bims-moremu Biomed News
on Molecular regulators of muscle mass
Issue of 2026–02–22
forty-two papers selected by
Anna Vainshtein, Craft Science Inc.
  1. PDGFRβ signaling restrains myocyte function to limit the regenerative capacity of skeletal muscle.
  2. Therapeutic strategies targeting muscle stem cells in satellite cell-opathies.
  3. Mustn1 ablation in male mice results in fiber type and gene expression alterations during skeletal muscle regeneration.
  4. Cross-Platform Transcriptomic Analysis of 40 Human and Rodent Skeletal Muscle Exerkines.
  5. Neuromuscular Mechanisms and Oxidative Stress in Skeletal Muscle Atrophy: Emerging Stem Cell and Gene-Based Therapeutic Strategies.
  6. The Age-Dependent Resident Myonuclear Multi-Omic Response to an Acute Skeletal Muscle Hypertrophic Stimulus in Mice.
  7. Hb-EGF directs systemic muscle repair.
  8. Zinc Depletion Increases Susceptibility to AMPK-Induced Atrophic Responses in C2C12 Myotubes.
  9. Molecular mechanisms of skeletal muscle fibrosis and potential targeted therapeutic strategies.
  10. Thromboxane signalling links immune activation to enhanced glucose uptake in skeletal muscle.
  11. Palmitoylethanolamide (PEA) regulates cell cycle progression and promotes an anti-inflammatory transcriptomic signature in C2C12 skeletal muscle cells.
  12. LXR activation in skeletal muscle cells enhances differentiation and promotes protein synthesis.
  13. The Mislocalization of TDP-43 to Mitochondria Impairs Myotube Maturation.
  14. Characterizing mitochondrial phenotypes and MERCS in aged human skeletal muscle myoblasts.
  15. Gait analysis for functional evaluation in a surgical hindlimb suspension model of muscle atrophy.
  16. Skeletal muscle in spinal muscular atrophy: Critical insights from pathogenesis to therapeutic strategies.
  17. Muscle regeneration on a chip: exercise-induced microtrauma and optimal mechanical stimulation regimen.
  18. Striatal Dopamine and Skeletal Muscle Energy Metabolism in Older Adults.
  19. Distinct HIF1α and HIF2α functions control skeletal muscle metabolism and erythropoiesis.
  20. Sarcopenia: An overview of emerging therapies and pathophysiological insights in age-related skeletal muscle decline.
  21. The uncoordinated-5 homologue A is a key receptor in netrin-ligand-mediated fast-twitch myotube formation in male mice.
  22. NSAIDs and muscle hypertrophy: Methodological concerns and alternative interpretations.
  23. Molecular insight into transcriptome profiling of aerobic exercise induced changes in aged skeletal muscle.
  24. How Acute and Chronic Exercise Regulate Muscle Atrophic Genes to Mitigate Sarcopenia: A Narrative Review.
  25. Oligomer-dependent and -independent pathogenesis of muscular dystrophy-associated mutations within the penta-EF-hand domain of calpain-3.
  26. Ceramide metabolism in oxidative and glycolytic muscle: significance for lipid-induced insulin resistance.
  27. Colocalization and functional analyses identify GBE1 as a gene linking muscle strength and cardiometabolic fitness.
  28. Inositol hexakisphosphate kinase 1 is implicated in the insulin response to protein ingestion in older adults.
  29. Menopause, Female Sex Hormones, Skeletal Muscle Mass and Muscle Protein Turnover in Humans.
  30. T-cadherin, a major adiponectin binding partner, suppresses ERK signaling in metabolic tissues.
  31. Aryl hydrocarbon receptor signaling in osteosarcopenia: an integrative framework for musculoskeletal aging.
  32. Exosomal microRNAs as Central Regulators of Cancer Cachexia: Multi-Omics Insights into Muscle Wasting and Adipose Browning.
  33. Sex differences in cardiovascular mechanisms underlying exercise intolerance in type 2 diabetes: the role of skeletal muscle microvasculature.
  34. Profiling the epigenomic landscape of late embryonic and adult mouse hind limb muscles.
  35. Single-Cell RNAseq Identifies Heterogeneity in Myoblasts From Older Adults With Differences Related to Muscle Mass and Function.
  36. Muscle-immune metabolic crosstalk: shared pathways in cachexia and exercise.
  37. Human neuromuscular organoids mimic cancer-induced muscle cachexia.
  38. The role of exosomal miRNA-125b derived from colon cancer-associated fibroblasts in skeletal muscle cachexia.
  39. GSDME/IL-18 pyroptotic axis prevents myosteatosis by expanding tissue-resident macrophages to promote muscle regeneration.
  40. Sex-dependent calcium dynamics in mouse skeletal muscle: Responses to cooling and caffeine.
  41. Loss of Myonuclei and Transcriptional Activity During Diaphragm Atrophy in Critically Ill Patients.
  42. MyoFuse is a fully AI-based workflow for automated quantification of skeletal muscle cell fusion in vitro.
  1. J Clin Invest. 2026 Feb 16. pii: e188272. [Epub ahead of print]136(4):
    PDGFRβ signaling restrains myocyte function to limit the regenerative capacity of skeletal muscle.
    Siwen Xue, Abigail M Benvie, Jamie E Blum, Benjamin D Cosgrove, Anna E Thalacker-Mercer, Daniel C Berry.
      Muscle cell fusion is critical for the formation and maintenance of multinucleated myotubes during skeletal muscle development and regeneration. However, the molecular mechanisms directing cell-cell fusion are not fully understood. Here, we identified platelet-derived growth factor receptor β (PDGFRβ) signaling as a key modulator of myocyte function in adult muscle cells. Our findings demonstrated that genetic deletion of Pdgfrb enhanced muscle regeneration and increased myofiber size, whereas Pdgfrb activation impaired muscle repair. Inhibition of PDGFRβ activity promoted myonuclear accretion in both mouse and human myotubes, whereas PDGFRβ activation stalled myotube development by preventing cell spreading to limit fusion potential. Furthermore, PDGFRβ activity cooperated with TGF-β signaling to regulate myocyte size and fusion. Mechanistically, PDGFRβ signaling required STAT1 activation, and blocking STAT1 phosphorylation enhanced myofiber repair and size during regeneration. Collectively, PDGFRβ signaling acts as a regenerative checkpoint and represents a potential clinical target to improve skeletal muscle repair.
    Keywords:  Adult stem cells; Development; Muscle biology; Signal transduction; Skeletal muscle
    DOI:  https://doi.org/10.1172/JCI188272
  2. J Neuromuscul Dis. 2026 Feb 19. 22143602251414570
    Therapeutic strategies targeting muscle stem cells in satellite cell-opathies.
    Pauline Garcia, Inès Mokhtari, Nicolas A Dumont.
      Satellite cells, the resident muscle stem cells, are essential for skeletal muscle post-natal growth and regeneration. Dysfunction in these cells contributes to a group of muscle disorders known as satellite cell-opathies, which can be categorized into primary and secondary forms. Primary satellite cell-opathies stem from intrinsic defects within satellite cells, including genetic mutations that impair their survival, self-renewal, proliferation, or differentiation. Alternatively, secondary satellite cell-opathies result from pathological conditions affecting both the satellite cells and the muscle fibers. This review explores the pathophysiology of satellite cell-opathies, highlighting key molecular mechanisms underlying their dysfunction. Additionally, we discuss emerging therapeutic approaches, including gene therapy, pharmacological interventions, and cell-based therapies, which aim to restore satellite cell function and promote muscle regeneration. A deeper comprehension of these mechanisms and satellite cell-targeted strategies is essential to drive the development of innovative therapies for this emerging class of muscle disorders.
    Keywords:  cell therapy; gene therapy; muscular dystrophies; myogenesis; neuromuscular diseases; regenerative therapies; satellite cells; stem cells
    DOI:  https://doi.org/10.1177/22143602251414570
  3. Physiol Rep. 2026 Feb;14(4): e70772
    Mustn1 ablation in male mice results in fiber type and gene expression alterations during skeletal muscle regeneration.
    Kaitlin Tagliaferri, Nithya Thomas, Michael Atallah, Stavroula Triantafillou, Michael Hadjiargyrou.
      We previously developed a Mustn1 conditional knockout (KO) mouse model targeting Pax7-expressing skeletal muscle satellite cells and showed its role in glucose metabolism, strength, gait, peak contractile strength, and myofiber composition. To investigate Mustn1's role in muscle regeneration, we used these KO mice in a cardiotoxin (CTX)-induced tibialis anterior injury model. Despite no major histological differences or deficits in ladder climbing between KO and wild-type (WT) mice at post-injury (Day 2-10), we observed significant shifts in fiber type composition. Mustn1 KO mice had more Type IIa fibers at Day 5, while Type IIx and IIb fibers were reduced at Day 2 and 10, respectively. Additionally, we observed increases in Type I fiber cross-sectional area in the Mustn1 KO mice at Day 0 and 2. Lower numbers of centrally nucleated fibers were also seen in the Mustn1 KO mice at Day 10. Pax7+ cells were also greater in numbers in the Mustn1 KO mice at Day 2 and 10. Lastly, expression of myogenic genes also differed significantly between the two strains. These data suggest that Mustn1 is integral to skeletal muscle fiber composition and myogenic gene expression thereby facilitating muscle repair and regeneration.
    Keywords:  Mustn1; cardiotoxin; fiber‐type; regeneration; skeletal muscle
    DOI:  https://doi.org/10.14814/phy2.70772
  4. Muscles. 2026 Feb 13. pii: 15. [Epub ahead of print]5(1):
    Cross-Platform Transcriptomic Analysis of 40 Human and Rodent Skeletal Muscle Exerkines.
    Hash Brown Taha, Nathan Robbins, Firas-Shah Zoha, Shirley Zhu, Nandhana Vivek, Aleksander Bogoniewski.
      Animal and human studies show that exercise induces organism-wide molecular adaptations that are partly mediated by exerkines which are secreted factors that enable inter-organ communication between tissues such as skeletal muscle, adipose tissue, liver and the brain. However, the tissue-specific responsiveness of individual exerkines and how these responses differ across species, exercise conditions and sexes remain poorly understood. To address this gap, we systematically analyzed skeletal muscle transcriptomic responses of 40 exerkines using three publicly available datasets including MetaMEx, Extrameta and the MoTrPAC 6-month-old rat training dataset. We reviewed exerkine-specific regulation in humans, mice and rats across acute and chronic exercise and inactivity. We determined conserved, non-conserved, and discordant exerkines across species and whether they were dependent on exercise modality or sex. Our review reveals substantial heterogeneity in skeletal muscle transcriptomic exerkine regulation with only a small subset showing conserved changes across species. Additionally, a key limitation is that our analysis was limited to transcriptomic data and may not reflect protein-level abundance, secretion, or uptake by recipient tissues. Therefore, we highlight a need for multi species and multi condition approaches when selecting exerkines as biomarkers or surrogate therapeutic targets.
