bims-moremu Biomed News
on Molecular regulators of muscle mass
Issue of 2026–05–31
thirty-six papers selected by
Anna Vainshtein, Craft Science Inc.
  1. Unfolding Resilience: Molecular Integration of the Integrated Stress Response and Mitochondrial UPR in Skeletal Muscle Homeostasis.
  2. Multicellular senescence impairs skeletal muscle recovery following disuse in aging.
  3. Myonuclear Dynamics After Skeletal Muscle Surgical Injury.
  4. Co-expression network analysis reveals repression of Igf2bp2 by REV-ERBβ in skeletal muscle.
  5. Targeting the Skeletal Muscle Microenvironment: A Novel Therapeutic Strategy for Skeletal Muscle Aging.
  6. Beyond the first bout: Adaptations to repeated injuries across physiological and pathological conditions.
  7. RYR1+ skeletal muscle-derived extracellular vesicles are exercise responsive and associated with insulin action.
  8. Skeletal muscle proteomics links mitochondrial abundance with peak fat oxidation in physically active young males.
  9. Sema4A Protects Against Muscle Atrophy and Promotes Repair by Regulating Intracellular Metabolic Signalling.
  10. Changes in palmitate- and stearate-containing glycerophospholipids in skeletal muscle during clenbuterol-induced fast-twitch fiber transition and hypertrophy.
  11. B cells just got a workout.
  12. Mechanical Signaling Regulates DNA Methylation to Maintain Muscle Stem Cell Quiescence.
  13. Tamoxifen promotes myogenic differentiation and skeletal muscle regeneration via activation of the GRP94.
  14. Regulatory mechanisms of mitochondrial function by cancer-derived exosomes in cachexia.
  15. Nanotechnology-mediated strategies for skeletal muscle repair and regeneration: targeted intervention, functional remodeling, and translational challenges.
  16. Skeletal muscle-specific myostatin overexpression promotes muscle oxidative capacity and fatigue resistance in transgenic mice.
  17. A novel TAp63γ-Airn regulatory axis governs early myogenic gene networks.
  18. Defective plasticity in dermatomyositis patients muscle stem cells is associated with sustained intrinsic inflammatory signaling and disruption of the histone H3.3 chromatin loading pathway.
  19. Small Extracellular Vesicle Release Following Electrical Pulse Stimulation of C2C12 Myotubes: Effects on microRNA Cargo and Myoblast Migration and Differentiation.
  20. Inhibition of TWEAK/Fn14 Ameliorates Sarcopenic Obesity by Restoring Mitochondrial Biogenesis via the AMPK/SIRT1/PGC-1α Axis.
  21. Molecular Mechanisms and Research Progress of Long Non-Coding RNAs in Regulating Mammalian Skeletal Muscle Development.
  22. Dose-Dependent Effects of Dihydronicotinamide Riboside on Human Engineered Skeletal Muscle Development.
  23. In Vivo Assessment of dbDNA GNEwt/bi-shRNA-GNEM743T Lipoplex for GNE Myopathy: Improved Potency and Safety.
  24. Skeletal Muscle miRNA Patterns in High-Altitude Trekkers: Exploratory Identification of Molecular Signatures of Cellular and Endocrine Adaptation.
  25. Mesenchymal Stromal Cell-Mediated Intercellular Communication: Mapping the Interactome for Skeletal Muscle Homeostasis and Regeneration.
  26. Exploring the role of parathyroid hormone in sarcopenia: A review.
  27. Progressive Myopenia and Functional Decline in the Winnie Mouse Model of Chronic Colitis.
  28. The Gut-Muscle Axis in Sarcopenia: Mechanisms, Evidence Gaps and Translational Challenges.
  29. Regulation of Small RNAs by Exercise and Their Role in Insulin Sensitivity.
  30. Lactylation and lactate: insights into muscle cell epigenetic regulators in exercise.
  31. Short-Term Combined Tat-Beclin1 and Endurance Training Improves Age-Related Decline in Physical Function in Male Mice.
  32. Impact of microRNAs and long noncoding RNAs in skeletal and cardiac muscles.
  33. From homeostasis to pathology, organelle-specific autophagy in skeletal muscle: a PRISMA-ScR scoping review.
  34. Extracellular vesicle transcriptomic analysis to investigate muscle adaptation in microgravity.
  35. Isolation and Biophysical Characterization of Extracellular Vesicles Released by Myocytes.
  36. Novel biomarkers for sarcopenia: a narrative review.
  1. Muscles. 2026 May 22. pii: 39. [Epub ahead of print]5(2):
    Unfolding Resilience: Molecular Integration of the Integrated Stress Response and Mitochondrial UPR in Skeletal Muscle Homeostasis.
    Victoria C Sanfrancesco, Daniella Della Mea, David A Hood.
      To maintain homeostatic conditions and optimal function during stressors, mitochondria initiate retrograde signaling. The mitochondrial integrated stress response (ISR) and unfolded protein response (UPRmt) are critical quality control mechanisms activated during instances of mitochondrial perturbations. Restoration of mitochondrial homeostasis is orchestrated by three transcription factors, ATF4, CHOP, and ATF5, which upregulate protective genes to counteract stress. As the health and function of skeletal muscle are heavily dependent on a highly adaptive mitochondrial network, defining how mitochondrial health is maintained across various conditions is essential. Although several studies demonstrate the importance of these responses following instances of stress, the signaling mechanisms required to initiate such pathways remain poorly characterized in skeletal muscle. This review examines how the mitochondrial ISR/UPRmt and related transcription factors respond to organellar stress by emphasizing the molecular events that occur during exercise, aging and muscle disuse. By consolidating the literature, this work aims to highlight the current understanding of mitochondrial stress response signaling within skeletal muscle and thus emphasize areas for future research and potential therapeutic strategies during divergent metabolic conditions.
    Keywords:  ATF4; ATF5; CHOP; adaptation; aging; exercise; integrated stress response; mitochondria; muscle inactivity; skeletal muscle; stress response; unfolded protein response
    DOI:  https://doi.org/10.3390/muscles5020039
  2. Sci Adv. 2026 May 29. 12(22): eaed5255
    Multicellular senescence impairs skeletal muscle recovery following disuse in aging.
    Paul-Emile Bourrant, Elena M Yee, Zachary J Fennel, Robert J Castro, Chad M Skiles, Jonathan J Petrocelli, Naomi M M P de Hart, Lisa A Lesniewski, Anna E Beaudin, Katsuhiko Funai, Christopher S Fry, Micah J Drummond.
      Aged skeletal muscle has a diminished capacity to recover after disuse. Although muscle regrowth requires coordinated interactions between immune and progenitor cells, the mechanisms of impaired remodeling in aged skeletal muscle remain poorly understood yet possibly involve the accumulation of senescent cells. We used a flow cytometry approach coupled with scRNAseq to determine the muscle senescent cell identity and transcriptional landscape during skeletal muscle recovery following disuse atrophy. Young and aged mice underwent 14 days of hindlimb unloading followed by reloading (7 or 14 days). At recovery, old mice showed smaller myofibers and abnormal muscle macrophage dynamics corresponding to greater collagen content. These outcomes coincided with elevated markers of muscle senescence (p21 and γH2AX) and increased SPiDER-β-Gal+ cells, which inversely correlated with muscle mass. Single-cell resolution of SPiDER+ cells unmasked several senescent interstitial muscle vascular and stromal populations. Senescent interstitial cell populations were enriched in aged muscle and displayed a senescence-associated secretory phenotype (SASP) across multiple stromal, vascular, and immune cell types. Senolytic treatment reduced overall senescent cell burden, attenuated macrophage accumulation, and restored muscle mass and function in aged mice following disuse. These findings identify a multicellular senescence environment within the muscle interstitial niche as a hallmark of impaired muscle recovery following disuse.
    DOI:  https://doi.org/10.1126/sciadv.aed5255
  3. bioRxiv. 2026 May 13. pii: 2026.05.12.724630. [Epub ahead of print]
    Myonuclear Dynamics After Skeletal Muscle Surgical Injury.
    Micah Goeke, Nathan Serrano, Pieter Jan Koopmans, Kevin A Murach.
      A hallmark of damaged skeletal muscle fibers is displaced myonuclei that are no longer peripherally positioned. Displaced myonuclei are dogmatically thought to be derived exclusively from muscle stem cell (satellite cell) fusion. Using a surgical resection muscle injury model and in vivo recombination-independent resident myonuclear labeling, we detail the prevalence, time course, and origin of displaced myonuclei in response to a non-chemically-mediated muscle trauma. We found that: 1) non-satellite cell-derived (resident) displaced myonuclei emerge seven days after surgical injury in similar proportion to exogenous (satellite cell-derived) displaced myonuclei in intact muscle fibers, with a biased prevalence in myosin heavy chain IIB muscle fibers, 2) muscle fibers with multiple (≥2) displaced resident myonuclei was an unexpected but noteworthy feature of muscle fibers 7 days after injury, 3) embryonic myosin-expressing fibers at seven days post-surgery expectedly contain predominantly satellite-cell derived displaced myonuclei, but a subset have displaced resident myonuclei, and 4) satellite cell numbers in intact muscle do not increase until 7 days post-surgery. These data may help inform whether to target satellite cell-initiated processes, myonuclear-initiated processes, or both to facilitate muscle fiber injury repair. This information could lead to more effective therapeutic strategies for treating muscle trauma.
