bims-moremu Biomed News
on Molecular regulators of muscle mass
Issue of 2025–08–10
forty-two papers selected by
Anna Vainshtein, Craft Science Inc.
  1. Muscle memory theory: A critical evaluation.
  2. Chronic activation of a key exercise signal transducer, CaMKII, drives skeletal muscle aging and sarcopenia.
  3. Redox-regulated signalling of adaptations to contractile activity in skeletal muscle: Implications for age-related muscle weakness.
  4. The paradox of hnRNPK: both absence and excess impair skeletal muscle function in mice.
  5. STAC3 binding to CaV1.1 II-III loop is nonessential but critically supports skeletal muscle excitation-contraction coupling.
  6. AMPK/mTOR balance during exercise: implications for insulin resistance in aging muscle.
  7. Degradative Signaling in ATG7-Deficient Skeletal Muscle Following Cardiotoxin Injury.
  8. Leukocyte-type 12/15-lipoxygenase is essential for timely inflammation-resolution and effective tissue regeneration following skeletal muscle injury.
  9. Sympathetic innervation maintains the murine quiescent skeletal muscle stem cell pool via perivascular-derived Angpt1.
  10. Transcriptomic time course of skeletal muscle disuse and rehabilitation in middle-aged adults.
  11. SkeletAge: Transcriptomics-based Aging Clock Identifies 26 New Targets in Skeletal Muscle Aging.
  12. Screening and identification of muscle pericyte selective markers.
  13. Age-related declines in mitochondrial Prdx6 contribute to dysregulated muscle bioenergetics.
  14. Combined stimuli of elasticity and microgrooves form aligned myotubes that characterize slow twitch muscles.
  15. Cold Stress Regulates Muscle Development and Promotes Muscle Fiber Transformation by Regulating Mib1/Notch Pathway.
  16. Voluntary Activity Wheel Running Improves Hyperammonaemia-Induced Skeletal Muscle Molecular and Metabolic Perturbations in Mice.
  17. Multi-dimensional metabolomic remodeling under diverse muscle atrophic stimuli in vivo.
  18. In vitro muscle contraction: A technical review on electrical pulse stimulation in C2C12 cells.
  19. Response of UBR-box E3 ubiquitin ligases and protein quality control pathways to perturbations in protein synthesis and skeletal muscle size.
  20. P-Rex2 suppresses glucose uptake into liver and skeletal muscle through different adaptor functions.
  21. FBXL3 serves as a suppressor of regenerative myogenesis.
  22. Altered Acute Metabolic Response to Muscle Stimulation in Muscular Dystrophic Mice Observed by Phosphorus-31 Magnetic Resonance Spectroscopy and Fingerprinting.
  23. The impact of exercise on skeletal muscle proteome of prediabetic subjects analyzed with data independent mass spectrometry.
  24. Molecular genetics of skeletal muscle channelopathies.
  25. Exercise training increases skeletal muscle sphingomyelinases and affects mitochondrial quality control in men with type 2 diabetes.
  26. Ryanodine receptor stabilizer S-107 rescues slow-type rat soleus muscle function after 7-day hindlimb unloading.
  27. MRI-based 3D Estimation of Skeletal Muscle Architecture and Strain during Contraction.
  28. Muscle Endurance Training in a Person with Friedreich's Ataxia.
  29. The contralateral repeated bout effect is not caused by adaptations in skeletal muscle.
  30. A Straightforward Approach to Analyze Skeletal Muscle MRI in Limb-Girdle Muscular Dystrophy for Differential Diagnosis: A Systematic Review.
  31. Pro-inflammatory cytokines as regulators of protein tyrosine phosphatases and insulin signaling in murine skeletal muscle cells.
  32. Hormonal Influences on Skeletal Muscle Function in Women across Life Stages: A Systematic Review.
  33. Dystrophin/mini-dystrophin expression analysis by immunoaffinity liquid chromatography-tandem mass spectrometry after gene therapy for DMD.
  34. Transcription factor MAFA regulates muscle growth via calcium ion channels and receptor tyrosine kinase activation.
  35. Symphony of regulated cell death: Unveiling therapeutic horizons in sarcopenia.
  36. Inhibition of Unc119b improves insulin sensitivity through potentiation of Rac1 activation in skeletal muscle and brown adipose tissue.
  37. Noninvasive Assessments of Mitochondrial Capacity in People with Mitochondrial Myopathies.
  38. EnsembleAge: enhancing epigenetic age assessment with a multi-clock framework.
  39. ALY688 Attenuates Iron-Induced ER Stress and Insulin Resistance via Activation of ER-Phagy.
  40. hUC-MSCs and derived exosomes attenuate DEX-induced muscle atrophy through modulation of estrogen signaling pathway.
