-like growth factor 1 (IGF-1) signaling, but its role in skeletal muscle regeneration remains unclear. To address this, we analyzed a TNS2-related immunoreactive signal detected with an anti-phospho-TNS2 (Tyr483) antibody during C2C12 myogenic differentiation and in a cardiotoxin (CTX)-induced tibialis anterior (TA) injury model, and assessed regeneration in Tns2nph mutant mice. Under basal conditions, Tns2nph mice showed no obvious abnormalities in muscle histology, myofiber size, or phosphorylation of Akt and p70 ribosomal protein S6 kinase (p70S6K), a canonical downstream effector of mTORC1 signaling, compared with wild-type (WT) mice, although the soleus muscle/body weight ratio was slightly increased. In C2C12 cells, the anti-phospho-TNS2 (Tyr483)-reactive signal was stronger during proliferation than during differentiation. In vivo, this signal increased transiently during the early phase of CTX-mediated regeneration. After injury, Tns2nph mice showed a greater number of centrally nucleated fibers at day 4, larger myofibers at day 7, and a higher TA muscle/body weight ratio at day 15. In addition, phosphorylation of p70S6K was increased in regenerating muscle in Tns2nph mice. These findings suggest that TNS2-related signaling may act as a context-dependent modulator of regenerative myofiber growth, possibly through augmented anabolic signaling during early regeneration.

Keywords:  Tensin2; cardiotoxin; muscle regeneration; p70S6K; skeletal muscle

DOI:  https://doi.org/10.1538/expanim.26-0039
ERJ Open Res. 2026 May;pii: 00887-2025. [Epub ahead of print]12(3):

Skeletal muscle dysfunction in COPD: miRNAs, myokines and exercise.

Mauro Maniscalco, Salvatore Fuschillo, Pasquale Ambrosino, Claudio Candia, Arcangela di Domenico, Carmen Lombardi, Andrea Motta, Nicolino Ambrosino.

COPD is a multifactorial and heterogeneous disorder, a leading cause of morbidity and mortality worldwide. Not only does its progression compromise lung function, but it is also associated to systemic complications, including skeletal muscle dysfunction. Skeletal muscle dysfunction affects up to 35% of individuals diagnosed with COPD and is marked by muscle atrophy and altered fibre composition, thus resulting in reduced strength, endurance and physical capacity with an increased mortality risk. Multiple factors, including physical inactivity, oxidative stress, chronic inflammation, mitochondrial dysfunction and impaired autophagy, contribute to the development of skeletal muscle dysfunction. Pulmonary rehabilitation, including exercise training, is a key nonpharmacological intervention that mitigates muscle dysfunction by enhancing protein synthesis and promoting beneficial systemic adaptations. These adaptations are mediated by molecular signals such as myokines and microRNAs (miRNAs), regulating inter-organ communication and gene expression relevant to muscle metabolism and homeostasis. Myokines act as messengers between skeletal muscle and other organs, while miRNAs play pivotal roles in muscle remodelling and exercise adaptation. Therefore, the modulation of specific miRNAs may be a promising therapeutic avenue for addressing skeletal muscle dysfunction in COPD. This review explores the interplay between myokines, miRNAs and skeletal muscle dysfunction in COPD and highlights the potential of miRNAs as biomarkers and therapeutic targets in pulmonary rehabilitation.

DOI: https://doi.org/10.1183/23120541.00887-2025
FASEB J. 2026 May 31. 40(10): e71944

Ferroptosis as a Nexus in Skeletal Muscle Pathophysiology: From Molecular Networks to Precision Medicine.

Yanan Ji, Lei Qi, Jiacheng Sun, Jie Wang, Tongxin Shang, Hualin Sun.

  Ferroptosis, an iron-dependent cell death driven by lipid peroxidation, is a central pathological mechanism unifying diverse skeletal muscle disorders, including atrophy (e.g., sarcopenia, CKD), impaired regeneration, and acute injury. This review synthesizes recent evidence to map a multilayered regulatory network encompassing dysregulated iron/lipid metabolism, collapsed antioxidant defenses (e.g., GPX4, FSP1, GCH1), organelle cross-talk, and complex signaling pathways (e.g., NRF2, p53). Critical translational gaps persist, such as a lack of human validation, insufficient understanding of context-dependent regulation, and challenges in biomarker development. Future directions must prioritize human biomarker discovery, elucidate nonautonomous drivers (e.g., senescent macrophages), evaluate organelle-targeted therapies, and advance biomarker-stratified trials with repurposed drugs (e.g., SGLT2 inhibitors) to enable ferroptosis-targeted precision medicine for muscle diseases.

Keywords:  ferroptosis; iron metabolism; lipid peroxidation; muscle regeneration; skeletal muscle atrophy; targeted therapy

DOI:  https://doi.org/10.1096/fj.202600887R
Best Pract Res Clin Endocrinol Metab. 2026 May 11. pii: S1521-690X(26)00032-1. [Epub ahead of print] 102110

Thyroid hormones as permissive regulators of skeletal muscle protein accretion and oxidative capacity: Implications for resistance and endurance training.

Julia Brenmoehl, Christina Walz, Andreas Hoeflich.