    DOI:  https://doi.org/10.64898/2026.05.12.724630
  4. bioRxiv. 2026 May 15. pii: 2026.05.13.724827. [Epub ahead of print]
    Co-expression network analysis reveals repression of Igf2bp2 by REV-ERBβ in skeletal muscle.
    Vishnu A M, Qing Zhang, Shriyansh Srivastava, Kevin B Koronowski, Ashutosh Srivastava.
      The circadian clock genes Bmal1 and Nr1d1/2 (REV-ERBα/β) regulate skeletal muscle metabolism and homeostasis, yet the precise genes and mechanisms involved remain incompletely understood. Here, we perform Weighted Gene Co-expression Network Analysis (WGCNA) on skeletal muscle circadian transcriptomes with varying Bmal1 operational status to identify genes central to muscle circadian function. The largest WGCNA module, potentially under Bmal1 regulation, contains clock and muscle-specific output genes governed hierarchically by hub genes including Igf2bp2 , an RNA-binding protein involved in muscle progenitor growth and maintenance. Igf2bp2 expression is rhythmic in mouse and human muscle and functional experiments in muscle-specific Bmal1 knockout mice show that Igf2bp2 is upregulated by loss of Bmal1 at ZT8 and negatively correlated with Nr1d2 , suggesting de-repression through REV-ERBβ as a regulatory mechanism. Luciferase reporter experiments in cultured myotubes show that REV-ERBβ, but not REV-ERBα, represses Igf2bp2 transcription and that repression is mediated by non-canonical GCC motifs in the Igf2bp2 promoter region. Together, these findings uncover a circadian Nr1d2-Igf2bp2 regulatory axis linking transcriptional and post-transcriptional regulation in skeletal muscle, with implications for muscle homeostasis.
    Highlights: Igf2bp2 clusters with Nr1d2 ( Rev-erbβ ) in circadian co-expression network Bmal1 or Rev-erbɑ/β knockout upregulates Igf2bp2 in muscle Igf2bp2 is rhythmic in WT muscle but arrhythmic in clock mutant muscle REV-ERBβ represses Igf2bp2 transcription in myotubes REV-ERBβ repression requires GCC motifs in the Igf2bp2 promoter.
    DOI:  https://doi.org/10.64898/2026.05.13.724827
  5. FASEB J. 2026 May 31. 40(10): e71936
    Targeting the Skeletal Muscle Microenvironment: A Novel Therapeutic Strategy for Skeletal Muscle Aging.
    Yujia Yu, Yu He, Yan Wang, Chunhua Wu, Rui Zhou, Feng Chen, Wen Ma.
      Sarcopenia, a hallmark of skeletal muscle aging, is a significant public health concern that substantially compromises the quality of life in the elderly. While conventional research has predominantly focused on intrinsic pathological alterations within muscle fibers, it has often overlooked the diverse cell-cell and interorgan communications mediated by nonmuscle cells in the skeletal muscle microenvironment. This microenvironment, comprising the extracellular matrix, multiple cellular components, secreted factors, and metabolites, plays a crucial role in regulating muscle homeostasis and regeneration, serving as a key driver of skeletal muscle aging. As the microenvironment undergoes profound remodeling with advancing age, this review systematically examines novel intervention strategies targeting it. By aiming to achieve coordinated multipathway remodeling of this niche, these approaches offer a fresh theoretical foundation and novel clinical avenues for delaying or reversing sarcopenia. Future research should prioritize elucidating these microenvironmental regulatory mechanisms, refining personalized intervention protocols, and rigorously validating translational applications.
    Keywords:  cytokines; extracellular matrix; intervention strategies; sarcopenia; skeletal muscle aging; skeletal muscle microenvironment
    DOI:  https://doi.org/10.1096/fj.202601360R
  6. Physiol Rep. 2026 May;14(10): e70929
    Beyond the first bout: Adaptations to repeated injuries across physiological and pathological conditions.
    Cory W Baumann, Christopher P Ingalls, Kazunori Nosaka, Jarrod A Call.
      Skeletal muscle exhibits remarkable plasticity following injury, yet most research has focused on responses to a single bout of eccentric contractions. This review addresses adaptations to repeated eccentric contraction-induced injuries across physiological and pathological conditions, with emphasis on insights from preclinical rodent models. In healthy muscle, the repeated bout effect (RBE) reduces strength loss and accelerates recovery after subsequent bouts. However, these adaptations are highly condition dependent. Aging can attenuate the RBE, while dystrophic muscle remains vulnerable to repeated injury despite compensatory remodeling. Other factors, including but not limited to, chronic alcohol intake and malignant hyperthermia can influence these responses, though their effects vary and do not universally abolish adaptation. Collectively, these findings highlight that the trajectory of muscle adaptation depends on its physiological state and underlying pathology. Understanding these condition-specific mechanisms is essential for developing targeted strategies to optimize recovery, maximize adaptations, and preserve muscle health across diverse populations.
    Keywords:  aging; eccentric contractions; muscular dystrophy; repeated bout effect; skeletal muscle adaptation
    DOI:  https://doi.org/10.14814/phy2.70929
  7. J Transl Med. 2026 May 26. pii: 707. [Epub ahead of print]24(1):
    RYR1+ skeletal muscle-derived extracellular vesicles are exercise responsive and associated with insulin action.
    Xin Zhang, Christopher G Vann, David B Bartlett, Alastair Khodabukus, George A Truskey, Nenad Bursac, Joseph A Houmard, Johanna L Johnson, Kim M Huffman, Brian J Andonian, William E Kraus, Virginia Byers Kraus.
       BACKGROUND: Skeletal muscle is a central regulator of insulin sensitivity and glucose homeostasis. The ryanodine receptor 1 (RYR1) is highly expressed in skeletal muscle and plays a key role in myogenic differentiation. We hypothesize that RYR1+ extracellular vesicles (EVs) represent a skeletal muscle-derived EV subpopulation whose abundance and small RNA (smRNA) cargo are associated with aging, insulin action, and exercise responsiveness.
    METHODS: We tested this hypothesis through in vitro analyses of smRNAs of skeletal muscle-derived EVs and in vivo evaluation of their exercise responsiveness and association with insulin action in older adults. Using an integrated workflow combining centrifugation, polymer-based precipitation, and single-EV sorting, we isolated RYR1+ and RYR- EVs secreted from myobundles-3D contractile skeletal muscle tissues engineered from primary muscle progenitor cells obtained from healthy donors (n = 6). We also isolated plasma EVs from 48 human participants and performed targeted high-resolution flow cytometry to evaluate EV biomarkers associated with aging, insulin action, and exercise responsiveness in older adults.
    RESULTS: By smRNA sequencing, compared to myobundle RYR- EVs, RYR1+ EVs contained three unique microRNAs (miRNAs) and an additional 21 miRNAs with significantly greater abundance (including canonical myoMiRs miR-206, miR-1-3p, and miR-208a-3p). Of the 24 RYR1+ EV-enriched miRNAs, experimentally-supported mRNA targets (n = 422) are involved in pathways governing cell proliferation, apoptosis, senescence, insulin and glucose signaling. In two independent cohorts, including older adults with prediabetes or unknown prediabetes status, frequencies of RYR1+ EV subsets were significantly upregulated by chronic exercise with greater RYR1+ EV frequencies associated with better insulin action.
    CONCLUSIONS: These complementary in vitro and in vivo data identify skeletal muscle-derived RYR1+ EVs as upregulated by exercise and as carriers of miRNAs linked to insulin action in older adults, including those with prediabetes. These results highlight skeletal muscle-derived EVs as novel biomarkers and potential mediators of systemic metabolic regulation and healthy aging.
    Keywords:  Exercise; Extracellular vesicles; HOMA-IR; Insulin; MiRNA; Single vesicle sorting; Skeletal muscle; piRNA
    DOI:  https://doi.org/10.1186/s12967-026-08215-w
  8. J Physiol. 2026 May 28.
    Skeletal muscle proteomics links mitochondrial abundance with peak fat oxidation in physically active young males.
    Eloise K Tarry, Shaun Mason, Ghazanfar Abbas Khan, Sofie G Vestergaard, Emilie A Petersen, Mike C Olsen, Maria Hansen, Arthur Ingersen, Kirsten F Howlett, Steen Larsen, Christopher S Shaw, Jørn W Helge.