    Keywords:  exercise; exerkines; meta-analysis; skeletal muscle; transcriptomics
    DOI:  https://doi.org/10.3390/muscles5010015
  5. Muscles. 2026 Feb 10. pii: 13. [Epub ahead of print]5(1):
    Neuromuscular Mechanisms and Oxidative Stress in Skeletal Muscle Atrophy: Emerging Stem Cell and Gene-Based Therapeutic Strategies.
    Sathish Kumar Gunasekaran, Mandam Amzad Khan, Mehwish Mirza, Santhosh Shanthi Bhupathi, Mohamed Sheik Tharik Abdul Azeeze.
      Skeletal muscle atrophy emerges from intertwined neuromuscular and metabolic failures, in which neuromuscular junction destabilization, excitation contraction coupling defects, and mitochondrial dysfunction collectively intensify calcium dysregulation and drive the accumulation of reactive oxygen and nitrogen species (RONS), reinforcing proteolytic and catabolic signaling programs. To integrate recent evidence on the neuromuscular redox interface and highlight therapeutic strategies that target these interdependent drivers of atrophy. RONS-mediated activation of NF-κB and FOXO pathways accelerates ubiquitin proteasome and autophagy lysosome degradation, leading to motor unit loss. Stem cell therapies (satellite cells, MSCs, and iPSC progenitors) seek to restore regenerative potential but face hurdles in engraftment and reinnervation. Gene-based interventions, including antioxidant gene delivery, Nrf2 activation, RNA modulators, and CRISPR editing, offer new avenues but remain limited by safety and delivery barriers. Bioengineering platforms such as hydrogels, decellularized scaffolds, and extracellular vesicles provide architectural, trophic, and immunomodulatory support. Translational progress requires rigorous safety pipelines, mechanistic biomarkers of motor unit recovery, and modular combination regimens that integrate cells, genes, scaffolds, and rehabilitative input. By aligning neuromuscular biology with redox control, emerging strategies hold promise to rebuild innervated, fatigue-resistant muscle across acquired and genetic atrophy syndromes.
    Keywords:  FOXO; NF-κB; gene therapy; mitochondrial dysfunction; neuromuscular junction; skeletal muscle atrophy; stem cell therapy; ubiquitin-proteasome system
    DOI:  https://doi.org/10.3390/muscles5010013
  6. Adv Sci (Weinh). 2026 Feb 17. e21633
    The Age-Dependent Resident Myonuclear Multi-Omic Response to an Acute Skeletal Muscle Hypertrophic Stimulus in Mice.
    Pieter J Koopmans, Ronald G Jones, Ana Regina Cabrera, Francielly Morena, Nicholas P Greene, John J McCarthy, Ahmed Ismaeel, Yuan Wen, Kevin A Murach.
      A detailed analysis of how muscle fiber nuclei (myonuclei) respond to a hypertrophic stimulus could provide a critical step toward understanding compromised skeletal muscle plasticity with age. We used recombination-independent doxycycline-inducible myonucleus-specific fluorescent labelling, tissue RNA-sequencing, myonuclear DNA methylation analysis, multi-omic integration, and single myonucleus RNA-sequencing (smnRNA-seq) to define the molecular characteristics of adult (6-8 month) and aged (24 month) murine skeletal muscle after acute mechanical overload (MOV). In adult and aged MOV muscles, we found that: 1) similarities in the transcriptional response to loading-specifically in metabolism genes - were partly explained by a post-transcriptional microRNA-mediated mechanism that we corroborated using an inducible muscle fiber-specific miR-1 knockout model, 2) differences in age-dependent transcriptional responses were linked to the magnitude and location of differential DNA methylation in resident myonuclei, specifically around genes such as Myc, Runx1, Mybph, Ankrd1, collagen (Col) genes, and minichromosome maintenance (Mcm) genes, 3) adult and aged resident myonuclear transcriptomes had differing enrichment for innervation-related transcripts as well as unique transcriptional profiles in an Atf3+ "sarcomere assembly" population after MOV, and 4) cellular deconvolution analysis and smnRNA-seq supports a role for neuromuscular junction regulation in age-specific hypertrophic adaptation. These data are a roadmap for uncovering molecular targets to enhance aged muscle adaptability.
    Keywords:  RNA‐seq; RRBS; aging; overload; smnRNA‐seq
    DOI:  https://doi.org/10.1002/advs.202521633
  7. Development. 2026 Feb 20. pii: dev.204993. [Epub ahead of print]
    Hb-EGF directs systemic muscle repair.
    Haley C Dean, Vishnu M Saraswathy, Amulya Saini, Sibani Nachadalingam, Jennifer McAdow, Amruta Tendolkar, Mayssa H Mokalled, A N Johnson.
      Regenerative capacity varies between tissues, species, stages of the life cycle. Regenerative capacity also varies with the magnitude of the injury, even within a single tissue. Vertebrate skeletal muscle fully regenerates in response to small-scale injuries, but large-scale injuries often lead to incomplete repair and debilitating loss of muscle use. To understand if small- and large-scale muscle injuries activate distinct regenerative programs, we developed a systemic muscle injury model in zebrafish. Transcriptomic analysis of muscle and non-muscle tissues revealed that systemic and local muscle injuries elicit distinct molecular responses, both quantitatively and qualitatively. We found systemic muscle injury activates the expression of Heparin binding epidermal-like growth factor (Hb-EGF) in the epidermis, and Hb-EGF is necessary for systemic muscle repair. Conversely, local muscle injury did not induce Hb-EGF expression and Hb-EGF was not required for local muscle repair. These studies suggest that large- and small-scale muscle injuries activate different regenerative programs, resulting in either systemic or local repair.
    Keywords:  Hb-EGF; Muscle regeneration; Regenerative capacity; Systemic muscle injury; Zebrafish
    DOI:  https://doi.org/10.1242/dev.204993
  8. Pathophysiology. 2026 Feb 02. pii: 12. [Epub ahead of print]33(1):
    Zinc Depletion Increases Susceptibility to AMPK-Induced Atrophic Responses in C2C12 Myotubes.
    Taishi Imoto, Junpei Ishizaka, Yukinori Tamura.
      Background: AMP-activated protein kinase (AMPK) acts as a key energy sensor that negatively regulates skeletal muscle mass. Zinc is an essential trace element that is required for myogenic differentiation and protein synthesis, while zinc deficiency has been associated with muscle atrophy in vivo. However, how zinc status modulates AMPK activation itself or alters downstream responses to AMPK signaling in muscle cells remains unclear. Methods: C2C12 myotubes were cultured under zinc-depleted (ZnD), zinc-sufficient (20 μM; Zn20), or zinc-supplemented (40 μM; Zn40) conditions. AMPK was activated by AICAR, and zinc status-dependent responses were evaluated using molecular and morphological analyses. Results: AICAR increased intracellular zinc levels in Zn20 and Zn40 but not in ZnD. Zinc transporter expression exhibited gene-specific regulation: Zip3 was upregulated across all zinc conditions, Zip14 was significantly induced in ZnD and Zn40, and Zip10 was selectively upregulated in Zn40. AICAR induced myotube atrophy in all groups; however, the reduction in myotube diameter was significantly greater under zinc-depleted conditions. Zinc depletion was associated with transcriptional upregulation of FoxO1, FoxO3, Atrogin-1, and MuRF1 in response to AICAR, while AMPK activation and suppression of S6K1 phosphorylation occurred to a similar extent regardless of zinc status. Conclusions: These findings indicate that zinc availability does not alter AMPK activation itself but modulates downstream atrophic responses to AMPK signaling. Under conditions of AMPK activation, adequate zinc availability is accompanied by increased intracellular zinc levels and stress-responsive ZIP regulation, which may limit excessive atrophic gene induction, whereas zinc depletion increases susceptibility to AMPK-induced atrophic responses in skeletal muscle cells.
    Keywords:  AMP-activated protein kinase; FoxO transcription factors; skeletal muscle atrophy; ubiquitin–proteasome system; zinc depletion
    DOI:  https://doi.org/10.3390/pathophysiology33010012
  9. Front Immunol. 2026 ;17 1714238
    Molecular mechanisms of skeletal muscle fibrosis and potential targeted therapeutic strategies.
    Jiahuan Gong, Jingxuan Xu, Jitai Zhang, Yuntian Shen, Hualin Sun, Bingqian Chen.
      Skeletal muscle fibrosis is a pathological process characterized by excessive deposition of extracellular matrix (ECM). It commonly occurs in various diseases such as muscular dystrophy, aging, cancer cachexia, and muscle injury. This condition leads to destruction of muscle structure, loss of function, and impaired regeneration, significantly affecting patients' quality of life. This review systematically summarizes the molecular mechanisms underlying skeletal muscle fibrosis. Key signaling pathways include transforming growth factor-beta (TGF-β)/Smad, yes-associated protein/transcriptional coactivator with PDZ-binding motif (YAP/TAZ), inflammation and immune regulation, oxidative stress, and microRNA-mediated regulation. The roles of fibro/adipogenic progenitors (FAPs), macrophages, and myofibroblasts in this process are also discussed. Among these, the TGF-β/Smad pathway acts as a central driver of fibrosis by promoting the differentiation of FAPs into myofibroblasts and stimulating ECM synthesis. YAP/TAZ integrates mechanical and biochemical signals, further amplifying the fibrotic response. Inflammation, oxidative stress, and epigenetic regulators such as miRNAs and lncRNAs also contribute through complex networks. Regarding therapeutic strategies, this article highlights various interventions including pharmacological inhibition (e.g., TGF-β inhibitors, angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers (ACEIs/ARBs), antioxidants), gene- and RNA-targeting therapies (e.g., miRNA mimics or inhibitors), cell-based therapies (e.g., Mesenchymal Stem Cells (MSCs)), biological agents (e.g., anti-connective tissue growth factor (CTGF) antibodies), as well as physical and nutritional interventions (e.g., electroacupuncture, magnetic stimulation, natural compounds). These approaches demonstrate strong anti-fibrotic potential by modulating ECM metabolism, the immune microenvironment, and cellular behaviors. However, current research still faces challenges such as disease heterogeneity, optimal treatment timing, drug delivery issues, and long-term safety concerns. Therefore, future studies should focus on developing highly specific targeted therapies, integrating multi-omics technologies and imaging assessments, and advancing personalized combination strategies to ultimately achieve effective prevention and treatment of skeletal muscle fibrosis.
    Keywords:  FAPs; TGF-β; YAP/TAZ; anti-fibrotic therapy; skeletal muscle fibrosis
    DOI:  https://doi.org/10.3389/fimmu.2026.1714238
  10. Diabetologia. 2026 Feb 20.
    Thromboxane signalling links immune activation to enhanced glucose uptake in skeletal muscle.
    Ahmed M Abdelmoez, Maxence Jollet, Xue Yu, David Rizo-Roca, Alesandra A Marica, Joaquin Ortiz de Zevallos, Lucile Dollet, Melissa L Borg, Marie Björnholm, Antonio Checa, Tommy Olsson, Julia Otten, Juleen R Zierath, Anna Krook, Thue W Schwartz, Alexander V Chibalin, Nicolas J Pillon.