  Thyroid hormones (THs) are fundamental regulators of skeletal muscle energy metabolism and protein turnover. Instead of directly stimulating muscle growth, they create the intracellular environment required for effective adaptation to exercise. Adequate TH availability supports mitochondrial integrity, ribosome biogenesis, and coordinated protein turnover, thereby enabling the translation of anabolic signaling into structural adaptation and remodeling. Accordingly, reduced translational efficiency during hypothyroidism may blunt hypertrophic responses. In contrast, hyperthyroidism accelerates proteolytic pathways and compromises net protein gain despite elevated turnover. Training modalities determine the physiological outcome within this endocrine context, with endurance exercise primarily enhancing oxidative remodeling, while resistance training, when sufficient biosynthetic capacity is present, can stimulate myofibrillar accretion. Reduced energy availability lowers T3 concentrations and may attenuate adaptive efficiency across both modalities. Overall, thyroid status emerges as a critical determinant of muscle remodeling capacity, underscoring the clinical relevance of thyroid assessment in exercise-based interventions.

Keywords:  endurance training; euthyroidism; exercise; hyperthyroidism; hypothyroidism; resistance exercise; thyroid hormones

DOI:  https://doi.org/10.1016/j.beem.2026.102110
J Physiol. 2026 May 21.

Restoration of neuromuscular function by mitochondrial transplantation in injured mouse skeletal muscle.

Stephen E Alway, Peter J Ferrandi, Hector G Paez, Christopher R Pitzer, Junaith S Mohamed, Michael R Deschenes, James A Carson.

  Rehabilitative activity can improve injury repair, but it risks additional damage and reduces the functional recovery of regenerating muscle. This study tested the hypothesis that moderate electrically evoked contractions would slow restoration of neuromuscular function after cardiotoxin-induced injury; however exogenous mitochondrial transplantation (MT) would enhance recovery of contractile function after injury. Cardiotoxin was injected into the tibialis anterior of C57BL/6 mice (10-12 weeks of age) to induce muscle necrosis. Exogenous mitochondria or phosphate-buffered saline (PBS) were injected into the mouse tail vein after cardiotoxin injury. Injured muscles were either rested or given 40 Hz submaximal electrically evoked contractions to cardiotoxin-injured muscles during the recovery period. Relative to intra-animal non-damaged control muscles restoration of peak tetanic torque after both rested and evoked contractions during recovery and twitch torque was greater, and the difference between control and injured muscle twitch one-half relaxation time was lower in injured muscles that were rested for 10 days after injury and received MT compared to PBS-treated muscles. Neuromuscular junction efficiency in cardiotoxin-injured muscles was ∼70% of control undamaged muscles, but MT improved the recovery of neuromuscular junction efficiency to produce torque by 14 days after cardiotoxin injury in muscles that received additional damage induced by evoked contractions during the recovery period. These data suggest that MT enhances the recovery of neuromuscular function when the muscle is rested after injury, but it provides limited improvement in muscle function when the muscle is challenged with electrically evoked contractions in the recovery period after injury. KEY POINTS: Mitochondrial transplantation by systemically infusing healthy donor mitochondria into injured mice improved the recovery of maximal torque production of injured muscles when evoked contractions were provided to the regenerating muscle during the recovery period after injury. Mitochondrial transplantation improved the restoration of neuromuscular junction efficiency after muscle injury. The recovery of maximal torque capabilities function following cardiotoxin-induced tibialis anterior muscle injury was attenuated by electrically evoked muscle contractions conducted every other day during the recovery period in young adult mice.

Keywords:  mitochondria; muscle contractile properties; muscle injury; neuromuscular junction; regeneration

DOI:  https://doi.org/10.1113/JP290801
Physiol Rep. 2026 May;14(10): e70916

Voluntary wheel running attenuates peptidoglycan-polysaccharide-induced inflammation and preserves skeletal muscle remodeling in male C57BL/6J mice.

Ryoga Kinoshita, Tatsuhiro Yamaguchi, Satoru Ato, Karina Kouzaki, Yuki Tamura, Koichi Nakazato.

  Chronic systemic inflammation (CSI) is associated with skeletal muscle dysfunction and may impair adaptive responses. This study investigated whether skeletal muscle responses to voluntary wheel running (VWR) are maintained following exposure to CSI. Twelve-week-old male C57BL/6J mice were assigned to Saline+Sedentary, Peptidoglycan-Polysaccharide (PG-PS) + Sedentary, Saline+Exercise, and PG-PS + Exercise groups (n = 12 per group), with PG-PS used to induce CSI. Following 3 weeks of intervention, blood and lower-leg skeletal muscles were collected. Total running distance did not differ between exercise groups. PG-PS administration increased serum tumor necrosis factor-α and interleukin-1β levels in sedentary mice, whereas these levels were attenuated in VWR mice. Under sedentary conditions, soleus muscle weight and fiber cross-sectional area (CSA) were lower in PG-PS-treated mice. Exercise was associated with higher soleus muscle mass and fiber CSA in both saline- and PG-PS-treated mice. PG-PS increased 4-hydroxynonenal levels in the soleus muscle, whereas VWR was associated with lower levels. VWR markedly increased muscle protein synthesis and reduced markers of muscle protein breakdown, indicating enhanced protein turnover independent of PG-PS treatment. These findings suggest that exercise-induced increases in muscle mass and fiber size occur independent of PG-PS treatment. Clinically, whole-body exercise may represent a physiologically relevant, non-pharmacological strategy to support skeletal muscle health under chronic inflammatory conditions.

Keywords:  chronic systemic inflammation; exercise; skeletal muscle

DOI:  https://doi.org/10.14814/phy2.70916
Nucleic Acids Res. 2026 May 05. pii: gkag497. [Epub ahead of print]54(9):

Heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) maintains muscle progenitor identity by stabilizing the Ppp1r1b-lncRNA-PRC2 complex.

Xuedong Kang, Yan Zhao, Stanley F Nelson, April Pyle, Aldons J Lusis, Marlin Touma.

Heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) is a multifunctional RNA-binding protein of the hnRNP family, yet its role in long non-coding RNA (lncRNA)-mediated epigenetic regulation during myogenesis remains unclear. The lncRNA Ppp1r1b-lncRNA is an established regulator of myogenesis that functions through interaction with Polycomb repressive complex 2 (PRC2) at myogenic gene promoters. Here, we investigated the role of hnRNPA1 in Ppp1r1b-lncRNA-mediated regulation of myogenesis. Fluorescence in situ hybridization (FISH) revealed the subcellular localization of Ppp1r1b-lncRNA, and RNA pulldown coupled with mass spectrometry identified associated proteins. Both hnRNPA1 and EZH2 were found to bind Ppp1r1b-lncRNA, but at distinct regions. Knockdown of hnRNPA1 in mouse C2C12 myoblasts reduced the interaction between Ppp1r1b-lncRNA and EZH2, as determined by RNA immunoprecipitation (RIP), decreased promoter occupancy of Ppp1r1b-lncRNA, as assessed by chromatin isolation by RNA purification (CHIRP), and reduced H3K27me3 levels at the MyoD1 and Myogenin promoters, as shown by chromatin immunoprecipitation (ChIP). These changes led to increased expression of muscle-specific transcription factors and sarcomeric genes, thereby disrupting the undifferentiated state. Furthermore, hnRNPA1 knockdown disrupted the interaction between the human ortholog PPP1R1B-lncRNA and PRC2 in human skeletal muscle precursor cells (hSMPCs). Together, these findings demonstrate that hnRNPA1 maintains the integrity of the Ppp1r1b-lncRNA-PRC2 complex and ensures proper epigenetic regulation of myogenic gene expression. This conserved hnRNPA1-Ppp1r1b-lncRNA-PRC2 regulatory axis represents a potential therapeutic target for muscle regeneration.

DOI: https://doi.org/10.1093/nar/gkag497
Best Pract Res Clin Endocrinol Metab. 2026 May 07. pii: S1521-690X(26)00034-5. [Epub ahead of print] 102112

Influence of the adaptation of lactate accumulation rate through physical training on muscle mass regulation.

Nico Nitzsche, Victoria Oehme, Ralf Haase.

  Skeletal muscle mass is regulated by the interaction of mechanical, metabolic, hormonal, and nutritional factors. Beyond contractile adaptations, training-induced changes in glucose metabolism and glycolytic enzyme activity may contribute substantially to muscle mass regulation. In this context, the lactate accumulation rate (vLapeak) has recently gained attention as an indirect marker of glycolytic flux. This narrative review examines the potential relevance of training-induced vLapeak adaptations for the regulation of skeletal muscle mass. Current evidence suggests that resistance training is able to adapt vLapeak, likely reflecting enhanced glycolytic enzyme activity, greater recruitment of fast-twitch fibers, and sarcoplasmic adaptations associated with muscle hypertrophy. Ageing, inactivity, and disease are associated with declines in muscle mass, strength, and the activity of enzymes involved in anaerobic and aerobic metabolism, suggesting that reduced glycolytic capacity may contribute to impaired muscle quality. Although its clinical relevance for monitoring muscle mass remains insufficiently established, preliminary findings suggest that altered lactate accumulation characteristics may reflect impaired muscular metabolic capacity in chronic disease. Overall, vLapeak appears to be a promising metabolic indicator of skeletal muscle adaptations relevant to muscle mass regulation. However, further longitudinal and mechanistic studies are needed to clarify its validity and clinical applicability.

Keywords:  glycolytic flux; hypertrophy; resistance exercise; sarcopenia; sarcoplasmic

DOI:  https://doi.org/10.1016/j.beem.2026.102112
bioRxiv. 2026 Mar 02. pii: 2026.02.27.702183. [Epub ahead of print]

Multi-Omic, Multi-Tissue Responses to Acute Exercise in Sedentary Adults: Findings from the Molecular Transducers of Physical Activity Consortium.

MoTrPAC Study Group

Regular physical activity represents one of the greatest mechanisms for maintaining human health, yet the underlying molecular transducers of these benefits remain incompletely understood. Multi-omic assays now provide new opportunities to study the coordinated molecular responses of body tissues to different exercise modalities. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) was established to address this need by creating a molecular map of the response to physical activity. Described here is the first human cohort of MoTrPAC: sedentary adults enrolled prior to study suspension during the COVID-19 pandemic (N=175) randomized to either endurance or resistance exercise, or non-exercise control. From these participants, we detail their global acute molecular response in skeletal muscle, adipose tissue, and blood, integrated at multiple levels: tissue, exercise modality, timepoint, and omic category. These analyses characterize key molecular pathways, identify central regulators, and implicate novel candidate exerkines in mediating multi-organ exercise effects.

DOI: https://doi.org/10.64898/2026.02.27.702183
J Appl Physiol (1985). 2026 May 21.

Increasing intramuscular fluid volume increases passive tension in mammalian skeletal muscle.

Samantha P Falcone, Richard L Marsh, Ofubofu K Cairns, Thomas J Roberts.

  Experimental work in amphibian skeletal muscle and modeling studies have demonstrated that intramuscular fluid volume is an important determinant of the passive force that develops during lengthening. However, this effect has yet to be investigated in mammalian skeletal muscle. Therefore, we exposed isolated mouse soleus and extensor digitorum longus (EDL) muscles to a graded series of hypotonic solutions to promote fluid uptake while measuring passive force development, muscle mass, and 2D projected muscle area. Normalized to the tension measured at 1.2 L0 in isotonic Ringer's solution, the relative passive forces in the soleus were 1.14, 1.31, 1.52, and 1.92 in 70%, 60%, 55%, and 50% relative tonicity, respectively. Comparable values for the EDL were 1.13, 1.78, and 2.10 in 70%, 60%, and 55% relative tonicity, respectively. In both muscles, increases in passive force were accompanied by increases in mass and projected area. We also investigated the effect of muscle tension on fluid uptake. Soleus muscles left slack and allowed to shorten when exposed to a hypotonic solution gained much more mass compared to muscles held at the predicted length for maximal active force production, which suggests that at this length water uptake is limited by the buildup of hydrostatic pressure. Our findings support the hypothesis that in mammalian muscle, intramuscular fluid volume is an important determinant of passive force development. These results could have implications for human movement performance, where muscle volume change has been observed in vivo.