      The interindividual variability in peak fat oxidation (PFO) and the intensity at which this occurs (Fatmax) has been attributed to physiological factors, diet and physical activity; however, few studies have examined the contribution of skeletal muscle characteristics. The present study examined the relationship between PFO, Fatmax and the skeletal muscle proteome in young, physically active males. Thirty-four young, lean males were phenotyped through assessment of aerobic capacity, PFO, body composition, fasting blood samples and a muscle biopsy. Liquid chromatography mass spectrometry based proteomics was used to assess skeletal muscle protein abundance. Only absolute PFO (g min-1) was positively correlated with V̇O2peak${{\dot{V}}_{{{{\mathrm{O}}}_2}{\mathrm{peak}}}}$ (r = 0.496, P = 0.003). Few skeletal muscle proteins correlated with absolute PFO, whereas relative PFO and Fatmax were positively associated with numerous mitochondrial proteins enriched in metabolic pathways, oxidative phosphorylation and other mitochondrial processes. Mitochondrial proteome abundance was positively correlated with both relative PFO (r = 0.633, P < 0.001) and Fatmax (r = 0.595, P < 0.001). Mitochondrial complex-specific analysis demonstrated that respiratory complex V was associated with both relative PFO and Fatmax. Multiple regression analyses indicated that mitochondrial abundance and muscle glycogen explained 55% of the variability in relative PFO, whereas mitochondrial abundance alone explained 43% of the variability in Fatmax. Absolute PFO was explained by a combination of V̇O2peak${{\dot{V}}_{{{{\mathrm{O}}}_2}{\mathrm{peak}}}}$ , mitochondrial abundance and muscle glycogen content (r2 = 0.562). This untargeted proteomic approach highlights that skeletal muscle mitochondrial content contributes to the interindividual variability in PFO and Fatmax in lean, active young males. KEY POINTS: This study used an untargeted proteomics approach to explore the links between the skeletal muscle proteome and peak fat oxidation (PFO) in young, physically active males. Absolute PFO was primarily associated with maximal aerobic capacity. When expressed relative to fat-free mass, PFO was closely associated with skeletal muscle proteins enriched in oxidative metabolism and mitochondrial pathways. Mitochondrial abundance assessed by mitochondrial proteome content and citrate synthase activity was positively related to relative PFO and the intensity at which this occurs (Fatmax). Mitochondrial respiratory complex V was consistently related to both relative PFO and Fatmax. Mitochondrial content independently contributed to both PFO and Fatmax, highlighting mitochondrial content as a key determinant of the maximal capacity for fat oxidation.
    Keywords:  exercise; fat oxidation; metabolism; muscle; proteomics
    DOI:  https://doi.org/10.1113/JP290966
  9. J Cachexia Sarcopenia Muscle. 2026 Jun;17(3): e70315
    Sema4A Protects Against Muscle Atrophy and Promotes Repair by Regulating Intracellular Metabolic Signalling.
    Caiyun Wang, Honghong Chen, Lingjie Shen, Shenhan Xu, Jie Xu, Qiuyuan Huang, Weiheng Zhang, Chengshou Lin, Jun Chang, Xinhua Liu, Wugui Chen.
       BACKGROUND: Skeletal muscle atrophy is a debilitating condition associated with diverse diseases and clinical interventions. Although triggers such as glucocorticoid excess or direct muscle injury disrupt the balance between protein homeostasis and tissue repair, the upstream molecular signals that actively preserve muscle integrity remain largely unknown. Semaphorin 4A (Sema4A) is a Class IV transmembrane semaphorin traditionally recognized for its roles in neural development and immune regulation; however, its function in skeletal muscle maintenance has not been explored.
    METHODS: We first examined Sema4A expression in established models of muscle catabolism. Subsequently, adeno-associated virus (AAV)-mediated Sema4A restoration was employed to evaluate its therapeutic potential in both dexamethasone-induced atrophy and acute injury mouse models. Mechanistic studies were performed in C2C12 myotubes using gain- and loss-of-function approaches.
    RESULTS: Sema4A expression was significantly downregulated under atrophic conditions (p < 0.05). Restoration of Sema4A effectively attenuated dexamethasone-induced muscle loss (4.766 vs. 5.075 mg/g B.W., p = 0.0414) and accelerated functional recovery (6.219 × 10-2 vs. 7.124 × 10-2 N/g B.W., p = 0.0422). We identified Plexin B2 (Plxnb2) as the functional receptor mediating these effects. At the molecular level, Sema4A signalling suppressed FoxO3a nuclear translocation (FoxO3a positive cells: vector-Dex 27.99% vs. OE-Sema4A-Dex 12.49%, p < 0.05), thereby inhibiting the expression of key atrogenes, while simultaneously reactivating the PI3K-AKT-mTOR anabolic pathway. This reprogramming of intracellular metabolic signalling was further associated with the establishment of a reparative immune microenvironment, a process potentially modulated by muscle-derived factors such as Gdf15.
    CONCLUSIONS: Our study identifies Sema4A as a novel protective regulator that mitigates muscle atrophy and enhances regeneration through a dual mechanism: restoring intracellular anabolic signalling and fostering a proregenerative immune niche. These findings highlight Sema4A as a promising therapeutic target for the treatment of muscle-wasting disorders.
    Keywords:  FoxO3a; Plexin B2; Semaphorin 4A; muscle atrophy; muscle repair
    DOI:  https://doi.org/10.1002/jcsm.70315
  10. J Physiol Sci. 2026 May 21. pii: S1880-6546(26)00027-2. [Epub ahead of print]76(2): 100081
    Changes in palmitate- and stearate-containing glycerophospholipids in skeletal muscle during clenbuterol-induced fast-twitch fiber transition and hypertrophy.
    Yuna Suzuki, Tomoki Sato, Satoshi Ohuchi, Sango Nakashima, Noriyuki Miyoshi, Shinji Miura.
      Fast- and slow-twitch skeletal muscle fibers exhibit distinct glycerophospholipid compositions, and slow-twitch transition is accompanied by characteristic changes in glycerophospholipid molecular species. However, whether glycerophospholipid composition is remodeled during fast-twitch fiber transition and skeletal muscle hypertrophy remains unclear. In this study, we examined changes in palmitate- and stearate-containing glycerophospholipids using a mouse model of clenbuterol-induced fast-twitch transition and hypertrophy. Clenbuterol administration increased the proportion of fast-twitch fibers and induced skeletal muscle hypertrophy. Lipidomic analysis revealed a significant increase in palmitate-containing phosphatidylcholine and a decrease in stearate-containing phosphatidylcholine in the tibialis anterior and soleus muscles. Consistent with these glycerophospholipid alterations, the expression of several acyltransferases, such as glycerol-3-phosphate acyltransferase 3 (GPAT3), involved in glycerophospholipid acyl-chain determination was significantly altered. These findings demonstrate that glycerophospholipid composition is remodeled during fast-twitch fiber transition and muscle hypertrophy, highlighting lipid remodeling as a component of skeletal muscle phenotypic adaptation.
    Keywords:  Clenbuterol; Fast-twitch fiber transition; Glycerophospholipid; Muscle; Muscle hypertrophy; Phosphatidylcholine
    DOI:  https://doi.org/10.1016/j.jphyss.2026.100081
  11. Cell. 2026 May 28. pii: S0092-8674(26)00513-1. [Epub ahead of print]189(11): 3181-3183
    B cells just got a workout.
    Maria E Moreno-Fernandez, Senad Divanovic.
      In this issue of Cell, Mao et al. reveal that B cells play an unexpected, immune-independent role in exercise physiology by facilitating multi-organ communication. Secreting TGF-β1, they transcriptionally reprogram hepatic glutamine metabolism via GLS2 and SLC7A5, preserving skeletal muscle glutamate levels, which sustain mitochondrial function, Ca2⁺ signaling, and ATP production, enhancing exercise capacity.
    DOI:  https://doi.org/10.1016/j.cell.2026.04.046
  12. bioRxiv. 2026 May 17. pii: 2026.05.15.725521. [Epub ahead of print]
    Mechanical Signaling Regulates DNA Methylation to Maintain Muscle Stem Cell Quiescence.
    Pukana Jayaraman, Paige R Deltener, Justice Paintsil, Christian O Abosede, Atreyi Ghatak, Sarah Abrahamson, Chris W D Jurgens, Damien Parrello, Susan Eliazer.
      Skeletal muscle stem cells (MuSCs) reside within a mechanically dynamic niche where they integrate biophysical and biochemical cues to maintain quiescence. Here, we show that substrate stiffness and RhoA-dependent signaling regulate MuSC fate. MuSCs cultured on soft matrices or depleted of RhoA exhibit altered morphology, diminished actomyosin organization, and undergo premature activation. Loss of RhoA reshapes the DNA methylation landscape, leading to widespread changes in gene expression and alternative splicing. Dnmt3a was among the genes transcriptionally downregulated following loss of RhoA signaling. Mechanistically, RhoA maintains Dnmt3a expression by promoting SP1 occupancy at its promoter. Importantly, loss of Dnmt3a in quiescent MuSCs is sufficient to drive activation, identifying Dnmt3a as a key epigenetic effector downstream of mechanical signaling. Together, these findings define a mechanotransduction-epigenetic axis in which RhoA maintains stem cell quiescence by preserving DNA methylation programs through Dnmt3A.