       AIMS/HYPOTHESIS: Exercise elicits a spectrum of metabolic and inflammatory responses that are crucial for skeletal muscle adaptation and overall health, particularly in the context of metabolic diseases, yet the contribution of prostanoid signalling to these processes remains unclear. We hypothesised that exercise-induced thromboxane production enhances skeletal muscle glucose uptake and improves whole-body glucose control.
    METHODS: Plasma prostanoids were quantified in men and women with normal glucose tolerance or type 2 diabetes before, immediately after and 3 h after a single bout of exercise. Cyclooxygenase (COX-2) transcript levels were evaluated in human skeletal muscle, whole blood, peripheral blood mononuclear cells and skeletal muscle-resident immune cells. Metabolic and transcriptomic effects of thromboxane receptor activation were analysed in mouse C2C12, rat L6 and human primary skeletal muscle cells. Glucose tolerance in vivo was assessed following i.p. administration of the thromboxane receptor agonist I-BOP in male and female mice. Tissue-specific glucose uptake was quantified by measuring radiolabelled 2-deoxyglucose incorporation during an IVGTT.
    RESULTS: Acute exercise increased plasma thromboxane B₂ concentrations and skeletal muscle mRNA levels of PTGS2 (encoding COX-2) selectively in monocyte/macrophage populations. In skeletal muscle cells, the thromboxane receptor agonist I-BOP increased glucose uptake in a dose-dependent manner up to 2.5-fold within 4 h and enhanced glycogen synthesis by 430%. Transcriptomic and signalling analysis revealed activation of protein kinase A and cytoskeletal remodelling pathways linked to GLUT4 trafficking. In vivo, I-BOP improved glucose tolerance in male mice in a dose-dependent manner, without altering insulin levels. Thromboxane receptor stimulation increased glucose uptake in extensor digitorum longus muscle by 43%. Importantly, thromboxane receptor activation preserved its glucose-lowering efficacy in diet-induced obese male mice.
    CONCLUSIONS/INTERPRETATION: Exercise induces skeletal muscle-derived thromboxane production through macrophage-specific COX-2 activation. Thromboxane receptor stimulation enhances glucose uptake and glycogen storage via cytoskeletal remodelling, partially mimicking the acute exercise transcriptomic response. In vivo, thromboxane receptor activation improves glucose tolerance and skeletal muscle glucose uptake, with preserved efficacy in obesity. These findings identify thromboxane signalling as a previously unrecognised immunometabolic axis linking inflammation to glucose regulation and highlight the thromboxane receptor as a potential therapeutic target for metabolic disease.
    Keywords:  Exercise; Glucose; Metabolism; Skeletal muscle; Thromboxane; Type 2 diabetes
    DOI:  https://doi.org/10.1007/s00125-026-06684-8
  11. Physiol Rep. 2026 Feb;14(4): e70780
    Palmitoylethanolamide (PEA) regulates cell cycle progression and promotes an anti-inflammatory transcriptomic signature in C2C12 skeletal muscle cells.
    Paige L Cole, Scott H Gillham, Mark R Viggars, Graeme L Close, Daniel J Owens.
      Palmitoylethanolamide (PEA) is an endogenous lipid mediator with immunomodulatory actions, yet its effects in skeletal muscle remain poorly defined. We examined whether PEA influences myogenesis and profiled the acute transcriptomic response of differentiated C2C12 myotubes to 10 μM PEA. PEA decreased myotube number (90.3 ± 10.6 vs. 112.6 ± 10.1 control) while increasing nuclear fusion index (37.8 ± 5.7% vs. 30.7 ± 3.2%); myotube area was unchanged. In myoblasts, 24 h PEA increased G0/G1 (48.2 ± 1.2% vs. 42.3 ± 1.9%) and reduced S-phase (21.7 ± 1.2% vs. 25.5 ± 1.2%), consistent with G1 arrest. RNA sequencing identified 1952 differentially expressed genes enriched for cytokine-receptor interactions and inflammatory signaling. PEA downregulated NF-κB target cytokines while upregulating interferon-related and chemokine genes, indicating an anti-inflammatory/immune-priming profile. N-acylethanolamine acid amidase was highly expressed and induced, whereas fatty acid amide hydrolase remained low and unchanged, suggesting muscle-specific reliance on NAAA metabolism. These data show that PEA biases skeletal muscle toward a less proliferative but more fused and inflammation-resolving phenotype, with transcriptional reprogramming of immune pathways and preferential NAAA engagement. These findings motivate in vivo studies to test whether such actions benefit muscle regeneration, adaptation, or anti-atrophy interventions.
    Keywords:  N‐acylethanolamines; immunomodulation; myogenesis
    DOI:  https://doi.org/10.14814/phy2.70780
  12. Am J Physiol Endocrinol Metab. 2026 Feb 18.
    LXR activation in skeletal muscle cells enhances differentiation and promotes protein synthesis.
    Hayataka Takase, Miho Chikazawa, Makoto Noguchi, Ikuyo Ichi, Yu Takahashi, Yoshio Yamauchi, Makoto Shimizu, Ryuichiro Sato, Takashi Sasaki.
      Skeletal muscle possesses a remarkable capacity for regeneration, which is largely orchestrated by muscle satellite cells (MuSCs), a population of tissue-resident stem cells. Upon injury, these cells sense cues from their niche, transition from quiescence to activation, and subsequently undergo proliferation and differentiation to restore damaged myofibers. Although cholesterol, an essential component of the plasma membrane, is critical for cell growth and membrane dynamics, the regulatory landscape governing cholesterol metabolism during muscle regeneration remains poorly defined. In this study, we investigated the temporal expression patterns of lipid-associated genes during regeneration and identified a pronounced upregulation of liver X receptor (LXR) target genes 3 days post-injury, implicating oxysterol-mediated signaling as a potential modulator of the regenerative process. Furthermore, gas chromatography-mass spectrometry (GC-MS) analyses revealed elevated levels of oxysterols, specifically 4β-hydroxycholesterol and 25-hydroxycholesterol, in response to muscle injury induced by cardiotoxin (CTX) or barium chloride (BaCl₂). Complementary in vitro experiments demonstrated that the administration of LXR agonists promoted myogenic differentiation in cultured skeletal muscle cells, whereas pharmacological inhibition of LXR signaling impaired this process. Importantly, LXR activation attenuates lipopolysaccharide (LPS)-induced inflammatory responses in myocytes and concurrently enhances anabolic signaling through the Akt-mTOR axis, leading to increased protein synthesis. Collectively, these findings highlight the previously underappreciated role of cholesterol-derived metabolites in coordinating muscle regeneration, suggesting that LXR-mediated transcriptional programs simultaneously govern differentiation, inflammation, and biosynthetic capacity in regenerating skeletal muscle.
    Keywords:  cholesterol; liver x receptor; muscle differentiation; muscle regeneration; oxysterol
    DOI:  https://doi.org/10.1152/ajpendo.00261.2025
  13. FASEB J. 2026 Feb 28. 40(4): e71603
    The Mislocalization of TDP-43 to Mitochondria Impairs Myotube Maturation.
    Yalan Wan, Zhen Yu, Juan Yang, Wei Zhang, Meng Yu, Lingchao Meng, Zhaoxia Wang, Yun Yuan, Linhao Ruan, Jianwen Deng, Peng Wang.
      Aggregation of TDP-43 in neuronal cells is a defining neuropathological hallmark of amyotrophic lateral sclerosis (ALS). Emerging evidence suggests that TDP-43 pathology also occurs in skeletal muscle fibers, but its functional significance in myocytes remains poorly understood. In this study, we utilized the C2C12 myoblast cell to investigate the subcellular localization of TDP-43 during myogenic differentiation. Our findings demonstrate that TDP-43 progressively translocates to mitochondria in parallel with myotube maturation. Notably, increased mitochondrial localization of TDP-43 was also observed in skeletal muscle tissues from patients with ALS, corroborating the clinical relevance of this phenomenon. Functional assays revealed that inhibition of TDP-43 mitochondrial translocation significantly enhances myotube maturation. Collectively, these results support a pathophysiological role for aberrant mitochondrial mislocalization of TDP-43 in regulating myogenic differentiation and contributing to muscle degeneration in TDP-43 proteinopathies.
    Keywords:  TDP‐43; amyotrophic lateral sclerosis; mitochondria; myotube maturation
    DOI:  https://doi.org/10.1096/fj.202504624R
  14. PLoS One. 2026 ;21(2): e0343604
    Characterizing mitochondrial phenotypes and MERCS in aged human skeletal muscle myoblasts.
    Yufu Unten, Kazuaki Takafuji, Yumiko Masukagami, Isshin Shiiba, Keigo Horiuchi, Filip Husnik, Shigeru Yanagi, Norifumi Tateishi, Toshihide Suzuki.
      Age-associated declines in skeletal muscle function are linked to cellular senescence and mitochondrial alterations, yet mitochondrial phenotypes in aged human myoblasts remain insufficiently characterized. Here, we examined primary skeletal muscle myoblasts from young and elderly donors to assess mitochondrial function, morphology, and mitochondria-endoplasmic reticulum (ER) contact sites (MERCS). Myoblasts from older donors exhibited senescence features, including elevated SA-β-gal activity and reduced Lamin B1 expression, accompanied by increased mitochondrial oxidative stress. Despite marked mitochondrial hyperfusion and increased mitochondrial DNA content, mitochondrial oxygen consumption rate and membrane potential per mitochondrial area were comparable between young and old cells. MERCS were significantly elevated in aged myoblasts and were reduced by scavenging mitochondrial reactive oxygen species (mtROS), indicating an association between oxidative stress and MERCS formation. These findings suggest that mitochondrial hyperfusion and enhanced MERCS accompany cellular aging in human myoblasts and may contribute to maintaining mitochondrial function under elevated oxidative stress.
    DOI:  https://doi.org/10.1371/journal.pone.0343604
  15. J Physiol. 2026 Feb 17.
    Gait analysis for functional evaluation in a surgical hindlimb suspension model of muscle atrophy.
    Yanping Xu, Zhentao Zhang, Peng Chen, Natalie Kellon, Ashley He, Usman Alizai, Sunjoon Lee, Keerthika Sathish, Zhiyu Yan, Xinyu Zhou, Laura Kutz, Diamantis I Tsilimigras, Timothy M Pawlik, Hua Zhu.