Keywords:  Intramuscular fluid volume; Passive force; mammalian skeletal muscle

DOI:  https://doi.org/10.1152/japplphysiol.00992.2025
Front Mol Biosci. 2026 ;13 1727633

HSF1 modulates lipid metabolism and ferroptosis in sarcopenia: a novel diagnostic biomarker and therapeutic target.

Dalu Cheng, Zhitao Shangguan, Xiaoqing Ye, Gang Chen, Qiong Lin, Jiandong Li.

   Background: Sarcopenia, an age-correlated decline in skeletal muscle mass and function, has been increasingly linked to ferroptosis, which is an iron-dependent form of regulated cell death driven by lipid peroxidation. Nevertheless, the diagnostic potential and mechanistic role of ferroptosis-relevant genes (FRGs) in sarcopenia remains poorly understood.
Methods: We integrated bioinformatics analyses and experimental validation to identify and characterize key FRGs in sarcopenia. By employing RNA-seq data from public datasets (GSE25941 and GSE9103), we identified differentially expressed FRGs and applied weighted gene co-expression network analysis (WGCNA) and multiple machine learning algorithms (comprising LASSO, SVM, KNN, XGBoost, and NNET) to screen for diagnostic biomarkers.
Results: Six hub FRGs (ACSL6, CDKN1A, ATG4D, DECR1, HSF1, and MIB1) were identified with AUC>0.8 as robust diagnostic biomarkers, among which HSF1 exhibited the highest diagnostic value (AUC = 0.9247). Molecular docking suggested quercetin and cycloheximide as potential therapeutic agents targeting HSF1. As demonstrated by functional experiments in C2C12 myoblasts, HSF1 silencing facilitated lipid metabolism, elevated ferroptosis markers, and induced muscle atrophy, while its overexpression attenuated these effects.
Conclusion: Our findings not only underscore the significance of FRGs in sarcopenia pathogenesis but also highlight their potential as diagnostic markers and therapeutic targets.

Keywords:  diagnostic markers; ferroptosis-relevant genes; lipid metabolism; machine learning algorithms; sarcopenia

DOI:  https://doi.org/10.3389/fmolb.2026.1727633
J Appl Physiol (1985). 2026 May 22.

Research into Resistance Training Response Heterogeneity: a Summary of the 2025 Conference at the University of Jyväskylä.

Michael D Roberts, Marcas M Bamman, Troy A Hornberger, Abigail L Mackey, Wim Derave, Philip J Atherton, Stuart M Phillips, Brad J Schoenfeld, Gustavo A Nader, Anne Hecksteden, Juha J Hulmi, Elina Sillanpää, Cleiton A Libardi, Juha P Ahtiainen.

  The Inter-Individual Variation in Resistance Training Response Conference was hosted at the University of Jyväskylä, Finland November 19-21, 2025. This paper summarizes key themes that emerged across lectures and discussions. First, resistance training induces multi-dimensional adaptations at the tissue, muscle fiber, and ultrastructural levels, including radial muscle fiber hypertrophy through increased myofibril number, longitudinal growth through sarcomere addition throughout the length (not ends) of muscle fibers, and metabolic adaptations that emulate other models of rapid cell growth. Second, training program variables including weekly sets, volume-load, rest interval duration, and training proximity to failure meaningfully influence hypertrophic outcomes in the general population, whereas exercise selection can be flexible. Third, age as well as molecular signatures prior to and in response to training influence inter-individual response heterogeneity. Finally, while inter-individual variability in observed hypertrophic responses is considerable, delineating true inter-individual variability from random variation remains challenging. Hence, study design considerations that can be thoughtfully applied to enhance rigor include repeat validation trials, unilateral within-subject designs, minimum clinically important difference thresholds, and multivariate composite responder classifications. This paper aims to summarize conference highlights while also providing meaningful implications for both researchers and practitioners and advancing current thinking on heterogeneity in the resistance training response.

Keywords:  resistance training; response heterogeneity; skeletal muscle; study design

DOI:  https://doi.org/10.1152/japplphysiol.00289.2026
Med Sci Sports Exerc. 2026 May 18.

Menstrual Cycle Phase Does Not Influence Training-Induced Muscle Hypertrophy or Strength: A Randomized Controlled Trial.

Alysha C D'Souza, Derrick W Van Every, Anmol Bhinder, Shivani Elango, Grace A C Lamont, Matthew J Lees, Changhyun Lim, James McKendry, James P Newbold, Colter Naphin, Irena A Rebalka, Lauren Roxburgh, Anojan Suthaharan, Brandan K Wilson, Stuart M Phillips.