    DOI:  https://doi.org/10.64898/2026.05.15.725521
  13. Biochem Biophys Res Commun. 2026 May 23. pii: S0006-291X(26)00786-2. [Epub ahead of print]827 154022
    Tamoxifen promotes myogenic differentiation and skeletal muscle regeneration via activation of the GRP94.
    Lei Xing, Kun Zhang, Yi Han, Huaixin Teng, Yuxi Wang, Shuang Li.
      Efficient skeletal muscle repair remains a significant clinical challenge due to the lack of safe pharmacological interventions. Our work identifies Tamoxifen as a potent driver of muscle regeneration, operating through the GRP94. In C2C12 myoblasts, Tamoxifen treatment directly triggered myogenic differentiation and accelerated myotube formation in a dose-dependent manner, alongside the marked upregulation of MyoD, Myogenin (MyoG), and MYHC. These pro-myogenic effects were effectively abolished upon GRP94 inhibition, confirming its role as an essential mediator. In vivo, using a bupivacaine-induced injury model, we observed that 10 mg/kg Tamoxifen significantly expedited tissue repair and increased the cross-sectional area (CSA) of regenerating myofibers. Collectively, our findings demonstrate for the first time that Tamoxifen orchestrates muscle repair by modulating GRP94, offering a promising strategy for treating acute injury and chronic muscle wasting.
    Keywords:  GRP94; Myogenic differentiation; Regeneration; Skeletal muscle injury; Tamoxifen
    DOI:  https://doi.org/10.1016/j.bbrc.2026.154022
  14. Front Oncol. 2026 ;16 1715589
    Regulatory mechanisms of mitochondrial function by cancer-derived exosomes in cachexia.
    Ryotaro Tomida, Keisuke Ozaki, Yukako Tanaka, Rina Komatsu, Syuya Hirata, Takayuki Uchida, Junya Furukawa, Takeshi Nikawa, Tomoya Fukawa.
       Background: Cancer cachexia is a multifactorial syndrome characterized by progressive skeletal muscle wasting and impaired response to conventional nutritional support, affecting up to 80% of advanced cancer patients and contributing to poor prognosis. Excessive fatty acid oxidation and mitochondrial reactive oxygen species (ROS) generation have been implicated in cachexia-associated muscle atrophy, but the underlying mechanisms remain unclear.
    Methods and results: We investigated the role of cancer cell-derived exosomes in metabolic alterations of skeletal muscle cells. Exosomes from a pro-cachectic renal carcinoma cell line (RXF393) induced myotube atrophy, enhanced mitochondrial ROS production, impaired mitochondrial respiration, and reduced expression of isocitrate dehydrogenase 2 (IDH2) and respiratory chain complex subunits compared to observations in non-cachectic controls. miRNA profiling identified enrichment of miR-1260b in pro-cachectic exosomes, and transfection with a miR-1260b mimic reproduced these phenotypes, including IDH2 downregulation, impaired antioxidant defense, and mitochondrial dysfunction.
    Conclusion: These findings demonstrate that cancer-derived exosomal miR-1260b suppresses IDH2, disrupts mitochondrial redox balance, and promotes muscle wasting. This study reveals a mechanistic link between exosomal miRNAs and mitochondrial dysfunction in cancer cachexia and suggests that maintaining mitochondrial redox homeostasis may represent a novel therapeutic strategy.
    Keywords:  cancer cachexia; exosome; isocitrate dehydrogenase 2; miR-1260b; mitochondrial dysfunction; reactive oxygen species; renal cell carcinoma
    DOI:  https://doi.org/10.3389/fonc.2026.1715589
  15. J Nanobiotechnology. 2026 May 27.
    Nanotechnology-mediated strategies for skeletal muscle repair and regeneration: targeted intervention, functional remodeling, and translational challenges.
    Chengyan Guo, Xianji Wei, Wenjing Li, Guanyi Wang, Binghong Gao, Lingli Zhang, Bo Gao.
      Skeletal muscle is an important locomotor and metabolic organ in the human body and plays a central role in maintaining physical activity, energy homeostasis, and structural support. Although skeletal muscle possesses a certain regenerative potential, under pathological conditions such as aging, severe trauma, pathogen infection, myogenic malignancies, and other metabolic diseases, its repair process is often accompanied by impaired myogenic differentiation, inflammatory and oxidative stress imbalance, insufficient vascularization, and limited innervation, ultimately leading to structural muscle damage and functional impairment. These changes not only severely affect patients' quality of life but also impose a substantial economic burden on healthcare systems, making them an urgent public health issue. Existing therapeutic strategies, including pharmacological treatment, physical interventions, and surgical procedures, can alleviate symptoms to some extent. However, they generally remain limited by insufficient targeting, restricted local bioavailability, and unstable long-term efficacy. In recent years, nanotechnology has shown considerable application potential in skeletal muscle regeneration and related disease intervention, owing to its tunable physicochemical properties, delivery advantages, and tissue-biomimetic capabilities. Based on the specific pathological characteristics of skeletal muscle diseases, this Review systematically summarizes recent advances in nanotechnology, including drug delivery, scaffold construction, nanozyme design, and biomimetic tissue engineering. Particular emphasis is placed on their potential roles in promoting myogenic differentiation, alleviating inflammation and oxidative stress, combating infection and myogenic malignancies, supporting vascularization, and facilitating the recovery of neural structure and function. In addition, this Review further analyzes the clinical challenges and future directions of nanotechnology in the field of skeletal muscle diseases, aiming to provide a reference for related research and the optimization of therapeutic strategies for skeletal muscle disorders.
    Keywords:  Biomimetic scaffolds; Nanotechnology; Nanozymes; Regeneration; Repair; Skeletal muscle; Targeted drug delivery
    DOI:  https://doi.org/10.1186/s12951-026-04610-z
  16. Exp Physiol. 2026 May 28.
    Skeletal muscle-specific myostatin overexpression promotes muscle oxidative capacity and fatigue resistance in transgenic mice.
    Andy V Khamoui, Andrea Abraham, Janos Porszasz, Istvan Kovanecz, Silvana Constantinescu, Harry B Rossiter, Suzanne Reisz-Porszasz.
      In addition to controlling muscle mass, myostatin may support oxidative metabolism and endurance. Loss of function through gene knockout or post-natal blockade generally lowers muscle oxidative capacity and increases fatigability. These observations imply that myostatin activation could promote a more oxidative and less fatigable muscle phenotype. Gain-of-function approaches that activate myostatin in vivo, however, are largely absent. To test whether myostatin promotes oxidative metabolism in muscle, we constructed transgenic (TG) mice with myostatin (Mstn) gene overexpression restricted to skeletal muscle by inserting an Mstn cDNA construct under the MCK promoter to drive muscle-specific expression of recombinant myostatin protein. On standard diet, TG had greater oxidative fibre expression, greater coupled maximal mitochondrial oxidative phosphorylation (OXPHOS), and increased in situ muscle fatigue resistance. Untargeted metabolomics identified greater stored carbohydrate and glycolytic intermediates in TG muscle, lower lactate/pyruvate and lower AMP that together indicate TG muscle to be energetically primed for carbohydrate-fuelled OXPHOS. Further, TG had enhanced synthesis of spermidine, a polyamine and autophagy inducer implicated in mitochondrial quality control and geroprotection, and large changes in polyunsaturated fatty acid composition with reduced long-chain saturated fat. When challenged by lipid overload, TG displayed some features of intolerance related to glucose clearance and contractility, but also compelling signs of resilience including maintenance of mitochondrial respiratory control and running critical power. Together, these data show that myostatin is not only a regulator of skeletal muscle mass but a central mediator of diverse metabolic pathways that reinforce muscle homeostasis and organismal resilience including carbohydrate metabolism, bioactive lipids, polyamine compounds and mitochondrial respiration.
    Keywords:  metabolism; mitochondria; mouse; muscle fatigue; muscle physiology; oxidative phosphorylation
    DOI:  https://doi.org/10.1113/EP093775
  17. Biol Direct. 2026 May 28. pii: 80. [Epub ahead of print]21(1):
    A novel TAp63γ-Airn regulatory axis governs early myogenic gene networks.
    Veronica Ciuffoli, Maria Cristina Piro, Alessia Angelin, Giulio Colasanto, Huiqing Zhou, Jieqiong Qu, Anna Maria Lena, Gerry Melino, Eleonora Candi.
      Skeletal muscle development relies on tightly coordinated transcriptional programs, yet the contribution of long non-coding RNAs (lncRNAs) to myogenesis remains largely unexplored. We previously demonstrated that the transcription factor TAp63γ is upregulated during myoblast differentiation and regulates the expression of genes involved in early stages of myogenic maturation. Here, combining transcriptome profiling with p63 ChIP-seq analysis in differentiating mouse myoblasts, we identify the lncRNA Airn as a direct transcriptional target of TAp63γ. Our findings position Airn as a previously unrecognized regulator of myogenic commitment that modulates both MyoD and MyoG expression at the mRNA and protein levels. Our work uncovers a novel TAp63γ-Airn axis essential for proper skeletal muscle differentiation and with potential relevance to muscle-wasting diseases.