      Disuse-induced skeletal muscle atrophy, commonly resulting from bedrest, immobilisation or spaceflight, leads to rapid loss of muscle mass and impaired mobility. Although muscle mass and contractile force are standard assessments in experimental models, these measures often fail to capture neuromuscular co-ordination deficits essential for effective movement. To better characterise these deficits, we employed a mouse hindlimb suspension (HLS) model for 14 days to induce disuse atrophy, confirmed by reductions in muscle mass, fibre type remodelling and satellite cell depletion, all of which were only partially reversed after a 7-day reloading period. In vivo analysis showed that gastrocnemius contractile force was significantly reduced following HLS and recovered incompletely after reloading. To functionally assess mobility, we implemented a non-invasive treadmill-based gait analysis, which revealed domain-specific impairments across neural control/rhythm, neuromuscular co-ordination and stability/variability, which were only partially restored after reloading, whereas muscle strength-related metrics such as paw drag showed mild but consistent alterations. At the molecular level, we identified elevated expression of MG29, subcellular redistribution of MG53 and altered expression of neuromuscular function-related genes (e.g. Ninj1, Prkg1, Ryr1 and S100a1), suggesting that MG29 and MG53 may contribute to impaired muscle plasticity and synaptic remodelling. Overall, our findings demonstrate that gait analysis can enhance the functional assessment of muscle disuse and recovery, offering a translational tool to evaluate interventions targeting atrophy-related mobility decline. KEY POINTS: Hindlimb suspension induces muscle atrophy and contractile loss, but functional consequences are not fully captured by traditional measurements. Gait analysis provides a non-invasive framework to evaluate neuromuscular performance across four domains: muscle strength/size, neural control/rhythm, neuromuscular co-ordination and stability/variability. Hindlimb suspension caused domain-specific impairments in rhythm control, co-ordination and stability, which were only partially restored after reloading, whereas strength-related metrics such as paw drag showed mild but consistent alterations. Correlation analyses revealed parallel reductions in propulsion- and rhythm-related gait metrics alongside decreases in muscle fibre size and tetanic force, indicating a functional-structural linkage between gait output and muscle integrity. Functional impairment is associated with satellite cell loss, MG29 upregulation, MG53 redistribution and neuromuscular function-related gene alteration. These findings identify gait metrics as biomarkers that may serve as early, non-invasive indicators of muscle disuse and recovery, providing mechanistic insights and a new tool to evaluate interventions targeting atrophy-related mobility loss.
    Keywords:  gait analysis; hindlimb suspension; mitsugumin 29; mitsugumin 53; muscle atrophy
    DOI:  https://doi.org/10.1113/JP289401
  16. Neurobiol Dis. 2026 Feb 18. pii: S0969-9961(26)00068-9. [Epub ahead of print] 107324
    Skeletal muscle in spinal muscular atrophy: Critical insights from pathogenesis to therapeutic strategies.
    Linda Ottoboni, Chiara Panicucci, Giulia Magni, Delia Gagliardi, Michela Ripolone, Laura Napoli, Maurizio Moggio, Giacomo Pietro Comi, Claudio Bruno, Stefania Paola Corti.
      Spinal muscular atrophy (SMA) is a genetic neuromuscular disorder caused by loss of the survival motor neuron (SMN) protein. While SMA was originally viewed as a pure motor neuron disease, it is currently considered a multi-system disorder in which skeletal muscle plays a pathogenic role. Muscular defects, such as impaired myogenesis and mitochondrial dysfunction, contribute to pathogenesis partly independently of denervation. Accumulating evidence suggests that the SMN deficit impairs muscle development from the earliest stages of fetal life, with delayed myotube maturation and modification of the expression of myogenic regulatory factors. This leads to pathology characterized by selective fiber atrophy, metabolic disturbances, and severe involvement of axial and intercostal musculature with relative sparing of the diaphragm. Furthermore, despite the revolutionary therapeutic effects of nusinersen, risdiplam, and onasemnogene abeparvovec, skeletal muscle abnormalities remain frequent, particularly in symptomatic patients, highlighting the need for muscle-directed therapies. Of the current candidate approaches, myostatin inhibition, targeting a negative regulator of muscle mass, is the most clinically advanced, while other strategies such as mitochondrial protection remain at earlier developmental stages. Work with neuromuscular models and stem cell-derived organoids continues to shed light on the SMN-mediated interactions between muscle and nerve. Collectively, these findings indicate that skeletal muscle is both a key driver of SMA pathology and an essential target for novel therapies.
    Keywords:  Molecular therapies; Myogenesis; Neuromuscular junction; SMN protein; Satellite cell; Skeletal muscle; Spinal muscular atrophy (SMA); Therapeutic strategy
    DOI:  https://doi.org/10.1016/j.nbd.2026.107324
  17. Lab Chip. 2026 Feb 18.
    Muscle regeneration on a chip: exercise-induced microtrauma and optimal mechanical stimulation regimen.
    Hongze Yin, Juan Zhang, Jing Zhou, Hui Ying Yang, Jiahao Wang, Yue Wang, Na Liu, Tao Yue.
      Skeletal muscles, through their coordinated interaction with bones and joints, enable diverse human movements and are essential for maintaining normal physiological functions and overall health. However, the physiological state of skeletal muscles and the mechanisms underlying muscle growth during exercise remain incompletely understood. To address this, we propose a multifunctional microfluidic chip system capable of simulating two distinct modes of movement. By modulating device parameters, this system enables in situ induction of muscle injury and subsequent mechanical repair. Our findings reveal that high-intensity exercise induces myoblast damage and cell detachment. Low-intensity exercise, over time, promotes activation of mechanosensitive ion channels (Piezo1) in myoblasts, upregulation of adhesion proteins (Talin1), cytoskeletal reorganization, and longitudinal myotube fusion along the mechanical stimulation axis. The regenerated myotubes exhibit distinct striations of actin and myosin filaments, accompanied by elevated expression of myogenic genes, indicating maturational development. Furthermore, a simplified numerical simulation model validates the platform's efficacy in studying muscle injury and repair processes. This work provides a novel strategy for future research on skeletal muscle disease modeling and therapeutic development.
    DOI:  https://doi.org/10.1039/d5lc00513b
  18. J Gerontol A Biol Sci Med Sci. 2026 Feb 14. pii: glag039. [Epub ahead of print]
    Striatal Dopamine and Skeletal Muscle Energy Metabolism in Older Adults.
    Caterina Rosano, Nico I Bohnen, Brian Lopresti, Lana M Chahine, Haley N Barnes, Stephanie L Studenski, Nancy W Glynn, Anne B Newman, David J Marcinek, Russell T Hepple, Paul Coen.
       BACKGROUND: Dopamine (DA) in the central nervous system is considered a master regulator of mobility performance and vigor, but its mechanistic relationship with skeletal muscle energetics is unclear.
    METHODS: We tested the cross-sectional association of striatal DA and skeletal muscle mitochondrial function in 146 older adults participating in the Study of Muscle, Mobility and Aging (75.4 years old, 54% women). Striatal DA was measured using (+)-a-[11C] dihydrotetrabenazine (DTBZ) PET imaging for the limbic, sensorimotor, and executive control subregions. Mitochondrial capacity to produce ATP (ATPmax, mM ATP/s) was measured in vivo using 31P magnetic resonance spectroscopy after repeated voluntary muscle contractions. Ex-vivo respirometry assays from biopsies of resting muscle captured complementary aspects of mitochondrial function under optimal conditions.
    RESULTS: In multivariable linear regression models, [11C]DTBZ in the limbic striatum, but not other subregions, was positively associated with greater ATPmax in vivo, independent of demographics, muscle volume, leg power, white matter hyperintensities, gray matter atrophy, moderate-to-vigorous physical activity and diabetes (β  =  0.275, standard error 0.108, p = 0.019). [11C]DTBZ was not associated with the ex-vivo mitochondrial respiration markers (p > 0.2).
    CONCLUSIONS: The role of striatal limbic DA and the energetic capacity of skeletal muscles should be further investigated in older adults.
    Keywords:  Limbic Network; Muscle Energetics; Striatal Dopamine
    DOI:  https://doi.org/10.1093/gerona/glag039
  19. J Clin Invest. 2026 Feb 17. pii: e195411. [Epub ahead of print]
    Distinct HIF1α and HIF2α functions control skeletal muscle metabolism and erythropoiesis.
    Junhyeong Lee, Merc Emil Matienzo, Sangyi Lim, Edzel Evallo, Yeongsin Kim, Sujin Jang, Keon Kim, Chang Hyeon Choi, Youn Ho Han, Chang-Min Lee, Tae-Il Jeon, Sang-Ik Park, Jun Wu, Dong-Il Kim, Min-Jung Park.
      Skeletal muscle frequently experiences oxygen depletion, especially during exercise, and the alpha subunit of the hypoxia-inducible factors (HIF1α and HIF2α) plays a crucial role in mediating cellular adaptation to low oxygen levels. However, although significant, the absence of an appropriate experimental mouse model leaves the precise roles of HIFα in myofibers unclear. Therefore, this study developed mice with myofiber-specific knockouts of prolyl hydroxylase proteins (PHDs), in which HIFα is stabilized, and inducible myofiber-specific overexpression of stable HIF1α or HIF2α to explore the role of HIFα in myofibers. Using three distinct mouse models, we found that HIF1α increased the number of oxidative fibers but paradoxically impaired exercise performance and mitochondrial function. Comparatively, HIF2α exerted protection mechanisms against glucose intolerance and diet-induced obesity. Notably, HIF2α stabilization in skeletal muscle markedly elevated erythropoietin (EPO) levels in muscle and serum but not in the kidney and liver, suggesting skeletal muscle is a previously unrecognized site of EPO production in the body. Thus, this study demonstrates the distinct roles of HIF1α and HIF2α in skeletal muscle, newly uncovering that the PHD-HIF2α axis produces EPO from myofibers.
    Keywords:  Hypoxia; Metabolism; Mitochondria; Muscle; Muscle biology
    DOI:  https://doi.org/10.1172/JCI195411
  20. Biochem Pharmacol. 2026 Feb 18. pii: S0006-2952(26)00144-9. [Epub ahead of print] 117813
    Sarcopenia: An overview of emerging therapies and pathophysiological insights in age-related skeletal muscle decline.
    Deepak Mishra, Lucy Mohapatra.
      Sarcopenia is characterized by an age-associated decline of skeletal muscle mass and function. It has been recognized as a clinical disease by the World Health Organization since 2016. This condition is commonly linked with signs of physical frailty, functional limitations, higher frequency of falls, increased hospitalization, and a rise in mortality rates, and it is gaining recognition as a crucial geriatric syndrome considering the increasing life expectancy and the growing elderly population worldwide. A few pathological mechanisms of sarcopenia have been identified, even though its etiologies are still unclear. These mechanisms include cellular senescence, oxidative stress, and apoptosis along with "inflammaging. It also involves changes in the types of muscle fibers, satellite cells, mitochondrial function, myokines, and inflammatory cytokines in aged sarcopenic muscle as compared with young or healthy aged muscles. Ultimately, this review explores new therapeutic avenues for the management of sarcopenia. There is not a well-recognized treatment for sarcopenia clinically now. However, there are a variety of pharmacological and non-pharmacological approaches that have been used to manage sarcopenia. Among the non-pharmacological interventions, diverse exercise protocols are supplemented by potent nutritional components. Exercise mimetics, myokines and monoclonal antibodies, nicotinamide adenine dinucleotide (NAD+) stimulators, mitochondrial boosters, and compounds that regulate muscular apoptosis are all included in the pharmacological interventions. This consolidated body of knowledge is expected to enhance the formulation of more effective therapeutic strategies aimed at maintaining muscle mass in the elderly population, thus fostering the independence of senior individuals and mitigating the socioeconomic challenges related to sarcopenia.