   AIM: We investigated the influence of MCPBT on muscle hypertrophy and strength in response to RET over three MCs.
METHODS: Employing a randomized, unilateral design, twenty-four healthy, eumenorrheic females completed a within-participant resistance training trial across three consecutive MCs (12.2 ± 1.3 weeks; mean ± SD). Each individual's legs were randomly assigned to one of four conditions: non-exercising control (CON), continuous exercise training (balanced across both MC phases; EX), high-volume in the follicular phase with low volume in the luteal phase (HV-FOL), or the converse (HV-LUT). HV was defined as five sets per exercise twice weekly (≥10 sets·muscle⁻¹·week⁻¹), and low volume comprised one set per exercise twice weekly (≤5 sets·muscle⁻¹·week⁻¹). The primary outcome was thigh lean mass via dual-energy x-ray absorptiometry. Secondary outcomes were vastus lateralis cross-sectional area (VL CSA), leg fat-free mass (FFM) via bioelectrical impedance analysis, one-repetition maximum (1RM) strength and maximal voluntary isometric contraction.
RESULTS: All RET conditions produced greater gains than CON for thigh lean mass, VL CSA, FFM, and 1RM strength (all, p < 0.001), with no differences (all, p ≥ 0.17) between any of the training conditions (EX, HV-FOL, and HV-LUT).
CONCLUSIONS: MCPBT confers neither hypertrophy nor strength advantages over traditional continuous RET. Training volume-load, not MCPBT, was associated with several adaptations. MC phase-based adjustments in RET could be based on individual preference but are not necessary to achieve muscular adaptations to RET.

Keywords:  EUMENORRHEA; FEMALE; RESISTANCE EXERCISE; SKELETAL MUSCLE

DOI:  https://doi.org/10.1249/MSS.0000000000004031
Physiol Rep. 2026 May;14(10): e70928

EPAS1 is associated with human muscle fiber composition and endurance phenotypes.

Albina Z Dautova, Elena V Valeeva, Ekaterina A Semenova, Fanis A Mavliev, Alexey A Zverev, Andrey S Nazarenko, George John, Andrey V Zhelankin, Andrey K Larin, Nikolay A Kulemin, Rinat I Sultanov, Edward V Generozov, Ildus I Ahmetov.

  A recent study reported that endothelial PAS domain protein 1 (EPAS1; hypoxia-inducible factor 2α) acts downstream of PGC-1α to regulate the slow-twitch muscle fiber program in mice, yet its role in human physiology and exercise adaptation remains unclear. The aim of this study was threefold: (1) to investigate EPAS1 gene expression in human skeletal muscle and its association with muscle fiber composition and the expression of endurance-related genes; (2) to determine how EPAS1 expression responds to aerobic training; and (3) to examine whether EPAS1 genetic variation is linked to aerobic capacity, hemoglobin, and athletic status. The study involved 1234 subjects, including 943 athletes and 291 untrained individuals. EPAS1 gene expression was significantly higher in endurance athletes compared with power athletes (p = 0.011) and was positively associated with the proportion of slow-twitch muscle fibers in the vastus lateralis of untrained subjects (p = 0.0008) and athletes (p = 0.0033). EPAS1 expression was higher in females (p = 0.0028) and negatively associated with smoking status (p = 0.0007). Moreover, EPAS1 expression showed positive association with endurance-related genes, including ANGPT2, CKM, CPT1B, EPOR, FNDC5, HIF1A, KDR, MYBPC3, NFATC4, NOS3, PPARA, PPARD, PPARGC1A, UCP2, and VEGFA. Analysis of 24 publicly available skeletal muscle transcriptomic datasets demonstrated that EPAS1 expression increased significantly (meta-analysis p = 9.2 × 10-5) following aerobic training. Finally, genetically predicted higher EPAS1 expression (i.e., carriage of the EPAS1 rs6756667 A allele) was positively associated with endurance athlete status in both sexes (p = 0.0004) and with VO₂max (p = 0.046) and hemoglobin (p = 0.041) in male athletes. These findings potentially identify EPAS1 as an important genetic factor associated with muscle fiber composition, endurance-related phenotypes, and adaptation to aerobic training.

Keywords:  aerobic performance; athletic performance; genotype; muscle; polymorphism; talent

DOI:  https://doi.org/10.14814/phy2.70928
J Gen Physiol. 2026 Jul 06. pii: e202613986. [Epub ahead of print]158(4):

Subunit composition of the KATP channels that modulate contractility of skeletal muscle during fatigue.

Rosa Scala, Yuezhou Chen, Berk Mizrak, Gretchen A Meyer, Colin G Nichols.

ATP-sensitive potassium (KATP) channels are among the most expressed ion channels in skeletal muscle sarcolemma. While all KATP subunits can be detected in skeletal muscles, transcripts are enriched for KCNJ11 and ABCC9, suggesting that noncanonical Kir6.2/SUR2A assembly may constitute the majority of sarcolemmal KATP channels, but there has been no systematic dissection of KATP makeup in skeletal muscles. Here, we used a unique collection of murine lines selectively lacking specific channel-forming subunits (knockout, KO), and combined a genetic and pharmacological approach to determine which subunits of KATP channels are functionally relevant for skeletal muscle contraction. Under fatiguing conditions, isometric tetanic contraction experiments on murine extensor digitorum longus (EDL) revealed delayed loss of stimulated forces, and significant development of unstimulated forces, in muscles lacking Kir6.2 or SUR2 subunits, whereas loss of the SUR1 subunit did not impact muscle functionality. While pharmacological inhibition of sarcolemmal channels with glibenclamide causes comparable development of unstimulated force in wild-type muscles, acute pharmacological modulators of sarcolemmal KATP channels in isolated Kir6.2 or SUR2 KO muscles resulted in no changes in contractility properties, further consistent with no additional sarcolemmal KATP channels including Kir6.1 or SUR1 subunits. Our data show that fast-twitch skeletal muscle EDL relies on functional noncanonical KATP channels only made by ABCC9 (SUR2) and KCNJ11 (Kir6.2) gene products for contraction and suggest that similar contractile deficits will be present in ABCC9-dependent intellectual disability myopathy syndrome and KCNJ11-dependent congenital hyperinsulinism.