    Keywords:   Airn ; Muscle; MyoD; MyoG; TP63; lncRNA
    DOI:  https://doi.org/10.1186/s13062-026-00801-8
  18. NAR Mol Med. 2026 Apr;3(2): ugag022
    Defective plasticity in dermatomyositis patients muscle stem cells is associated with sustained intrinsic inflammatory signaling and disruption of the histone H3.3 chromatin loading pathway.
    Wilhelm Bouchereau, Linda Chenane, Michèle Weiss-Gayet, Lola Lessard, Yseult Cardona, Rémi Mounier, Laure Gallay, Yves Allenbach, Olivier Benveniste, Armelle Corpet, Bénédicte Chazaud, Patrick Lomonte.
      Skeletal muscle regeneration is driven by muscle stem cells (MuSCs), which proliferate, differentiate, and fuse to reform myofibers and restore muscle function. This myogenesis process is driven both by intrinsic MuSC properties and extrinsic cues. While coordinated inflammatory signals are necessary for healthy regeneration, chronic inflammation participates in various pathologies affecting the skeletal muscle. In the idiopathic inflammatory myopathy dermatomyositis (DM), MuSCs exhibit impaired myogenesis in vitro, indicating that they may have acquired intrinsic defects, contributing to the disease and providing a mechanism for sustained patient muscle weakness despite efficient anti-inflammatory treatments. Here, we investigated the transcriptomic regulation of DM-derived MuSCs, with a focus on the H3.3 histone variant that regulates myogenesis progression. DM-derived MuSCs were unable to effectively execute the myogenic transcriptional program during in vitro differentiation. They exhibited an activated canonical tumor necrosis factor (TNF)-⍺ signaling. They also showed reduced expression of H3.3 and its chaperone genes, coupled with a decrease in H3.3 deposition across the entire genome, and particularly at myogenic regulatory factor loci. The loss of H3.3 combined with elevated TNF-⍺ signaling was associated with a failure of DM-derived MuSCs to achieve myogenesis, suggesting a mechanistic link between epigenetic dysregulation and defective muscle regeneration in humans.
    DOI:  https://doi.org/10.1093/narmme/ugag022
  19. Int J Mol Sci. 2026 May 12. pii: 4320. [Epub ahead of print]27(10):
    Small Extracellular Vesicle Release Following Electrical Pulse Stimulation of C2C12 Myotubes: Effects on microRNA Cargo and Myoblast Migration and Differentiation.
    John S Hingle, Rhys S McColl, Ivan J Vechetti, Kathryn H Myburgh.
      The skeletal muscle (SkM) secretome has been widely studied since the establishment of its endocrine function. Extracellular vesicles (EVs) are the most recently identified elements of the SkM secretome. These nano-sized lipid-bound vesicles carry molecular cargo and function as a means of intercellular communication. The effect of exercise on SkM EV micro-RNA cargo (miRNAs) remains a challenge to elucidate. Electrical pulse stimulation (EPS) was applied to C2C12 myotubes at high (30 Hz) and low (2 Hz) frequencies. EVs released during 10 h of stimulation were isolated and characterized and used to treat myoblasts. Their miRNA cargo was sequenced. EVs were used to treat myoblasts (2.19 × 108 EVs per mL) to determine the effects on myoblast migration and differentiation. Sequencing revealed over 300 known miRNAs packaged into myotube EVs. Many were differentially expressed after EPS, either positively or negatively. Muscle-important miRNAs were present (miR-206 was 4.8-fold more prevalent than any other miRNA). EV treatments improved myoblast migration and differentiation without a frequency-specific influence. Gene Ontology analysis based on differentially expressed miRNAs between control and EPS-EVs indicates an effect of EPS frequency on muscle EV signaling.
    Keywords:  C2C12 myotubes; electrical pulse stimulation; extracellular vesicles; micro-RNA cargo
    DOI:  https://doi.org/10.3390/ijms27104320
  20. Diabetes Metab Syndr Obes. 2026 ;19 596507
    Inhibition of TWEAK/Fn14 Ameliorates Sarcopenic Obesity by Restoring Mitochondrial Biogenesis via the AMPK/SIRT1/PGC-1α Axis.
    Saiyare Xuekelati, Zhuoya Maimaitiwusiman, Yanying Guo, Shuke Guo, Qihong Xu, Jiayu Ke, Lei Xu, Yining Yang, Hongmei Wang.
       Purpose: Sarcopenic obesity (SO) represents a critical geriatric syndrome where muscle atrophy and obesity synergistically exacerbate metabolic dysfunction. While the TWEAK/Fn14 pathway is a known regulator of muscle wasting, its specific role and therapeutic potential in the pathogenesis of SO remain unclear.
    Methods: To mimic the lipid-rich microenvironment of SO, we utilized a "PrePA-Diff" in vitro model where C2C12 myoblasts were exposed to palmitic acid prior to differentiation. In vivo, SO was established by feeding aged (18-month-old) male C57BL/6 mice a high-fat diet (HFD) for 12 weeks. Subsequently, intramuscular injection of Adeno-associated virus (AAV)-shRNA was employed to specifically inhibit TWEAK expression in skeletal muscle. Mitochondrial function, inflammatory profiles, and signaling pathways were assessed using qPCR, Western blotting, ELISA, and functional assays.
    Results: Our results demonstrate that TWEAK inhibition effectively reverses the SO phenotype, characterized by improved grip strength, reduced adiposity, and lowered systemic inflammation and lipid levels. At the cellular level, TWEAK silencing rescued mitochondrial bioenergetics, indicated by enhanced ATP production and suppressed reactive oxygen species (ROS) generation and calcium influx. Molecularly, these protective effects were accompanied by the downregulation of p38 MAPK phosphorylation and the reactivation of the AMPK/SIRT1/PGC-1α signaling axis, a key driver of mitochondrial biogenesis.
    Conclusion: Our study identifies the TWEAK/Fn14 axis as a pivotal driver of SO pathology. We conclude that inhibiting TWEAK ameliorates sarcopenic obesity by restoring mitochondrial homeostasis via AMPK/SIRT1/PGC-1α signaling, highlighting TWEAK/Fn14 as a novel therapeutic target for age-related musculoskeletal and metabolic decline.
    Keywords:  TWEAK; aging; mitochondrial function; sarcopenic obesity; skeletal muscle
    DOI:  https://doi.org/10.2147/DMSO.S596507
  21. Genes (Basel). 2026 May 21. pii: 592. [Epub ahead of print]17(5):
    Molecular Mechanisms and Research Progress of Long Non-Coding RNAs in Regulating Mammalian Skeletal Muscle Development.
    Xiaojiao Cui, Yongming Zhang, Ren Mu, Huimin Wei, Min Li, Xingdong Wang.
      Long non-coding RNAs (lncRNAs) have emerged as pivotal regulators in mammalian skeletal muscle development, moving beyond their initial characterization as transcriptional "noise". Unlike previous reviews that focus primarily on individual IncRNA catalogues, this review systematically integrates recent advances across five dimensions: (1) molecular characteristics and multidimensional classification of muscle related lncRNAs; (2) stage-specific expression patterns spanning embryonic myogenesis, postnatal growth, adult maintenance, and regeneration; (3) underlying molecular mechanisms including chromatin remodeling, ceRNA networks, IncRNA protein interactions, and nucleocytoplasmic trafficking; (4) pathological implications in muscular dystrophy, atrophy, and neuromuscular diseases; (5) translational applications in precision animal breeding. We critically evaluate the controversial ceRNA hypothesis and highlight quantitative limitations in current evidence. By integrating existing knowledge into a multi-layer regulatory network model and addressing current technical challenges and controversies (e.g., the ceRNA stoichiometry debate), this review provides a comprehensive roadmap for future basic research and translational applications in muscle biology.
    Keywords:  CeRNA network controversy; gene regulation; long non-coding RNA; muscle regeneration; myogenesis; skeletal muscle development
    DOI:  https://doi.org/10.3390/genes17050592
  22. ACS Biomater Sci Eng. 2026 May 28.
    Dose-Dependent Effects of Dihydronicotinamide Riboside on Human Engineered Skeletal Muscle Development.
    Ashwin Venkateshvaran, Swarang Sachin Pundlik, Yavanica Suresh, Akshay Hegde, Bhushan Venkatesh, Sikhasmita Dowari, Diksha Gogia, Srujanika Rajalakshmi, Pushpita Saha, Alok Barik, Heera Lal, Nikhil Zachariah, Gautham Pranesh, G Mani Subramanian, Arvind Ramanathan.