  41. Transcriptomic Response to Neuromuscular Electrical Stimulation in Muscle, Brain and Plasma EVs in WT and Klotho-deficient Mice.
  42. Sarcosine shows promise in preventing sarcopenia.
  1. J Physiol. 2025 Aug 06.
    Muscle memory theory: A critical evaluation.
    Nathan Serrano, Esther E Dupont-Versteegden, Kevin A Murach.
      
    Keywords:  anabolic steroids; exercise; muscle atrophy; muscle hypertrophy; muscle memory; myonuclei; skeletal muscle
    DOI:  https://doi.org/10.1113/JP289597
  2. bioRxiv. 2025 Aug 02. pii: 2025.07.30.667744. [Epub ahead of print]
    Chronic activation of a key exercise signal transducer, CaMKII, drives skeletal muscle aging and sarcopenia.
    Michael R Bene, Tae Chung, William A Fountain, Giovanni Rosales-Soto, Erick Hernández-Ochoa, Corina Antonescu, Liliana Florea, Seeun J Jeong, Anne Le, Qian-Li Xue, Ahmet Hoke, Peter Abadir, Qinchuan Wang.
      Sarcopenia, the age-related loss of muscle strength and mass, contributes to adverse health outcomes in older adults. While exercise mitigates sarcopenia by transiently activating calcium (Ca 2+ )- and reactive oxygen species (ROS)-dependent signaling pathways that enhance muscle performance and adaptation, these same signals become chronically elevated in aged skeletal muscle and promote functional decline. Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) is a key transducer of both Ca 2+ and ROS signals during exercise. Here we show that CaMKII is chronically activated in aged muscles, promoting muscle dysfunction. Muscle-specific expression of a constitutively active CaMKII construct in young mice recapitulates features of aging muscles, including impaired contractility, progressive atrophy, mitochondrial disorganization, formation of tubular aggregates, and an older transcriptional profile characterized by the activation of inflammatory and stress response pathways. Mediation analysis identified altered heme metabolism as a potential mechanism of CaMKII-induced weakness, independent of muscle atrophy. Conversely, partial inhibition of CaMKII in aged muscle improved contractile function and shifted the transcriptome toward a more youthful state without inducing hypertrophy. These findings identify chronic CaMKII activation as a driver of functional and molecular muscle aging and support the concept that CaMKII exemplifies antagonistic pleiotropy, whereby its beneficial roles in promoting muscle performance and adaptation during youth may incur deleterious consequences in aging. We propose that persistent CaMKII activation in aged skeletal muscle reflects unresolved cellular stress and promotes maladaptive remodeling. Enhancing physiological reserve capacity through exercise, in combination with temporally targeted CaMKII inhibition, may help restore adaptive CaMKII signaling dynamics and preserve muscle function in aging.
    DOI:  https://doi.org/10.1101/2025.07.30.667744
  3. Exp Physiol. 2025 Aug 05.
    Redox-regulated signalling of adaptations to contractile activity in skeletal muscle: Implications for age-related muscle weakness.
    Malcolm J Jackson.
      Skeletal muscle adaptation to contractile activity is modulated by redox signalling, primarily through reactive oxygen species (ROS) such as hydrogen peroxide (H2O2). Early research framed ROS as deleterious byproducts of exercise, but subsequent studies have established their roles as signalling molecules involved in mitochondrial biogenesis, stress responses and metabolic regulation. Central to this process appear to be peroxiredoxins (Prdxs), particularly Prdx2, which current evidence suggests mediate redox relays by sensing physiological H2O2 levels and initiating transcriptional programs. Our recent findings demonstrate that low levels of H2O2, or electrically induced contractions, rapidly oxidise Prdx1, Prdx2 and Prdx3 in mouse muscle fibres. Transcriptomic analysis of human skeletal muscle myotubes confirmed that Prdx2 is essential for upregulating mitochondrial genes in response to H2O2 or contraction. With ageing, skeletal muscle exhibits impaired redox signalling with elevated ROS levels. Using an ageing mouse model, we observed diminished Prdx2 oxidation during contraction, suggesting redox signalling dysfunction. This impaired response likely contributes to sarcopenia by blunting the adaptive capacity of aged muscle. Our findings emphasise the importance of redox homeostasis (not merely ROS suppression) in maintaining muscle health. Understanding the nuanced role of ROS and Prdxs in exercise adaptation and ageing could inform therapeutic strategies aimed at restoring redox-sensitive signalling to preserve muscle function across the lifespan.
    Keywords:  NMJ; hydrogen peroxide; mitochondria; motor neuron
    DOI:  https://doi.org/10.1113/EP092458
  4. Skelet Muscle. 2025 Aug 07. 15(1): 20
    The paradox of hnRNPK: both absence and excess impair skeletal muscle function in mice.