DOI: https://doi.org/10.1085/jgp.202613986
Sci Am. 2026 Jun 01. 334(6): 88

New Ways to Keep Muscle as You Age: Ozempic, similar drugs and aging take off muscle. New therapies could retain it.

Lori Youmshajekian.

DOI: https://doi.org/10.1038/scientificamerican062026-1pTaHwhFiwLqeuvbshy2Kd
Bone Res. 2026 May 19. pii: 55. [Epub ahead of print]14(1):

Decoding cellular communication networks and signaling pathways in bone, skeletal muscle, and bone-muscle crosstalk through spatial transcriptomics in a young male mouse.

Chuan Qiu, Yisu Li, Yun Gong, William Sherman, Di Tian, Weiqiang Lin, Zehui Pan, Boluwatife Afolabi, Vivek Thumbigere, Kuanjui Su, Jeffrey Deng, Yuwei Hou, Shashank Mungasavalli Gnanesh, Zhe Luo, Qing Tian, Fernando Sanchez, Yiping Chen, Hui Shen, Hong-Wen Deng.

Bone and skeletal muscle are essential components of musculoskeletal system, enabling movement, load-bearing, and systemic homeostasis. These tissues communicate through dynamic bone-muscle crosstalk mediated by cytokines, growth factors, and extracellular-matrix (ECM) proteins. The spatial organization of these mediators is critical for maintaining tissue integrity, and its disruption contributes to diseases, such as osteoporosis, sarcopenia, and metabolic syndrome. Despite this importance, spatial transcriptomics (ST) studies of bone-muscle interactions remain limited. Here, we applied 10x Genomics Visium ST with computational tools, e.g., SMART and CellChat, to deconvolute cell-type composition and characterize cell-cell communication networks and ligand-receptor (L-R) interactions in mouse femur and adjacent skeletal muscle. We identified eight major cell types (erythroid cells, endothelial cells, skeletal muscle cells, osteoblasts, myeloid cells, monocytes/macrophages, mesenchymal stem cells, and adipocytes) with distinct spatial transcriptional profiles and thirteen CellChat-inferred pathways, such as ECM-receptor related (e.g., COLLAGEN, TENASCIN, THBS) and secreted-signaling involved (e.g., VEGF) pathways. Representative L-R pairs include Col1a1/Col1a2-Sdc4, mediating osteoblast-to-muscle interactions, and Col4a1-Sdc4, facilitating muscle-to-osteoblast interactions in COLLAGEN, Tnxb-Sdc4 in TENASCIN, supporting muscle-to-osteoblast/muscle/myeloid/endothelial communication, Comp-Sdc4 in THBS, driving monocyte/macrophage-to-osteoblast/muscle signaling, and Vegfa-Vegfr1/Vegfr2 in VEGF, mediating muscle-to-endothelial/myeloid signaling. Immunostaining validated colocalization of several representative L-R pairs with their corresponding cells. Additionally, independent mouse and human bone scRNA-seq datasets reproduced most of the pathways and L-R pairs identified in ST, underscoring the robustness and cross-species relevance of our findings. Together, we present an initial spatially resolved transcriptome-wide map of bone-muscle intercellular communication, providing novel insights into molecular crosstalk and establishing groundwork for future studies in musculoskeletal disorders.

DOI: https://doi.org/10.1038/s41413-026-00520-w
Methods Mol Biol. 2026 ;3010 123-130

MicroRNA Quantification on Fast and Slow-Twitch Skeletal Muscles of Mouse.

Magally Ramírez-Ramírez, María Luisa Benítez-Hess, Estela G García-González, J Manuel Hernández-Hernández.

  microRNAs (miRNAs) are noncoding RNAs of approximately 24 nucleotides long that are expressed in multiple tissues and organs. miRNAs regulate the expression of specific target genes, and their expression profile can provide insight into the cell biology altered by diseases or drug treatments. Research has demonstrated that several miRNAs regulate muscle differentiation and the specification of fiber type. Hence, an established tool to routinely quantify miRNA abundance is of the utmost importance. The stem-loop quantitative reverse transcription PCR (RT-qPCR) is a methodology that allows the analysis of a specific miRNA with high sensitivity. Upon hybridization with a structured stem-loop oligonucleotide to the 3' end of the target miRNA, a retro-transcription is possible for further qPCR quantification. In this chapter, we describe a protocol to quantify miRNAs in dissected mouse fast and slow-twitch muscle.

Keywords:  Fast-twitch fiber; MicroRNA; RNA isolation; Skeletal muscle; Slow-twitch fiber; Stem–loop PCR; miRNAs isolation

DOI:  https://doi.org/10.1007/978-1-0716-5126-1_13
Cell Rep. 2026 May 21. pii: S2211-1247(26)00440-7. [Epub ahead of print]45(6): 117362

Cachexia-induced alterations of miR-27a-3p drive cell-type specific effects in FAPs and tumor cells that coincide with muscle wasting.

Ashok Narasimhan, Chun Wai Cheung, Nasim Kajabadi, Bruce Lin, Lin Wei Tung, Chihkai Chang, Fabio M V Rossi.