    Keywords:  Aging; Apoptosis; Exercise; Inflammation; Mitochondria; Muscles; Myokines; Sarcopenia
    DOI:  https://doi.org/10.1016/j.bcp.2026.117813
  21. Physiol Rep. 2026 Feb;14(4): e70788
    The uncoordinated-5 homologue A is a key receptor in netrin-ligand-mediated fast-twitch myotube formation in male mice.
    Takahiro Maeno, Tomoki Ushijima, Koichi Ojima, Yohei Ogawa, Sayuki Hayashi, Hikaru Imakyure, Rika Osaki, Ryuki Oyama, Aoi Ogawa, Akimasa Takano, Kaoru Mizoguchi, Issei Yokoyama, Yusuke Komiya, Mako Nakamura, Ryuichi Tatsumi, Takahiro Suzuki.
      Myoblasts autonomously govern myofiber-type specification of newly formed myotubes through autocrine-paracrine-dependent manners mediated by multipotent modulators. Netrin-1, which is particularly produced in myoblasts isolated from the extensor digitorum longus (EDL; fast-twitch myofiber-abundant) rather than the soleus (slow-twitch myofiber-abundant), and netrin-4, which is abundantly expressed during myogenic differentiation initiation, stimulate the synthesis of fast-type myosin heavy chain (MyHC) isoforms. However, the mechanisms by which netrin-1 and netrin-4 promote fast-twitch myotube formation remain unclear. Here, we investigated the roles of netrin receptors, uncoordinated-5 homologues (UNC5A, -B, -C, and -D), deleted in colorectal cancer (DCC), and the DCC paralog (neogenin) during myogenic differentiation, focusing on fast-twitch myotube formation. We confirmed that UNC5A, UNC5B, UNC5C, and neogenin synthesis patterns in EDL myoblasts showed no marked differences compared with those in soleus myoblasts. Notably, UNC5A knockdown severely inhibited fast-twitch myotube formation compared with other receptor knockdown treatments and significantly reduced the synthesis of fast-type MyHC isoforms. Additional treatment with recombinant netrin-1 or netrin-4 induced fast-type MyHC mRNA expression; however, this effect was suppressed by UNC5A knockdown. These findings revealed that UNC5A is involved in fast-twitch myotube formation via netrin ligands, highlighting an autonomous fast-type myofiber commitment system within myoblasts.
    Keywords:  fast‐twitch myotube; myofiber type; myotube; netrin; satellite cell‐derived myoblast; uncoordinated‐5 homologue A
    DOI:  https://doi.org/10.14814/phy2.70788
  22. J Physiol. 2026 Feb 18.
    NSAIDs and muscle hypertrophy: Methodological concerns and alternative interpretations.
    Mirko Mandić, Thomas Gustafsson, Tommy R Lundberg.
      
    Keywords:  COX‐inhibiting drugs; anti‐inflammatory drugs; diclofenac; ibuprofen; resistance training; skeletal muscle
    DOI:  https://doi.org/10.1113/JP290811
  23. NPJ Aging. 2026 Feb 18.
    Molecular insight into transcriptome profiling of aerobic exercise induced changes in aged skeletal muscle.
    Masroor Anwar, Priyajit Kaur, Dinesh Gupta, Avinash Chakrawarty, A B Dey, Sharmistha Dey.
      Skeletal muscle aging causes loss of both muscle mss and strength, often leading to sarcopenia. Clinical manifestation of sarcopenia has been found to improve with exercise intervention. The molecular mechanisms in response to exercise intervention in aged skeletal muscles are not fully understood. We performed transcriptomic profiling of aged animal model with exercise intervention for identifying the plausible mechanism leading to enhanced muscle function. Expression levels of 43,629 RNAs were analyzed for the process of aging and exercise intervention. Differentially expressed genes showed 22,196 protein-coding and 21,433 non-coding RNAs that were found to be significantly altered with intervention. Genes associated with extracellular matrix and inflammatory responses exhibited significant change with intervention. Slpi (Secretory Leukocyte Protease Inhibitor)- a vital gene in the intervention group with its role as an inflammatory regulator and tissue repair gene. The activation of quisqualate receptor, neurotransmitter receptors and postsynaptic signal transmission pathways were most relevant for upregulated genes in the intervention group. Downregulated genes in the intervention group were mostly associated with ATP-dependent protein disaggregase activity. Our study provides a comprehensive analysis of the global transcriptome that governs aerobic exercise induced changes in aged muscle leading to compensatory adaptation with exercise in aged model group.
    DOI:  https://doi.org/10.1038/s41514-026-00336-2
  24. Sports Med. 2026 Feb 14.
    How Acute and Chronic Exercise Regulate Muscle Atrophic Genes to Mitigate Sarcopenia: A Narrative Review.
    Maysa Vieira de Sousa, Diana Bento da Silva Soares, Hassane Zouhal, Anthony C Hackney, Juan Del Coso, Samuel Katsuyuki Shinjo.
      Muscle atrophy is defined as the reduction in muscle mass and strength resulting from a decrease in muscle fiber size and protein content. Muscle atrophy may result from physical inactivity, aging, starvation, or extended periods of limb immobilization. In addition, there are clinical conditions that are intrinsically associated with progressive muscle wasting, such as cancer, diabetes, or chronic heart failure, among others, as these conditions often involve a catabolic hormonal status or a decrease in neuromuscular stimulation. Overall, muscle atrophy leads to significant loss of health and quality of life as it reduces the independence and mobility of individuals affected by this disorder. Physical inactivity is the most common cause of muscle atrophy, especially in older adults, as it increases inflammation factors (TNF-α, IL-1β, and IL-6) and glucocorticoid levels (e.g., cortisol), disrupts intracellular signaling (GH/IGF-1, testosterone, and myostatin), and triggers decreased signaling of growth factors, such as diminished phosphorylation of FoxO by Akt. As a result of this decreased signaling, FoxO translocates to the nucleus of the muscle cell and induces the expression of muscle atrophy-related genes such as ATROGIN-1 (formally designated as FBXO3, also known as MAFbx) and MuRF-1 (formally designated as TRIM-63, also known as IRF). The higher expression of the proteins encoded by these genes, Atrogin-1 and MuRF-1, activates the ubiquitin-proteasome system in the striated muscle tissue responsible for degrading and recycling damaged, misfolded, or unneeded proteins. Therefore, the lack of muscle activity due to prolonged physical inactivity leads to muscle protein degradation and ultimately to muscle wasting. In the elderly and other populations with clinical conditions, there is a progressive reduction in physical activity and changes in food intake that may accelerate the loss of muscle mass and function, as well as increase body fat, giving rise to the phenomenon of sarcopenia. These changes in body composition increase the risk of suffering from chronic diseases, with a clear impact on progressively reduced mobility and increased risk of falls. Acute and chronic exercise can partially interrupt this vicious cycle in older adults and sedentary populations with chronic diseases, as it can diminish muscle wasting by activating molecular mechanisms to enhance muscle growth. Specifically, exercise can enhance muscle protein synthesis by activating the mTOR pathway while reducing protein degradation by suppressing the expression of muscle atrophy genes. In this narrative review, we summarize the mechanisms of action of the genes associated with muscle atrophy, MuRF-1 and ATROGIN-1, and their differential expression patterns following experimental and clinical trials involving chronic and acute exercise exposure, along with other potential regulators implicated in muscle remodeling.
    DOI:  https://doi.org/10.1007/s40279-025-02383-3
  25. J Biol Chem. 2026 Feb 12. pii: S0021-9258(26)00147-X. [Epub ahead of print] 111277
    Oligomer-dependent and -independent pathogenesis of muscular dystrophy-associated mutations within the penta-EF-hand domain of calpain-3.
    Chihiro Hisatsune, Fumiko Shinkai-Ouchi, Shoji Hata, Yasuko Ono.
      Limb-girdle muscular dystrophy R1 (LGMDR1) is an autosomal recessive disorder caused by dysfunction of calpain-3 (CAPN3; also known as p94), a muscle-specific, Ca2+-dependent cysteine protease. LGMDR1 mutations are distributed throughout the Capn3 gene. Nevertheless, our knowledge of the biochemical and biological properties of individual LGMDR1 mutants is limited, hindering a full understanding of LGMDR1 pathogenesis. Here, we comprehensively examined the functional properties of LGMDR1 mutants within the penta-EF-hand (PEF) domain at the COOH-terminus of CAPN3, focusing on their autolytic processing, oligomerization, titin binding, and subcellular localization within sarcomeres of mouse skeletal muscle. We found that oligomer formation of CAPN3 through the PEF domain contributes to efficient NH2-terminal and IS1-region processing, which were impaired by specific LGMDR1 mutations within the PEF domain. Furthermore, while wild-type CAPN3 predominantly localized at the sarcomeric M-bands of tibialis anterior muscles in vivo, several LGMDR1 mutants were absent from the M-bands due to decreased binding to titin, a giant cytoskeletal protein, irrespective of their oligomerization status. These findings indicate that LGMDR1 mutations within the PEF domain disrupt the physiological function of CAPN3 through both oligomer-dependent and -independent mechanisms, highlighting two distinct pathways contributing to LGMDR1 pathogenesis.
    Keywords:  Calpain; M-band; Muscular dystrophy; Oligomer; Penta-EF-hand motif; Sarcomere
    DOI:  https://doi.org/10.1016/j.jbc.2026.111277
  26. Mol Metab. 2026 Feb 16. pii: S2212-8778(26)00020-7. [Epub ahead of print] 102336
    Ceramide metabolism in oxidative and glycolytic muscle: significance for lipid-induced insulin resistance.
    Tova Eurén, Mikael Flockhart, Timotej Strmeň, Xin Zhou, Oscar Horwath, William Apró, Sarah J Blackwood, Dominik Tischer, Marcus Moberg, Pär Steneberg, Helena Edlund, Abram Katz, Elin Chorell.