      Nicotinamide adenine dinucleotide (NAD+) precursors are explored for metabolic and longevity interventions; however, their impact on human skeletal muscle development remains unclear due to limitations of conventional 2D cultures and animal models. Here, we employed three-dimensional engineered skeletal muscle tissues derived from primary human myoblasts to investigate dose-dependent effects of dihydronicotinamide riboside (NRH), a potent NAD+ precursor. Moderate NRH exposure (25 μM) enhanced myogenic differentiation and fusion without affecting viability, aligning with physiologically relevant plasma levels. In contrast, a sustained high NRH concentration (500 μM) increased the myotube number and fast-twitch fiber area but disrupted sarcomeric organization, acetylcholine receptor clustering, and calcium signaling, with transcriptomic profiling revealing downregulation of myogenesis and metabolic pathways. These findings demonstrate that NRH exerts biphasic effects on human skeletal muscle differentiation and maturation, underscoring the utility of 3D engineered muscle tissues as a human-relevant platform to evaluate therapeutic and toxic doses of NAD+-boosting compounds.
    Keywords:  3D bioengineered skeletal muscle; 3D engineered skeletal muscle tissues technology; NAD+ metabolism; muscle differentiation; toxicological analysis
    DOI:  https://doi.org/10.1021/acsbiomaterials.5c02051
  23. J Gene Med. 2026 May;28(5): e70098
    In Vivo Assessment of dbDNA GNEwt/bi-shRNA-GNEM743T Lipoplex for GNE Myopathy: Improved Potency and Safety.
    Christopher M Jay, Fabienne Kerneis, Donald Rao, Alexander Nemunaitis, Ernest Bognar, Gladice Wallraven, Laura Stanbery, Rebecca Lutz, Adam Walter, Sep Sarshar, John Nemunaitis.
      GNE myopathy is an autosomal recessive disease, associated with skeletal muscle deterioration, which afflicts young adults. GNE plays a pivotal role in sialic acid production. Sialic acid acts as a buffer against reactive oxygen species generated during muscle contraction. Increased oxidative stress may relate to muscle atrophy involving patients with GNE myopathy. GNEM743T is the most common mutation leading to GNE myopathy. In our previous work, we demonstrated that a bifunctional plasmid that expresses wild type (wt) GNE and knocks down the GNEM743T mutant improves sialic acid production in vitro. Now, we expand evidence of in vivo activity of the bifunctional plasmid using a DOTAP-Cholesterol delivery vehicle and reduced toxic plasmid components using dbDNA conversion. We demonstrate that IV delivery of dbDNA lipoplex (LPX) in murine and rat models shows safety, increased DNA delivery, and improved RNA expression per LPX in skeletal muscle over non db plasmid at equal dose. Sialic acid protein expression was also shown increased in mouse muscle following IV treatment with dbDNA plasmid (pDNA) GNEwt/bi-shRNA-GNEM743T LPX. These results support further preclinical investigation to justify product IND development towards Phase 1 trial involving patients with GNE myopathy.
    Keywords:  GNE; HIBM; bi‐shRNA; dbDNA; doggybone DNA; lipoplex
    DOI:  https://doi.org/10.1002/jgm.70098
  24. Biomolecules. 2026 May 01. pii: 668. [Epub ahead of print]16(5):
    Skeletal Muscle miRNA Patterns in High-Altitude Trekkers: Exploratory Identification of Molecular Signatures of Cellular and Endocrine Adaptation.
    Tiziana Pietrangelo, Paolo Cocci, Danilo Bondi, Vittore Verratti, Carmen Santangelo, Lorenzo Marramiero, Francesco Alessandro Palermo.
      Exposure to high-altitude hypoxia leads to complex physiological and molecular adaptations, particularly in skeletal muscle. MicroRNAs (miRNAs), including muscle-enriched (myomiRNAs) and hypoxia-responsive (hypoxamiRNAs), play critical roles in regulating these responses. We investigated miRNA expression changes in the skeletal muscle of healthy, non-smoking Italian adults (mean age 36.7 ± 12.4 years) participating in the Himalayan expedition "Lobuche Peak-Pyramid Exploration & Physiology" conducted in the Sagaramāthā (Mount Everest) National Park, Nepal. The peak overnight stay altitude was ≈5000 m at the Pyramid International Laboratory-Observatory. Muscle biopsies were taken before and after the expedition from Vastus lateralis, at one-third of the distance from the upper margin of the rotula to the anterior superior iliac spine. Small RNA sequencing was used to profile differentially expressed miRNAs. Several miRNAs were differentially expressed (exploratory analysis), suggesting potential involvement in hypoxia-related adaptation. These encompass both canonical myomiRNAs (e.g., miR-206, miR-486-5p) and hypoxamiRNAs (e.g., miR-378a-5p, miR-199a-3p, let-7b-5p). In enrichment analysis, we found several connections between miRNAs and pathways that may play a role in physiological regeneration or differentiation in muscle cells. Among functions, focal adhesion (p-value = 0.001), regulation of actin cytoskeleton (p-value = 0.026), Rap-1 (p-value = 0.007), cAMP (p-value = 0.017), MAPK (p-value = 0.019), and Hippo (p-value = <0.001) signaling pathways were predicted to be the most targeted. These findings provide preliminary insights into physiological adaptation, requiring confirmation in larger and controlled cohorts.
    Keywords:  biomarkers; extreme environments; high-altitude hypoxia; microRNA (miRNA); skeletal muscle
    DOI:  https://doi.org/10.3390/biom16050668
  25. Adv Sci (Weinh). 2026 May 29. e07444
    Mesenchymal Stromal Cell-Mediated Intercellular Communication: Mapping the Interactome for Skeletal Muscle Homeostasis and Regeneration.
    Xingyu Liu, Edgar E Perez Carbajal, Yih-Chii Hwang, Sahil A Mapkar, Benjamin W Gilman, Sarah A Bliss, Lam B Tran, Kalgi T Mehta, Jacob O Banyasz, Ming Yu, Reynold R Liu, Matthew N Ly, Christapher S Morrissey, Michael N Wosczyna.
      Mesenchymal stromal cells (MSCs) support tissue homeostasis and regeneration, yet their molecular signals remain largely enigmatic. In skeletal muscle (SkM), MSCs, known as fibroadipogenic progenitors (FAPs), are essential for maintenance and repair, orchestrating these processes through intricate cellular communication networks. Given the critical role of SkM in lifelong health and longevity, FAP signaling has drawn significant interest as a potential therapeutic target and a model for MSC interactions. However, deciphering FAP-derived regulatory signals remains challenging due to their pleiotropic complexity. Here, we employ a systems-level approach to construct a comprehensive FAP interactome in both homeostatic and regenerating SkM. By integrating unique single-cell RNA sequencing atlases with advanced computational analyses, we identify putative FAP-mediated signaling pathways and validate their biological relevance through FAP depletion experiments, assessing disruptions in key pathways. This approach reveals novel signaling networks across diverse SkM cell populations, corroborates key FAP interactions from recent studies, and provides a valuable dataset for modeling MSC interactions and their roles in SkM homeostasis and regeneration.
    Keywords:  fibroadipogenic progenitor; intercellular communication; maintenance and regeneration; mesenchymal stem cell; skeletal muscle
    DOI:  https://doi.org/10.1002/advs.202507444
  26. Curr Opin Endocrinol Diabetes Obes. 2026 May 26.
    Exploring the role of parathyroid hormone in sarcopenia: A review.
    Ana Carolina Vieira Selva, Pushpa Suriyaarachchi, Gustavo Duque.
       PURPOSE OF REVIEW: Sarcopenia is a progressive, multifactorial geriatric syndrome linked to increased risk of falls, fractures, disability, frailty, and all-cause mortality. The pathophysiology of this complex syndrome remains unclear. Emerging evidence suggests that chronically elevated parathyroid hormone (PTH) concentration may contribute to muscle decline, increasing the risk of sarcopenia. This review evaluates the most recent evidence on the role of PTH in sarcopenia.
    RECENT FINDINGS: A recent meta-analysis of eleven observational studies involving 4759 participants supports an association between elevated PTH and a higher risk of sarcopenia. Proposed mechanisms include PTH-mediated alterations in serum calcium levels and modulation of muscle protein metabolism by PTH and its N-terminal fragment. The metabolic effects of elevated PTH may also indirectly affect muscle mass by altering skeletal muscle energy metabolism.
    SUMMARY: Elevated PTH concentration is increasingly linked to a higher risk of sarcopenia in older adults, although the biological mechanisms behind this remain only partially understood. Most current evidence comes from observational studies and cannot establish causation. Future research should focus on mechanistic studies in humans and interventional trials to determine whether higher PTH concentrations directly cause muscle decline and whether correcting PTH concentrations can lead to significant improvements in muscle mass and function.
    Keywords:  aging; geroscience; muscle; osteosarcopenia; parathyroid hormone; sarcopenia
    DOI:  https://doi.org/10.1097/MED.0000000000000963
  27. Muscles. 2026 May 12. pii: 38. [Epub ahead of print]5(2):
    Progressive Myopenia and Functional Decline in the Winnie Mouse Model of Chronic Colitis.
    Shilpa Sharma, Danielle Debruin, Jeannie Devereaux, Alan Hayes, Kulmira Nurgali, Gustavo Duque.