  The contribution of muscle-resident stromal cells to cancer-associated muscle wasting is poorly understood. We characterized the role of fibroadipogenic progenitors (FAPs) in pancreatic cancer-associated cachexia and investigated how dysregulated microRNAs in the tumor and FAPs drive muscle wasting. In cancer-bearing mice, FAPs engage in a chronic pro-inflammatory and pro-adipogenic program coinciding with muscle wasting. Additionally, in vitro and in vivo findings suggest that FAPs from cachectic mice cause muscle wasting, indicating that they may release pro-atrophic factors. Cancer-induced downregulation of miR-27a-3p in FAPs increased adipogenesis, whereas its upregulation in cancer cells increased proliferation and migration, highlighting the challenges of targeting pleiotropic molecules therapeutically. Knocking down miR-27a in the tumor improved both the micro- and macroenvironment of the muscle in vivo. Overall, we demonstrate that miR-27a-3p contributes to tumor progression and the dysregulation of FAPs, cooperatively driving muscle wasting. Our findings underscore the importance of tissue-specific targeting of microRNAs in cancer.

Keywords:  CP: metabolism; CP: molecular biology; PDAC; cachexia; fibroadipogenic progenitors; lipid metabolism; miR-27a-3p; miRNAs; muscle wasting; pancreatic cancer

DOI:  https://doi.org/10.1016/j.celrep.2026.117362
Mol Biol Rep. 2026 May 22. pii: 817. [Epub ahead of print]53(1):

DDRGK1 regulates muscle development by maintaining mitochondrial calcium homeostasis and oxidative phosphorylation via stabilizing IP3R.

Ping Li, Lingfei Li, Mali Guo, Junjie Xu, Yafei Cai.

   BACKGROUND: Mitochondrial calcium homeostasis is essential for oxidative phosphorylation (OXPHOS) and cellular energy production. DDRGK1 is an ER‑localized adaptor protein, which is critical for maintaining ER homeostasis, protein stability, and organelle communication. However, the role of DDRGK1 in regulating mitochondrial function remains largely unknown. This study aims to define the role of DDRGK1 in mitochondrial calcium signaling and bioenergetics.
METHODS AND RESULTS: Through biochemical analyses in cellular models, we identify DDRGK1 as a direct interactor and stabilizer of IP3R, preventing its ubiquitin-mediated degradation. DDRGK1 deficiency reduces IP3R protein levels, impairing mitochondrial calcium uptake and OXPHOS activity, as assessed by respirometry and ATP measurements. Consequent bioenergetic deficits are accompanied by calcium overload-induced ER stress, which activates C/EBP-homologous protein (CHOP) and suppresses the PGC‑1α pathway, thereby inhibiting mitochondrial biogenesis.
CONCLUSIONS: The DDRGK1-IP3R axis constitutes a critical regulatory module in mitochondrial calcium signaling and energy metabolism. Disruption of this axis underlies bioenergetic failure and provides mechanistic insight into the pathogenesis of skeletal muscle metabolic disorders and related mitochondrial diseases.

Keywords:  DDRGK1; ER-mitochondrial crosstalk; inositol 1,4,5-trisphosphate receptor; mitochondrial calcium homeostasis; oxidative phosphorylation

DOI:  https://doi.org/10.1007/s11033-026-12009-0
FASEB J. 2026 May 31. 40(10): e71898

Regulation of Satellite Cells and Myogenesis in Response to Eccentric Resistance Exercise in Hypoxic Conditions in Healthy Young Men.

Sophie van Doorslaer de Ten Ryen, Geoffrey Warnier, Nancy Antoine, Emilien Boyer, Pascal Kienlen-Campard, Sylvie Copine, Marc Francaux, Louise Deldicque.

  Satellite cells participate in myogenesis and contribute to skeletal muscle regeneration and hypertrophy. Amongst other stimuli, satellite cells can be activated by exercise and hypoxia. However, the cumulative effect of exercise on hypoxia on myogenesis is not well understood, certainly in humans. Furthermore, whether satellite cell activation and myogenesis differ between environmental hypoxia and blood flow restriction is not known. The purpose of this study was to analyze satellite cell and myogenic markers in response to acute eccentric resistance exercise in normoxia, normobaric environmental hypoxia, and with blood flow restriction (local hypoxia). Thirty-eight healthy young men were allocated to one of the three experimental conditions: normoxia (n = 13), normobaric environmental hypoxia (n = 12), and blood flow restriction (n = 13). They all performed 5 series of 15 repetitions at 60°/s for the knee extension and 30°/s for the knee flexion on an isokinetic dynamometer. Vastus lateralis muscle biopsies and blood samples were taken before, 1, 24, and 72 h after exercise. Myogenic regulatory factor expression was upregulated after exercise similarly in the normoxic and hypoxic groups and attenuated in the blood flow restriction group. Despite differential regulation of myogenic regulatory factor expression and circulating creatine kinase levels after eccentric resistance exercise, none of the investigated hypoxia markers and immediate early genes, inflammatory markers, growth factors, except insulin-like growth factor-1, and mitogen-activated protein kinase members were differently regulated between the groups. Contrary to our hypothesis, satellite cell activation and myogenesis were not potentiated by the combination of eccentric resistance exercise and hypoxic conditions.

Keywords:  blood flow restriction; exercise; hypoxia; myogenesis; regeneration; resistance; satellite cell; skeletal muscle

DOI:  https://doi.org/10.1096/fj.202600405RR
bioRxiv. 2026 May 10. pii: 2026.05.09.721064. [Epub ahead of print]

In vivo base editing via single myotrophic adeno-associated viruses in dystrophic mouse muscle and satellite cells.

Kuan-Hung Lin, Amy Lam, Samuel van Ooijen, Madeline Maier, Gracia Kassis, Regan Ellis, Kathleen Messemer, Jennifer Martin, Ramzi Khairallah, Amy Wagers.