      Altered ceramide accumulation contributes to skeletal muscle insulin resistance, but mechanisms underlying fibre-type-specific susceptibility remain unclear. We hypothesized that fibre-type-specific ceramide metabolism governs vulnerability to lipid-induced insulin resistance. Lipidomics and quantification of ceramide-pathway enzymes were performed in mouse skeletal muscles with distinct fibre-type composition (oxidative, mixed and glycolytic) from control-diet (n = 12) and high-fat-diet (HFD; n = 12) mice. In humans, lipidomics and enzyme profiling were done in vastus lateralis biopsies from 36 adults stratified into oxidative or glycolytic phenotypes; insulin sensitivity was determined by glucose tolerance testing. siRNA-mediated silencing of SGMS1 and SGMS2 followed by lipidomics probed sphingomyelin-ceramide cycling in human myoblasts. In mouse muscle, ceramide composition rather than total content, differed by fibre type: oxidative muscle was enriched in very-long-chain ceramides, whereas glycolytic and mixed muscles contained higher C18-ceramides, paralleled by fibre-type-specific expression of enzymes involved in de novo synthesis and sphingomyelin-ceramide cycling. HFD induced ceramide remodelling, with C18-ceramides accumulating in oxidative and mixed muscles and very-long-chain species decreasing in glycolytic muscle; among all assessed enzymes, only SGMS2 was significantly downregulated in oxidative muscle. In humans, an oxidative phenotype associated with higher very-long-chain ceramides and insulin sensitivity, whereas a glycolytic phenotype displayed higher C16-18 ceramides, higher SGMS1 and SMPD2 expression, and lower insulin sensitivity. Elastic net regression identified C16-18 ceramides and galactosylceramides as negative predictors of insulin sensitivity. SGMS2 silencing caused broader ceramide accumulation than SGMS1 silencing, supporting a central role for SGMS2-mediated sphingomyelin-ceramide cycling in limiting ceramide burden.
    Keywords:  Ceramide metabolism; Insulin resistance; Lipidomics; Skeletal muscle fibre; Sphingomyelin synthase 2 (SGMS2)
    DOI:  https://doi.org/10.1016/j.molmet.2026.102336
  27. Am J Physiol Endocrinol Metab. 2026 Feb 16.
    Colocalization and functional analyses identify GBE1 as a gene linking muscle strength and cardiometabolic fitness.
    Theresia M Schnurr, Miranda Lee Johnson, Christopher Jin, Kimmie Vestergaard Sørensen, Lindsey Kim, James W Jahng, Amanda Ramste, Ewa Bielczyk-Maczynska, Michael J Gloudemans, Peter Saliba-Gustafsson, Elena Vinton, Patrick L Jurney, Ivan Carcamo-Orive, Euan Ashley, Torben Hansen, Joshua W Knowles, Brian T Palmisano.
      Handgrip strength is a proxy for muscular fitness, an indicator for general health status, and is associated with cardiometabolic health. The mechanisms connecting handgrip strength to skeletal muscle function are incompletely understood. We applied integrated linkage-disequilibrium (LD)-adjusted colocalization analysis of genome-wide association study (GWAS) summary statistics for handgrip strength combined with expression and splicing quantitative trait loci from skeletal muscle and identified Glycogen branching enzyme 1 (GBE1) as a candidate gene for handgrip strength. CRISPRi knockdown of GBE1 in immortalized human skeletal muscle cells (HMCL-7304) demonstrated decreased glycogen content and accumulation of polyglucosan bodies. Knockdown of GBE1 led to increased oxygen consumption rate, oxidative stress, and changes in mitochondrial morphology. Transcriptomic profiling of GBE1 knockdown cells identified up-regulation of the human superoxide dismutase 2 (SOD2) and enrichment of pathways related to muscle contraction and oxidative stress responses. These functional genomic analyses prioritize GBE1 as a muscle-relevant candidate gene for handgrip strength and provide mechanistic insights to muscle fitness.
    Keywords:  Functional genomics; Glycogen branching enzyme 1; handgrip strength; mitochondrial function; oxidative stress responses
    DOI:  https://doi.org/10.1152/ajpendo.00470.2025
  28. Sci Rep. 2026 Feb 18.
    Inositol hexakisphosphate kinase 1 is implicated in the insulin response to protein ingestion in older adults.
    Richie D Barclay, Diana E Motei, Oana Ancu, Christopher J Tyler, Neale A Tillin, Volker Behrends, Nicholas A Burd, Nicholas M Hurren, Richard W A Mackenzie.
      Age-related muscle mass is driven by a reduction in insulin sensitivity partly mediated by reduced amino acid and anabolic signalling kinetics. Insulin activates Akt-mTORC1 signalling in skeletal muscle, with inositol hexakisphosphate kinase 1 (IP6K1) shown to inhibit this signalling pathway in pre-diabetic humans. We aimed to compare muscle and plasma IP6K1 in young vs older adults and the possible role of IP6K1 in the anabolic response to protein and protein plus resistance exercise (RE). Nine young (24.9 ± 0.4 years) and nine older (66.2 ± 0.5 years), moderately active adults received primed continuous infusions of L-[ring-2H5]phenylalanine in basal and postprandial state. Blood and muscle biopsy samples were collected prior to and following ingestion of 25 g whey protein with or without knee extension exercise to examine skeletal muscle protein signalling and whole-body phenylalanine kinetics. Young adults had greater plasma IP6K1 at all time points. Older adults had reduced muscle IP6K1 at 120 min post-exercise. Muscle IP6K1 decreased 240 min postprandially in young adults compared with basal and there was no effect of exercise in either group. Older adults presented with reduced plasma and muscle IP6K1 in both postprandially and post-RE states, as well as reduced phenylalanine rate of disappearance for the same comparisons. IP6K1 may be involved in the reduction in amino acid metabolism, and the insulin-mediated response to protein and RE.
    Keywords:  Ageing; Amino acids; IP6K1; Insulin resistance; Metabolism; Resistance exercise
    DOI:  https://doi.org/10.1038/s41598-026-35711-2
  29. J Cachexia Sarcopenia Muscle. 2026 Feb;17(1): e70232
    Menopause, Female Sex Hormones, Skeletal Muscle Mass and Muscle Protein Turnover in Humans.
    Campbell Menzies, Richard Bowtell, Natalie Shur, Matthew S Brook.
      Sarcopenia describes the loss of muscle mass and function with age. The increase in prevalence of sarcopenia in women appears to coincide with the onset of menopause, which is characterized by large changes to the hormonal milieu such as decreased oestrogen and progesterone concentrations. Although the timing of menopause and sarcopenia may coincide, there is a lack of high-quality evidence demonstrating a link between the two. This narrative review aims to assess evidence for the effects of menopause on muscle mass and muscle protein turnover. Longitudinal (n = 4/5) and cross-sectional (n = 7/11) studies demonstrate a reduction in lean or muscle mass across the menopausal transition with -2.5% and -5.7% reductions in perimenopausal and postmenopausal women, respectively, compared to premenopausal women. Most of this evidence (n = 10/11) is taken through assessment of lean body mass via dual-energy x-ray absorptiometry (DXA), which may underestimate changes in muscle mass. Assessment on changes to muscle protein turnover is largely limited to short-term measures of muscle protein synthesis (MPS), which may be elevated in older women versus younger women (n = 3/7) or age-matched males (n = 4/5). MPS responses to anabolic stimuli, such as resistance exercise (n = 3/4) or protein ingestion (n = 3/6), may be blunted in older women. Evidence assessing muscle protein breakdown (MPB) is lacking; however, evidence from animal and cell models demonstrates the role of estradiol in suppressing MPB, which may contribute to an increase in MPB following menopause. Advancements in understanding the role of the menopausal transition in the regulation of muscle mass, and subsequent effectiveness of interventions such as exercise or exogenous hormone provision will enable healthy ageing and sarcopenia prevention in older women.
    Keywords:  ageing; menopause; muscle mass; protein turnover; resistance exercise; sarcopenia
    DOI:  https://doi.org/10.1002/jcsm.70232
  30. Proc Natl Acad Sci U S A. 2026 Feb 24. 123(8): e2530597123
    T-cadherin, a major adiponectin binding partner, suppresses ERK signaling in metabolic tissues.
    Hirofumi Nagao, Yuta Kondo, Keitaro Kawada, Yuya Fujishima, Shunsuke Shiode, Yuhei Uehara, Shiro Fukuda, Yoshinari Obata, Shunbun Kita, Hitoshi Nishizawa, Iichiro Shimomura.
      T-cadherin, which is a major adiponectin binding partner, exerts various organ-protective effects. However, the specific changes in intracellular signaling that are induced by T-cadherin in metabolic tissues/cells remain unclear. We demonstrated that T-cadherin suppresses ERK signaling in both cultured cells and murine tissues. T-cadherin knockdown increased ERK phosphorylation in C2C12 myocytes and F2 endothelial cells, whereas T-cadherin overexpression suppressed ERK phosphorylation. Proteomic analysis revealed that many proteins that are downstream targets of ERK signaling were upregulated by T-cadherin knockdown in myocytes. T-cadherin knockdown in myocytes or knockout in heart or skeletal muscles altered the levels of membrane proteins that are involved in signal transduction, including IGF1R and EGFR. Ablation of T-cadherin in mice was accompanied by increased ERK signaling, leading to increased cardiac hypertrophy and decreased appropriate muscle atrophy during starvation. Thus, T-cadherin, whose protein expression is maintained by adiponectin, modulates intracellular signaling and regulates cardiac and skeletal muscle homeostasis in addition to promoting exosome production by adiponectin.
    Keywords:  ERK; GPI-anchor; IGF-1 receptor; T-cadherin; adiponectin
    DOI:  https://doi.org/10.1073/pnas.2530597123
  31. Biochimie. 2026 Feb 18. pii: S0300-9084(26)00052-0. [Epub ahead of print]
    Aryl hydrocarbon receptor signaling in osteosarcopenia: an integrative framework for musculoskeletal aging.
    Hassan Rammal, Alex M Noonan, Daniel Rivas, Dany S Sibai, Vincent Marcangeli, Gustavo Duque.
      Aging is accompanied by a progressive decline in tissue integrity and functional capacity and is a major risk factor for chronic disease. Osteosarcopenia, defined as the concurrent loss of bone and skeletal muscle mass and function, is a major contributor to frailty, fractures, disability, and reduced quality of life in older adults. While musculoskeletal aging has traditionally been attributed to endocrine and mechanical factors, growing evidence highlights an important role for environmental, microbial, and dietary signals in influencing tissue homeostasis across the lifespan. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that integrates these diverse cues and has emerged as a critical regulator of musculoskeletal homeostasis. In this review, we examine the emerging role of AhR signaling in the regulation of bone and skeletal muscle biology and discuss how context-dependent AhR signaling contributes to key hallmarks of aging, including oxidative stress, mitochondrial dysfunction, chronic inflammation, altered tryptophan metabolism, and gut dysbiosis. We propose that sustained or dysregulated AhR activation provides a mechanistic link between aging-related systemic stressors and the development of osteosarcopenia, highlighting AhR signaling as a potential target for preserving musculoskeletal health during aging.
    Keywords:  Aging; Aryl hydrocarbon receptor; bone; geroscience; muscle; osteosarcopenia
    DOI:  https://doi.org/10.1016/j.biochi.2026.02.016
  32. J Proteome Res. 2026 Feb 18.
    Exosomal microRNAs as Central Regulators of Cancer Cachexia: Multi-Omics Insights into Muscle Wasting and Adipose Browning.
    Farman Matloob Khan, Raafat El Awady, Shahid Mehmood, Zahid Hussain, Mohd Izani Othman, Abu Bakar Abdul Majeed.