      Muscle wasting contributes substantially to inflammatory bowel disease (IBD)-related disability, but its association with colitis severity across disease stages remains poorly characterized. We therefore assessed skeletal muscle mass, fiber morphology, and voluntary wheel-running performance in Winnie mice-a spontaneous Muc2 mutant model of chronic colitis-in separate female and male homozygous mutant and WT littermate cohorts. Assessments were performed at 5 weeks, before overt colitis, and at 15 weeks, in a cohort with more pronounced colitis. Outcomes included disease activity index (DAI), fecal lipocalin-2 (LCN-2), wheel-running metrics, soleus and tibialis anterior mass, and minimal Feret's diameter distributions. At 5 weeks, Winnie mice showed no overt disease activity and no consistent structural muscle deficit. In contrast, the 15-week cohort exhibited marked colitis in both sexes, with increased DAI and LCN-2, reduced voluntary wheel-running performance, lower soleus and tibialis anterior mass, and smaller muscle fiber diameters with left-shifted size distributions. Correlation analyses identified associations between fecal LCN-2, skeletal muscle mass and size, and wheel-running distance and velocity, supporting a link between intestinal inflammation and muscle impairment in this model. These cross-sectional data are consistent with reduced voluntary activity and structural myopathy during progression of spontaneous colitis. The Winnie mouse model therefore provides a clinically relevant preclinical platform to study IBD-associated muscle wasting and its association with intestinal inflammation.
    Keywords:  LCN-2; Winnie mouse; chronic colitis; muscle atrophy; myopenia
    DOI:  https://doi.org/10.3390/muscles5020038
  28. Biomedicines. 2026 Apr 23. pii: 976. [Epub ahead of print]14(5):
    The Gut-Muscle Axis in Sarcopenia: Mechanisms, Evidence Gaps and Translational Challenges.
    Stefano Andrea Marchitto, Gabriele Abbatecola, Rola S Zeidan, Lauren Morgan, Riccardo Calvani, Anna Picca, Mathias Schlögl, Matteo Tosato, Christiaan Leeuwenburgh, Stephen D Anton, Francesco Landi, Emanuele Marzetti, Stefano Cacciatore.
      Sarcopenia is an age-related skeletal muscle disorder characterized by reduced muscle mass, strength, and physical performance, as well as increased risk of disability, hospitalization, and mortality. Emerging evidence suggests that gut microbiota alterations may contribute to muscle decline via a microbiota-gut-muscle axis, acting as a context-dependent modulator rather than a primary causal driver. This narrative review synthesizes mechanistic, clinical, and translational evidence linking gut dysbiosis to sarcopenia. Preclinical studies show that microbiota modulation (e.g., antibiotics, probiotics, prebiotics, postbiotics, fecal microbiota transplantation) affects muscle mass, strength, and metabolism through pathways including inflammation, mitochondrial dysfunction, altered short-chain fatty acid production, and impaired anabolic signaling. In humans, observational studies associate lower microbial diversity and reduced short-chain fatty acid-producing taxa with poorer muscle outcomes, but findings are heterogeneous and non-causal. Interventional trials remain limited and characterized by small sample sizes, with effects more consistent for functional outcomes than muscle mass. Overall, the gut microbiota represents a modifiable contributor within the complex biology of sarcopenia. Future studies should integrate microbiome profiling and multi-omics approaches within well-designed clinical trials to identify responder phenotypes and define the role of microbiota-targeted strategies within multimodal interventions.
    Keywords:  aging; dysbiosis; gut microbiota; gut–muscle axis; inflammation; microbiota-targeted interventions; mitochondrial dysfunction; physical exercise; sarcopenia; short-chain fatty acids
    DOI:  https://doi.org/10.3390/biomedicines14050976
  29. bioRxiv. 2026 May 17. pii: 2026.05.12.724616. [Epub ahead of print]
    Regulation of Small RNAs by Exercise and Their Role in Insulin Sensitivity.
    Christopher G Vann, Akshay Bareja, Monica J Hubal, Syeda Iffat Naz, Sisi Ma, Melissa C Orenduff, Leanna M Ross, William C Bennett, Kim M Huffman, Constantin F Aliferis, William E Kraus, Virginia B Kraus.
      We investigated effects of three aerobic exercise interventions, varying in amount and intensity with durations of 8-9-months on small RNA (smRNA) expression and regulatory pathways in skeletal muscle and plasma from 120 participants. Using untargeted smRNA sequencing focused on miRNAs and piRNAs, adjusting for demographics and bodyweight, we identified 124 muscle smRNAs altered by exercise amount and 15 by intensity, and 47 plasma smRNAs altered by intensity and one by amount. These smRNAs were enriched in metabolic, transcriptional, translational, and cell cycle pathways. Exercise-induced changes in several smRNAs-six from muscle and five from plasma-and exercise-induced reduction in body weight, aligned with improvement in insulin sensitivity (p<0.05). These findings demonstrate tissue-specific regulation of smRNAs by exercise and identify potential candidates for exercise mimetics to modulate muscle insulin sensitivity.
    DOI:  https://doi.org/10.64898/2026.05.12.724616
  30. Mol Med. 2026 May 28.
    Lactylation and lactate: insights into muscle cell epigenetic regulators in exercise.
    Bo Chen, Jingbo Xia, Chaoge Wang, Min Hu, Jingwen Liao.
      Lactate was once regarded as a metabolic waste. However, recent studies have established its dual role as both a versatile signaling molecule and a substrate for a novel post-translational modification (PTMs)-lysine lactylation. Exercise, as a primary physiological stimulus for lactate production, provides an ideal context for exploring lactate-mediated epigenetic regulation. This regulatory mechanism is particularly relevant in muscle cells, which serve as both the main producers and consumers of lactate. This review focuses on three core muscle cell types: skeletal muscle cells, cardiomyocytes and vascular smooth muscle cells (VSMCs). We systematically elucidate the functional roles of the lactate-lactylation in these cells, examining how lactate can regulate cellular adaptation and pathological processes both independently and in concert with other PTMs. Furthermore, we analyze the distinct effects of diferent exercise modalities (ranging from moderate training to overtraining) on the lactylation dynamics, revealing its the dual functions of lactylation in exercise physiology and pathology. By integrating these mechanisms, this review provides a novel theoretical framework for understanding exercise-mediated muscle cell function and offers fresh perspectives for intervention strategies targeting metabolic and cardiovascular diseases.
    Keywords:  Exercise; Lactate signaling; Lactylation; Muscle cells; Post-translational modifications
    DOI:  https://doi.org/10.1186/s10020-026-01506-4
  31. bioRxiv. 2026 May 12. pii: 2026.05.07.723527. [Epub ahead of print]
    Short-Term Combined Tat-Beclin1 and Endurance Training Improves Age-Related Decline in Physical Function in Male Mice.
    Thuan Thien Tchen, Shakibur Rahman, Thaysa Ghiarone, Lynn A Spruce, Hossein Fazelina, Elizabeth M Brown, Charalampos Papachristou, Sue C Bodine, Vitor A Lira, Kleiton A S Silva.
      Autophagy is a hallmark of aging, but autophagy-related proteins have not been exclusively targeted to attenuate the progressive decline in physical function associated with aging. Here, we combined Tat-Beclin1, an autophagy agonist, and endurance training to determine whether Tat-Beclin1 enhances exercise adaptation in old male mice. Tat-Beclin1 was administered intraperitoneally (TB group, 15 mg/kg, 2x/week) as a standalone therapy, or in combination with endurance training (TB+Exe group, 70% of maximal running speed 3x/week) for 1 month in 23-month-old male C57BL/6J mice. Control groups were age-matched cage controls and exercise-only groups. Animals were assessed for grip strength, endurance capacity on a treadmill, and balance and coordination on a rotarod. Gastrocnemius/plantaris (G/P) and tibialis anterior muscles were harvested for western blotting, myofiber typing, and proteomic profiling (G/P only). TB+Exe led to significant increases in grip strength, endurance capacity, and balance and coordination performance beyond those observed in the TB and Exe groups alone. Autophagy markers, including Beclin1, the LC3B-II/I ratio, and p62, did not differ among groups. A proteomic analysis of the G/P muscle revealed that TB upregulated biological processes involved in muscle contraction and adaptation, whereas TB+Exe increased mitochondrial bioenergetic processes and, surprisingly, upregulated acute inflammatory responses, including proteins such as haptoglobin and orosomucoid-1. We conclude that combining Tat-Beclin1 and endurance training may represent a new approach to attenuate aging-related decline in physical function.
    New & Noteworthy: We show evidence that combining Tat-Beclin1 and endurance training (TB+Exe) resulted in greater improvements in physical function in 24-month-old male mice than either standalone therapy. We also show that TB+Exe upregulates traditional exercise-like biological processes and unexpectedly upregulates acute-inflammatory proteins (e.g., orosomucoid-1), which are thought to improve physical function in preclinical studies. Our study suggests that TB may be a new drug enhancing physical function, especially when combined with endurance training in old male mice.