Duchenne muscular dystrophy (DMD) is the most common, lethal X-linked neuromuscular disorder of childhood and is caused by mutations in the Dmd gene that disrupt dystrophin expression. Although adeno-associated virus-mediated gene therapies hold tremendous promise for DMD treatment, their clinical applications have been limited by dose-dependent vector and genome-level toxicities. Here, we developed and tested a single-vector adenine base editing strategy as a potentially safer genome editing approach to recode the pathogenic nonsense mutation into a benign missense mutation in mdx 4cv DMD mouse model. Delivered using a muscle-tropic adeno-associated virus (MyoAAV) at a clinically-feasible dose (4E13 VG/kg), this strategy enabled detectable molecular recoding of the mdx 4cv mutation in mice ranging in age from 3 days to 6 months. Yet, the overall efficiency and therapeutic impact of in vivo base editing with this system was highest in mice treated at the juvenile stage, with animals administered MyoAAV vectors at 3 weeks of age showing robust recovery of dystrophin expression and significant improvement in muscle contractile properties only one month later. Notably, introduction of adenine base editors either earlier in development, in neonatal mice, or later, in adulthood, yielded substantially lower editing efficiencies, particularly in muscle satellite cells whose editing is essential to ensure durable rescue of dystrophin expression in growing and regenerating muscle. Taken together, these results demonstrate the therapeutic potential of single-vector adenine base editing for DMD and underscore the importance of recipient age and disease stage in achieving optimal treatment outcomes for this and other genetic muscle disorders.

DOI: https://doi.org/10.64898/2026.05.09.721064
Proteomics. 2026 May 21. e70146

Temporal Proteomic Profiling Reveals Tissue-Specific and Coordinated Metabolic Reprogramming in Skeletal Muscle and Liver during Prolonged Fasting.

Leilei Cui, Lin Zeng, Mengqi Yang, Qiquan Wang, Chunping Huang, Liang Lin, Ping Li, Tao Liu, Weipeng Tong, Jiayi Sun, Hui Wei, Xinqiang Lan, Yang Xiang, Yu Su, Jian Li.

  Fasting triggers profound systemic metabolic adaptations that are essential for survival during nutrient scarcity, yet the temporal dynamics and cross-tissue coordination of proteomic remodeling remain incompletely characterized. Here, we employed quantitative proteomics to systematically profile the gastrocnemius (GA) muscle and liver of mice subjected to a 72 h fasting challenge at five time points (0, 12, 24, 48, and 72 h). Principal component analysis and hierarchical clustering revealed progressive, time-dependent proteomic reprogramming in both tissues, with distinct temporal trajectories of differentially expressed proteins (DEPs). GA muscle exhibited a biphasic response, with maximal downregulation at 48 h and peak upregulation at 72 h, whereas liver displayed a monotonic increase in DEPs, predominantly characterized by suppression of anabolic programs. Integrative cross-tissue analysis identified 97 conserved fasting-responsive proteins, including molecular chaperones (HSPA5, HSP90B1), complement components (C3), and coagulation factors (FGA, KNG1), which formed highly interconnected protein-protein interaction hubs. Fuzzy c-means clustering resolved five major temporal expression modules in each tissue, revealing coordinated shifts in mitochondrial metabolism, proteostasis, translation, and stress-response pathways. Spearman correlation analysis demonstrated moderate yet stable cross-tissue concordance (r = 0.43-0.48) throughout fasting, suggesting shared systemic regulatory mechanisms. Collectively, our findings provide a comprehensive temporal atlas of fasting-induced proteomic remodeling, revealing tissue-specific adaptive strategies alongside conserved molecular programs that orchestrate multi-organ metabolic homeostasis during prolonged nutrient deprivation.

Keywords:  cross‐tissue coordination; fasting; liver; metabolic adaptation; proteomics; skeletal muscle; temporal dynamics

DOI:  https://doi.org/10.1002/pmic.70146
J Appl Physiol (1985). 2026 May 19.

Beyond Birth Control: How Oral Contraceptives Impact Skeletal Muscle Health - a Systematic Review and Meta-Analysis.

Gabrielle Gilmer, Arielle J Hall, Christopher K Kargl, Salma O El-Mossier, Shragvi Balaji, George S Hussey, Amanda M Artsen, Kristen J Koltun, Amrita Sahu.

  Oral contraceptive pills (OCPs) are one of the most prescribed medications, yet we lack an understanding of if and how OCPs affect non-reproductive tissues. Given the well-documented effects of sex hormones on skeletal muscle, including on muscle mass, regeneration, and recovery, our review was aimed at assessing the impact of OCPs on skeletal muscle physiology in female humans and animals. We performed a literature search, title through full text screening, and citation search in accordance with PROSPERO guidelines. Rigor and reproducibility were assessed using the Modified Downs and Black Checklist. Meta-analyses were performed to assess the impact of OCPs on skeletal muscle outcomes. Although our search included both clinical and pre-clinical studies, the forty included studies were all clinical with no identified preclinical studies. Studies focused on young (20-30 y.o.) sedentary to active females with a healthy BMI (18-27 kg/m2) and included primarily strength and serum-based outcomes. All studies were retrospective and level III evidence. Notably, despite this literature spanning from the 1990's to 2025, rigor was in the 69th ± 6.5 percentile, and there was no correlation with rigor and year of publication. Meta-analyses did not detect an effect of OCPs on examined outcome measures; however, heterogeneity was high suggesting the lack of rejection of the null hypothesis may be driven by variations in studies, making it challenging to draw conclusions. Taken together, we recommend prospective preclinical and well-controlled clinical studies to examine the impact of OCPs on skeletal muscle in the setting of injury, disease, and varying demographics.

Keywords:  females; reproducibility; rigor; strength

DOI:  https://doi.org/10.1152/japplphysiol.00146.2026