      Cancer cachexia is a multifactorial syndrome marked by involuntary weight loss, skeletal muscle wasting, adipose tissue remodeling, and systemic metabolic dysfunction. Exosome-derived microRNAs (miRNAs) have emerged as key mediators, reprogramming host tissues and driving these hallmarks. However, no integrated framework has linked exosomal miRNAs to the proteomic and metabolomic alterations that characterize cachexia. This review critically synthesizes evidence on exosomal miRNAs in muscle atrophy, adipose browning, and systemic metabolic disruption. Tumor-secreted exosomal miRNAs activate proteolytic pathways (miR-21/29a via TLR7/8NF-κB/JNK), suppress antiapoptotic signals (miR-195a/125b targeting BCL-2), induce ER stress (miR-181a-3p), impair mitochondrial quality control (miR-122), and remodel metabolic signaling (miR-155, miR-183-5p). These mechanisms converge to produce proteomic signatures of enhanced proteolysis, apoptosis, and lipolysis, alongside metabolomic shifts toward amino acid efflux, fatty acid mobilization, and glycolytic inefficiency. This is the first integrated review linking exosomal miRNAs with proteomic and metabolomic signatures of cancer cachexia, offering a multiomics framework for biomarker discovery and therapeutic targeting. We highlight their potential as early biomarkers, therapeutic targets, and modulators of rehabilitation response, while outlining research gaps including limited clinical validation, intertumor heterogeneity, and the need for multiomics integration to advance translation into patient care.
    Keywords:  adipose tissue browning; cancer cachexia; exosome-derived microRNAs; metabolomic reprogramming; muscle wasting; proteomic dysregulation
    DOI:  https://doi.org/10.1021/acs.jproteome.5c01051
  33. Am J Physiol Heart Circ Physiol. 2026 Feb 21.
    Sex differences in cardiovascular mechanisms underlying exercise intolerance in type 2 diabetes: the role of skeletal muscle microvasculature.
    Sian A O'Gorman, Michelle A Keske, Lewan Parker, Gunveen Kaur, Julian W Sacre, Tasuku Terada, Kimberley L Way.
      Type 2 diabetes (T2D) disproportionately increases cardiovascular disease risk and premature mortality in females compared to males. Exercise intolerance is a hallmark symptom of T2D and an early indicator of cardiovascular dysfunction. While both central (cardiac) and peripheral (vascular, skeletal muscle) factors contribute to exercise intolerance in T2D, skeletal muscle microvascular dysfunction is increasingly recognized as an early contributor and key therapeutic target. However, the sex-specific cardiovascular mechanisms underlying exercise intolerance remain poorly understood. Females with T2D have lower exercise capacity and are less physically active than their male counterparts, which likely contributes to their heightened cardiovascular risk and worse clinical outcomes. Emerging evidence suggests that cardiac mechanisms may play a larger role in exercise intolerance in females, although sex differences in skeletal muscle microvascular function and dysfunction are poorly characterized. This narrative review synthesizes current research on the cardiovascular determinants of exercise intolerance in T2D, with a specific focus on the skeletal muscle microvasculature, and examines how sex differences in cardiovascular physiology and pathophysiology may affect exercise capacity. We highlight gaps in sex-specific research in healthy populations and individuals with T2D that limit insight into underlying disease mechanisms and effective therapies. Closing these gaps is essential for accurate risk assessment, timely diagnosis, and designing interventions that better address the cardiovascular needs of females with T2D.
    Keywords:  cardiovascular physiology; exercise intolerance; sex differences; skeletal muscle; type 2 diabetes
    DOI:  https://doi.org/10.1152/ajpheart.00787.2025
  34. Sci Rep. 2026 Feb 17.
    Profiling the epigenomic landscape of late embryonic and adult mouse hind limb muscles.
    Samantha R Queeno, Alexander S Okamoto, Damien M Callahan, Matthew C O'Neill, Terence D Capellini, Kirstin N Sterner.
      Skeletal muscles are essential for movement, supporting a wide range of locomotor behaviors. Muscle tissue is composed of multiple cell types including "fast" and "slow" myofibers, whose contractile properties are largely influenced by selective expression of myosin heavy chain (MyHC) isoforms. While 'super-enhancers' regulating MyHC gene clusters have been identified, the cis-regulatory elements (CREs) controlling non-MyHC genes important to myofiber physiology remain less defined. Here, we profile the regulatory landscape of two pairs of mouse hind limb muscles differing in MyHC expression at a late embryonic (E18.5) and adult time point to identify candidate CREs that may regulate genes important to myofiber type. Gene expression and chromatin accessibility analyses revealed that epigenetic differences at E18.5 largely reflect limb patterning, whereas adult differences reflect myofiber differentiation. We identified thousands of differentially accessible regions that may regulate genes important for muscle development, muscle biology, and myofiber identity. Among these, twelve conserved, muscle-specific CREs associated with myofiber type were tested for regulatory activity. Nine enhanced and three reduced gene activity in vitro, although their phenotypic effects remain unknown. By profiling multiple muscles across two time points, our study extends current understanding of conserved, muscle-specific CREs that regulate gene expression during myogenesis.
    Keywords:  Development; Enhancer; Locomotion; Metabolism; Mitochondria; Myosin heavy chain
    DOI:  https://doi.org/10.1038/s41598-025-32705-4
  35. J Cachexia Sarcopenia Muscle. 2026 Feb;17(1): e70213
    Single-Cell RNAseq Identifies Heterogeneity in Myoblasts From Older Adults With Differences Related to Muscle Mass and Function.
    Mark A Burton, Emma S Garratt, Hanan Y Sharkh, Matthew O Hewitt, Elie Antoun, Leo D Westbury, Elaine M Dennison, Nicholas C Harvey, Cyrus Cooper, Harnish P Patel, Keith M Godfrey, Karen A Lillycrop.
       BACKGROUND: Ageing is associated with the loss of muscle mass and function, with consequences for metabolic health, frailty and independence in later life. The aim of this study was to investigate the transcriptional heterogeneity of human proliferating muscle satellite/stem cells (myoblasts) from older adults and how this heterogeneity may vary between healthy individuals and those with low muscle mass and function.
    METHODS: Single-cell transcriptomic analysis was carried out on proliferating myoblasts isolated from vastus lateralis biopsies from 132 participants (34 male, 98 female) aged 72-83 years from the Hertfordshire Sarcopenia Study extension. Uniform Manifold Approximation and Projection (UMAP) clustering was applied to identify clusters of myoblasts with distinct transcriptional profiles, Gene Ontology analysis was used to identify pathways enriched among the clusters, and pseudotime trajectory analysis was used to identify inferred cell lineages. Differential gene expression within cell clusters, together with the proportions of cells within each cluster and lineage, were assessed with respect to participant appendicular lean-mass index (ALMi), grip strength, and gait speed.
    RESULTS: Thirteen distinct cell clusters based on the transcriptional heterogeneity of the myoblasts were identified. Clusters 0-6 contained the majority (94.6%) of cells. Marker genes were enriched for cytoplasmic translation (Cluster 0, false discovery rate [FDR] = 7.21 × 10-63), muscle development (Cluster 1, FDR = 2.25 × 10-13), cell proliferation (Clusters 2, 4 and 6, all FDR ≤ 0.05), extracellular matrix organisation (Cluster 3, FDR = 1.92 × 10-45) and RNA processing (Cluster 5, FDR = 1.89 × 10-08). Individuals with the highest grip strength and ALMi had a greater proportion of Cluster 1 and Cluster 5 cells. Gene expression analysis (FDR ≤ 0.05) within the clusters identified 22 differentially expressed transcripts with respect to ALMi in Cluster 2 and 13 with respect to grip strength in Cluster 1. Inferred lineage analysis identified cells transitioning along five trajectories (L1-L5), including cells in L1, L3 and L4 progressing towards a stressed pre-senescent/senescent (L1) or fibrogenic (L3 and L4) state, with cells in these lineages being more likely to originate from individuals with low ALMi (χ2 p = 1.11 × 10-146) and grip strength (χ2 p = 1.31 × 10-269).
    CONCLUSION: Our findings demonstrate considerable transcriptional heterogeneity in skeletal muscle myoblasts from older adults. This heterogeneity includes myoblasts from individuals with low muscle mass and strength progressing towards a fibrogenic or stressed state.
    Keywords:  ageing; cell heterogeneity; myoblasts; sarcopenia; single‐cell transcriptomics; skeletal muscle
    DOI:  https://doi.org/10.1002/jcsm.70213
  36. Curr Opin Biotechnol. 2026 Feb 19. pii: S0958-1669(26)00020-0. [Epub ahead of print]98 103455
    Muscle-immune metabolic crosstalk: shared pathways in cachexia and exercise.
    Stefanie Westermann, Bastian C Bennühr, Amy R Fumo, Maria Rohm, Karsten Hiller.
      Skeletal muscle and the immune system continuously exchange metabolites and signals that are essential for homeostasis. Disruption of this communication, such as during infection, inflammation, or cancer, triggers cachexia, a severe wasting syndrome characterized by altered amino acid flux, mitochondrial dysfunction, and systemic energy imbalance. By contrast, regular exercise activates overlapping pathways but directs them toward regeneration and hypertrophy, supported by controlled cytokine release and metabolite exchange. This review outlines the metabolic reprogramming that underlies muscle-immune crosstalk in cachexia and exercise, emphasizing how identical mediators, including interleukin-6, can promote either catabolism or adaptation depending on context. Understanding these shared yet divergent pathways opens avenues for therapeutic strategies that target metabolism and immune-metabolic communication.
    DOI:  https://doi.org/10.1016/j.copbio.2026.103455
  37. Cell Rep Methods. 2026 Feb 17. pii: S2667-2375(26)00031-7. [Epub ahead of print] 101331
    Human neuromuscular organoids mimic cancer-induced muscle cachexia.
    Pietro Chiolerio, Beatrice Auletta, Camilla Pezzini, Luigi Sartore, Giorgia Gregolon, Onelia Gagliano, Cecilia Laterza, Valeria Roxana Balmaceda Valdez, Davide Cacchiarelli, Camilla Luni, Carlo Viscomi, Melanie Planque, Sarah-Maria Fendt, Marco Sandri, Roberta Sartori, Anna Urciuolo.
      Cancer cachexia, a devastating metabolic wasting syndrome affecting up to 80% of solid cancer patients, remains incurable despite advances in tumor biology understanding. This study introduces neuromuscular organoids (NMOs) derived from human-induced pluripotent stem cells (hiPSCs) as a platform to investigate cancer-driven muscle cachexia. We found that NMOs respond well to atrophic stimuli and replicate the key features of cancer cachexia when treated with conditioned media derived from cachexia-inducing cancer cells. Specifically, cachectic NMOs showed muscle mass loss, impairment of muscle contraction, alteration of intracellular calcium homeostasis, appearance of mitochondrial dysfunction with a metabolic shift, and enhancement of autophagy. Based on these results, we propose NMOs derived from hiPSCs as an in vitro tool for investigating human muscle cachexia, with potential future avenues of patient-specific modeling and therapeutic screening.