    DOI:  https://doi.org/10.64898/2026.05.07.723527
  32. Curr Opin Physiol. 2025 Jun;pii: 100829. [Epub ahead of print]44
    Impact of microRNAs and long noncoding RNAs in skeletal and cardiac muscles.
    Gabriela P Diniz, Joanne Chan, John D Mably, Da-Zhi Wang.
      Recent advances in technology have accelerated our ability to define the functions of noncoding RNA (ncRNA). Beyond their known roles in regulating molecular and cellular processes, new mechanisms and interacting partners for ncRNAs have been revealed. In this review, we focus on recent discoveries of long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) in skeletal and cardiac muscles. In addition to sharing a sarcomeric organization and contractile function, both tissues also utilize similar mechanisms and genetic networks during myogenic differentiation, tissue repair, and regeneration and in disease progression. Thus, knowledge gained about the roles of these ncRNAs in cardiac and skeletal muscles may reveal shared mechanisms and functions relevant to both muscle types as well as to understanding their rules in other tissues. Ultimately, this information could be exploited to develop new diagnostic biomarkers and novel therapies for diseases affecting cardiac and skeletal muscle.
    DOI:  https://doi.org/10.1016/j.cophys.2025.100829
  33. Front Physiol. 2026 ;17 1822139
    From homeostasis to pathology, organelle-specific autophagy in skeletal muscle: a PRISMA-ScR scoping review.
    Chunxiao Wang, Guanghua Liu, Changsheng Guo, Qi Li, Feixiao Wang, Ming Zhang.
       Background: As the largest metabolic organ in the human body, skeletal muscle relies on the structural and functional integrity of its organelles for cellular viability and responsiveness. Organelle-specific autophagy, a major subtype of autophagy encompassing mitophagy, pexophagy, reticulophagy (ER-phagy), ribophagy, lysophagy, and nucleophagy, has been reported to exert a protective role in skeletal muscle by selectively eliminating damaged organelles and maintaining cellular homeostasis.
    Objective: This scoping review aims to systematically map the current literature on organelle-specific autophagy in skeletal muscle, clarifying the molecular mechanisms, physiological and pathological roles, and research gaps for the six types of organelle-specific autophagy.
    Methods: Following the PRISMA-ScR guidelines and the Joanna Briggs Institute framework, we searched PubMed, Embase, Web of Science, and Cochrane Library up to 21 March 2026 using keywords for skeletal muscle combined with mitophagy, pexophagy, ER-phagy, ribophagy, lysophagy, and nucleophagy. Studies involving humans, mice, rats, or skeletal muscle cells were included.
    Results: Among 113 included studies, human studies accounted for 15%, animal models 56%, and skeletal muscle cell lines 29%. By autophagy type, mitophagy dominated (87%, 98 studies), reticulophagy and lysophagy each accounted for 4% (five studies each), and lysophagy, pexophagy, ribophagy, and nucleophagy together comprised less than 5%. Regarding evidence level, among 24 human studies, 18 (75%) were cross-sectional observational studies or small case series (level 4), only three were randomized controlled trials (RCTs) (level 2b), and one was an individual RCT (level 1b); the overall evidence was predominantly low-level observational, with a lack of high-quality interventional clinical trials. For autophagic flux methodology, 53% of studies performed dual detection of LC3B and p62, 17% used lysosomal inhibitor blocking experiments, 64% used transmission electron microscopy (TEM) or tandem fluorescent probes, 23% combined bidirectional verification of autophagic function, and 18% examined intervention reversibility. Among 88 animal studies, low risk of bias (RoB) was found in 14 (16%), moderate RoB in 43 (49%), and high RoB in 30 (35%). For 46 cell experiments assessed by five self-established criteria, 83% used TEM to confirm autophagosomes, 28% used lysosomal inhibitors to validate flux, 72% used gene knockout/knockdown to verify mechanisms, 91% used skeletal muscle-derived cell lines, and 41% performed multi-time-point dynamic autophagy detection.
    Conclusions: Current research is severely lacking in nonmitophagy mechanisms, standardized dynamic flux assays, and high-quality clinical studies. Furthermore, systematic investigations of sex differences and muscle fiber type specificity are persistently absent, constraining the development of precise intervention strategies. Future efforts should strengthen multiorganelle autophagy network research and clinical translation to provide new targets for preventing and treating skeletal muscle disorders.
    Keywords:  ER-phagy; lysophagy; mitophagy; nucleophagy; pexophagy; ribophagy; skeletal muscle
    DOI:  https://doi.org/10.3389/fphys.2026.1822139
  34. iScience. 2026 Jun 19. 29(6): 115838
    Extracellular vesicle transcriptomic analysis to investigate muscle adaptation in microgravity.
    Samantha Ali, Maddalena Parafati, Zachary F Greenberg, Nina Erwin, Zon Thwin, Mei He, Siobhan Malany.
      Extracellular vesicles (EVs) serve as critical regulators of intercellular communication by carrying diverse molecular cargos which reflect cellular states associated with environmental stressors. We investigated transcriptomic profiles of EVs derived from human skeletal muscle tissue chips flown abroad the SpaceX CRS-25 mission to characterize age- and microgravity-induced adaptation. EVs were isolated using a novel magnetic capture-release method (ExCy) from conditioned media of muscle chips cultured in microgravity or ground control conditions. Next-generation sequencing and differential gene expression analysis were performed on EV RNA. In this exploratory study, we identified age- and spaceflight-specific transcriptomic signatures. Young donor-derived EVs in microgravity appear to exhibit upregulation of oxidative stress and signaling pathways, while older donor-derived EVs showed markers of mitochondrial quality control, ER stress, and proteostasis failure. Muscle-derived EVs capture environment- and age-dependent molecular signatures in space, supporting their use as non-invasive biomarkers for physiological stress and tissue adaptation under microgravity.
    Keywords:  cell biology; space sciences; transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2026.115838
  35. Bio Protoc. 2026 May 20. 16(10): e5698
    Isolation and Biophysical Characterization of Extracellular Vesicles Released by Myocytes.
    Kah Yong Goh, Wen Xing Lee, Hong-Wen Tang.
      Extracellular vesicles (EVs) are lipid bilayer-enclosed vesicles released by diverse cell types and found in various body fluids. Because their composition and cargo dynamically respond to physiological and environmental cues, EVs hold promise both as biomarkers and as carriers for therapeutic delivery. Skeletal muscle functions as an endocrine organ, secreting myokines and EVs that modulate a wide range of cellular processes. The murine C2C12 cell line is a widely used in vitro model for investigating muscle biology. Here, we describe a protocol for isolating EVs from differentiated C2C12 myocytes. The isolated EVs are characterized and validated using western blotting, transmission electron microscopy (TEM), and dynamic light scattering (DLS) analysis. This workflow provides a robust platform for studying the molecular composition and functional roles of muscle-derived EVs. Key features • Standardized protocol for isolating extracellular vesicles (EVs) from differentiated C2C12 myocytes. • High-purity EV isolation achieved through sequential ultracentrifugation and size-exclusion chromatography. • Generates EV samples compatible with diverse downstream applications, including western blotting, transmission electron microscopy (TEM), and dynamic light scattering (DLS) analysis. • Enables comparative studies of muscle-derived EV composition and functional changes under both control and treatment conditions in C2C12 myocytes.
    Keywords:  Dynamic light scattering (DLS); Extracellular vesicles (EVs); In vitro model; Myocytes; Skeletal muscle; Transmission electron microscopy; Western blotting
    DOI:  https://doi.org/10.21769/BioProtoc.5698
  36. J Orthop Surg Res. 2026 May 28.
    Novel biomarkers for sarcopenia: a narrative review.
    Xiaoxiao Chen, Fei Wu, Suqin Shi, Le Xia, Yurong Wang, Yu Wei, Jing Wang, Jiaqi Li, Min Zhu, Xiaojie Zhang, Jinqiang Zhuang.
      Sarcopenia is an age-related syndrome characterized by the progressive loss of skeletal muscle mass, strength, and function. It is associated with an increased risk of falls, disability, and mortality, as well as a significant healthcare burden. Traditional assessment of sarcopenia relies on imaging techniques and physical function tests, which have important limitations, including operational complexity, difficulty in early identification, and inability to reflect underlying molecular mechanisms. The emergence of candidate biomarkers-including muscle-specific factors, inflammation-related proteins, non-coding RNAs, and nutritional metabolites-has enabled a more precise elucidation of the pathophysiological mechanisms of the disease across multiple dimensions, such as protein homeostasis, chronic inflammation, post-transcriptional regulation, and energy metabolism. These advances provide new avenues for early identification, risk stratification, identification of disease subtypes, and the development of personalized intervention strategies. This article reviews the potential applications and current challenges of these candidate biomarkers in both clinical practice and research on sarcopenia.
    Keywords:  Biomarkers; Molecular mechanisms; Muscle atrophy; Sarcopenia
    DOI:  https://doi.org/10.1186/s13018-026-06880-7
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