    Keywords:  CP: cancer biology; CP: stem cell; autophagy; cancer cachexia; human induced pluripotent stem cells; in vitro human disease model; metabolic remodeling; mitochondrial dysfunction; neuromuscular junction; neuromuscular organoid; skeletal muscle wasting
    DOI:  https://doi.org/10.1016/j.crmeth.2026.101331
  38. PLoS One. 2026 ;21(2): e0342052
    The role of exosomal miRNA-125b derived from colon cancer-associated fibroblasts in skeletal muscle cachexia.
    Ho Seung Kim, Jinsu Kim, Bom Lee, Yonghyun Lee, So-Yeon Park, Bo-Young Oh, Kyung-Ah Cho, Soon Sup Chung, Gyoung Tae Noh.
      Cancer-associated cachexia is a multifactorial syndrome characterized by significant weight loss, primarily due to skeletal muscle atrophy. This condition impairs the quality of life and survival of patients with cancer. Although the mechanisms underlying cancer-associated cachexia, including exosomes and microRNAs (miRNAs), have been extensively explored, research specifically focusing on cancer-associated fibroblast (CAF)-derived exosomes is lacking. Therefore, in this study, we evaluated the effects of CAF-derived exosomal miRNAs from colon cancer on skeletal muscles using the Human Skeletal Muscle (HSkM) cell line. CAF-derived exosomes were isolated from colon cancer samples, and their effects on cell morphology were analyzed using confocal microscopy. The results indicate that treatment with CAF-derived exosomes significantly reduced myosin diameter. Moreover, miRNA sequencing revealed that miR-125b was enriched in CAF-derived exosomes. HSkM cells were subsequently transfected with a miR-125b mimic, which significantly reduced myosin diameter. Notably, co-treatment with CAF-derived exosomes and an miR-125b inhibitor reversed this effect. In conclusion, this study demonstrates the potential role of CAF-derived exosomes and miR-125b in cancer-associated cachexia, offering insights into the contribution of the tumor microenvironment and suggesting possible therapeutic targets.
    DOI:  https://doi.org/10.1371/journal.pone.0342052
  39. J Clin Invest. 2026 Feb 17. pii: e198076. [Epub ahead of print]
    GSDME/IL-18 pyroptotic axis prevents myosteatosis by expanding tissue-resident macrophages to promote muscle regeneration.
    Qi Cao, Jian Liu, Gang Huang, Su-Yuan Wang, Guo-Dong Lu, Yong Huang, Yi-Ting Chen, Zhen Zhang, Jiang-Tao Fu, Si-Jia Sun, Xiaofei Chen, Chunlin Zhuang, Chunquan Sheng, Fu-Ming Shen, Dong-Jie Li, Pei Wang.
      Metabolic-inflammatory crosstalk orchestrates muscle repair. Although pyroptosis typically aggravates sterile injury, we demonstrated that GSDME-dependent pyroptotic signaling associated with recruited myeloid cells paradoxically supported regeneration. GSDME expression was induced in post-surgical human muscle injury and murine damage models. Gsdme deficiency delayed functional recovery and exacerbated injury-induced myosteatosis, a pathological form of intramuscular ectopic fat deposition. Time-series and single-cell RNA-sequencing analyses revealed that GSDME loss shifted the transcriptional program from oxidative metabolism toward lipid storage and adipogenesis. Lipidomics confirmed aberrant accumulation of triacylglycerols and sphingolipids in Gsdme-deficient muscle. Single-cell profiling further identified divergent fibro-adipogenic progenitors (FAPs) states skewed toward adipogenesis, accompanied by impaired expansion of restorative Lyve1⁺Cd163⁺Txnip⁺ tissue-resident macrophages (TRMs)-validated by multiplex flow cytometry. Blocking CCR2-dependent monocyte recruitment produced regenerative defects comparable to those caused by Gsdme deficiency. Myeloid-specific Gsdme reintroduction rescued TRM expansion and function, curbed FAP adipogenic reprogramming, whereas FAP-specific expression proved ineffective. Mechanistically, IL-18 downstream of GSDME-dependent signaling engaged KLF4/JUN signaling in TRMs, sustaining their reparative and lipid-clearing capacity. This GSDME-IL-18-TRMs axis was compromised in aged muscle, yet exogenous IL-18 reversed myosteatosis and accelerated regeneration. Together, these findings suggest that GSDME-dependent pyroptotic signaling can act as a metabolic checkpoint that sustains TRM-driven lipid homeostasis to support muscle regeneration.
    Keywords:  Immunology; Inflammation; Macrophages; Metabolism; Signal transduction
    DOI:  https://doi.org/10.1172/JCI198076
  40. J Therm Biol. 2026 Feb 09. pii: S0306-4565(26)00045-8. [Epub ahead of print]136 104412
    Sex-dependent calcium dynamics in mouse skeletal muscle: Responses to cooling and caffeine.
    Kosei Hayakawa, Ryo Takagi, Ayaka Tabuchi, Haruka Ugawa, Daiki Watanabe, Daisuke Hoshino, David C Poole, Yutaka Kano.
      Intracellular calcium ion concentration ([Ca2+]i) regulation in skeletal muscle may vary with sex and muscle fiber type, but the precise nature of its response to temperature changes and pharmacological caffeine stimulation is not fully understood. This study aimed to elucidate sex-dependent and muscle fiber type-specific characteristics of muscle cooling, caffeine stimulation, and their combined effects. We investigated the effects of cooling (30 °C to 0 °C) and caffeine stimulation (1.25-80 mM) separately and in combination (cooling + 1.25 mM caffeine) in fast-twitch (plantaris, PLA) and slow-twitch (soleus, SOL) muscles of male and female C57BL/6J mice. [Ca2+]i dynamics were analyzed using in vivo Fura-2 bioimaging under isoflurane anesthesia. The temperature threshold for the onset of [Ca2+]i accumulation was significantly higher in SOL than in PLA, with no significant difference between sexes (males: PLA 2.3 ± 0.9 °C, SOL 4.5 ± 2.2 °C; females: PLA 2.3 ± 0.8 °C, SOL 4.3 ± 1.3 °C). Conversely, the [Ca2+]i response to caffeine was significantly higher in females than in males at high concentrations (80 mM). Furthermore, the combined stimulation of cooling and caffeine had a greater effect on females than on males. Our findings also indicate that the phosphorylation response of ryanodine receptors to caffeine was significantly higher in females than in males. In conclusion, while no sex differences were observed in the [Ca2+]i response to cooling, clear sex-dependent differences (males < females) were observed in the response to caffeine.
    Keywords:  Caffeine; Calcium homeostasis; Icing; Muscle fiber type; Sex difference
    DOI:  https://doi.org/10.1016/j.jtherbio.2026.104412
  41. J Cachexia Sarcopenia Muscle. 2026 Feb;17(1): e70228
    Loss of Myonuclei and Transcriptional Activity During Diaphragm Atrophy in Critically Ill Patients.
    Wout J Claassen, Marloes van den Berg, Zhong Hua Shi, Rianne J Baelde, Sylvia Bogaards, Luuk Bonis, Heleen Hakkeling, Arezou Bamyani, Gerben J Schaaf, Albertus Beishuizen, Chris Dickhoff, Reinier A Boon, Leo Heunks, Tyler J Kirby, Coen A C Ottenheijm.
       BACKGROUND: Diaphragm weakness frequently develops in critically ill patients and is explained by a combination of atrophy and myofiber dysfunction. Myofibers are large syncytial cells maintained by a population of myonuclei, which provide gene transcripts to a finite fiber volume, termed the myonuclear domain. Myonuclear number is a determinant of transcriptional capacity and therefore critical for diaphragm and peripheral muscle regeneration after critical illness. Changes in myonuclear number in myofibers undergoing atrophy have not been investigated in mechanically ventilated ICU patients, but they are of potential clinical importance. Our objective was to investigate if and how myonuclear number changes in the diaphragm of mechanically ventilated ICU patients and whether changes are associated with myofiber atrophy and clinical parameters.
    METHODS: We used a combination of transcriptomics, immunohistochemistry and confocal microscopy to study myonuclear alterations in the diaphragm and quadriceps biopsies from mechanically ventilated ICU patients (n = 24) and non-critically ill patients (n = 10).
    RESULTS: Compared to control patients, myonuclear number and myonuclear domain were reduced in critically ill patients with diaphragm myofiber atrophy (n = 14) (myonuclear number per mm of 133 [92-183] vs. 92 [83-105], p = 0.03 (slow myofibers) and 149 [118-189] vs. 88 [69-109], p = 0.004 (fast myofibers); myonuclear domain size was 44 [34-51] vs. 29 pL, p = 0.004 (slow myofibers) and 41 [39-48] vs. 27 pL, p = 0.001 (fast myofibers) of control patients and ICU patients with atrophy, respectively). Increased intrinsic apoptotic pathway activation was identified as a mechanism underlying myonuclear removal (percentage of apoptotic myonuclei of 0.64 [0.60-0.84] and 0.95 [0.84-1.2], p = 0.015 and increased percentage of activated caspase-3 positive myonuclei of 2,5 [1.6-3.3] vs. 5.7 [4.3-11], p = 0.001 in control patients and ICU patients with atrophy, respectively). Total transcriptional activity in myofibers decreased with myonuclear loss (RNA-Pol-2 Ser5 fluorescence intensity per fibre of 2.6 [2.2-3.3] vs. 5.8 [3.1-6.7] AU, p = 0.036 in control patients and ICU patients with atrophy, respectively). Furthermore, muscle stem cell number was reduced in the patients with diaphragm atrophy (PAX7 positive nuclei per myofiber of 0.10 [0.09-0.11] vs. 0.05 [0.04-0.07], p = 0.002 in control patients and ICU patients with atrophy, respectively). No correlation was found between myonuclear loss and duration or mode of mechanical ventilation.
    CONCLUSIONS: We identified myonuclear loss due to intrinsic apoptotic pathway activation as a potential mechanism underlying diaphragm atrophy in mechanically ventilated patients. The loss of myonuclei may contribute to impaired regeneration of myofibers after critical illness. Duration and mode of mechanical ventilation are not the major drivers of these modifications.
    Keywords:  critical care; diaphragm weakness; mechanical ventilation
    DOI:  https://doi.org/10.1002/jcsm.70228
  42. Sci Rep. 2026 Feb 17.
    MyoFuse is a fully AI-based workflow for automated quantification of skeletal muscle cell fusion in vitro.
    Benjamin Lair, Clément Cazorla, Alicia Lobeto, Axel Labour, Lorenzo Couloutchy, Claire Laurens, Arild C Rustan, Thomas Chaillou, Pierre Weiss, Remy Flores-Flores, Cedric Moro.
      
    Keywords:  Artificial intelligence; Fusion index; Myogenesis; Neural network; Skeletal muscle
    DOI:  https://doi.org/10.1038/s41598-026-40047-y
This page is being maintained by Thomas Krichel. It was last updated on 2026‒02‒22 at 4:31.