    Yongjie Xu, Yuxi Wang, Xiaofang Cheng, Mengjia Zhang, Nuo Chen, Jiahua Guo, Yueru Huang, Quanxi Li, Tianyu Li, Tiantian Meng, Cencen Li, Pengpeng Zhang, Haixia Xu.
       BACKGROUND: The RNA-binding protein hnRNPK is essential for animal growth and development, with a particular emphasis in myogenesis. Despite its importance, the precise mechanisms by which hnRNPK influences skeletal muscle physiology and development remain inadequately characterized.
    METHODS: To explore its regulatory function, we developed a Myf5-cre-mediated myoblast precursor-specific knockout mouse model (Hnrnpk mKO), an Acta1-CreEsr1-mediated myofiber-specific inducible knockout mouse model (Hnrnpk aKO), and an AAV9-mediated skeletal muscle-specific overexpression mouse model (AAV9-hnRNPK). Morphological alterations in skeletal muscle were assessed using hematoxylin and eosin (HE) staining subsequent to hnRNPK knockout or overexpression. Global gene expression changes in the tibialis anterior (TA) muscle were assessed via RNA sequencing (RNA-seq). Furthermore, reverse transcription quantitative polymerase chain reaction (RT-qPCR), western blot analysis, immunofluorescence, immunohistochemistry, co-immunoprecipitation (Co-IP), dual luciferase analysis, and reactive oxygen species (ROS) detection were utilized to elucidate the molecular mechanisms by which hnRNPK contributes to skeletal muscle development.
    RESULTS: Our findings indicate that the ablation of hnRNPK in myoblast precursors significantly impairs muscle development, disrupts fetal myogenesis, and results in embryonic lethality. In adult mice, both the loss and gain of hnRNPK function led to reduced muscle mass, decreased fiber size, and compromised skeletal muscle homeostasis. Importantly, the knockout of hnRNPK had a more substantial impact on skeletal muscle development compared to its overexpression, with myofiber-specific knockout leading to mortality within two weeks. Mechanistically, hnRNPK deficiency was associated with increased apoptosis and muscle atrophy, characterized by elevated expression of genes involved in apoptosis, muscle atrophy, and protein catabolism, along with impaired muscle contraction and extracellular matrix (ECM) organization. Conversely, hnRNPK overexpression was correlated with enhanced ferroptosis pathway and improved ECM organization, but was also associated with reduced oxidative phosphorylation and protein synthesis. The overexpression likely promotes ferroptosis via the hnRNPK/P53/Slc7a11/Gpx4 pathway, thereby accelerating muscle aging and reducing muscle mass.
    CONCLUSION: In conclusion, our findings underscore the critical importance of precise hnRNPK expression levels in maintaining skeletal muscle health. Both deficiency and overexpression of hnRNPK disrupt skeletal muscle development, highlighting its pivotal role in muscle physiology.
    CLINICAL TRIAL NUMBER: Not applicable.
    Keywords:  HnRNPK; Knockout; Mice; Muscle atrophy; Overexpression; Skeletal muscle
    DOI:  https://doi.org/10.1186/s13395-025-00393-3
  5. JCI Insight. 2025 Aug 08. pii: e191053. [Epub ahead of print]10(15):
    STAC3 binding to CaV1.1 II-III loop is nonessential but critically supports skeletal muscle excitation-contraction coupling.
    Wietske E Tuinte, Enikő Török, Petronel Tuluc, Fabiana Fattori, Adele D'Amico, Marta Campiglio.
      Skeletal muscle excitation-contraction (EC) coupling depends on the direct coupling between CaV1.1 on the sarcolemma and ryanodine receptor (RyR1) on the sarcoplasmic reticulum. A key regulator of this process is STAC3, a protein essential for both the functional expression of CaV1.1 and its conformational coupling with RyR1. Mutations in Stac3 cause STAC3 disorder, a congenital myopathy characterized by muscle weakness. STAC3 interacts with CaV1.1 in 2 key regions: the II-III loop and the proximal C-terminus. While the II-III loop has been previously found to be essential for skeletal muscle EC coupling, here we demonstrated that the interaction between STAC3 and the proximal C-terminus is necessary and sufficient for CaV1.1 functional expression and minimal EC coupling. In contrast, the interaction with the II-III loop is not essential for EC coupling, though it plays a facilitating role in enhancing the process. Supporting this finding, we identified a patient with STAC3 disorder carrying a mutation that deletes the domain of STAC3 involved in the II-III loop interaction. Collectively, our results established that STAC3 binding to CaV1.1 C-terminus is essential for its functional expression, whereas STAC3 interaction with the II-III loop serves to enhance the conformational coupling with RyR1.
    Keywords:  Calcium channels; Excitation contraction coupling; Muscle biology; Neuroscience; Skeletal muscle
    DOI:  https://doi.org/10.1172/jci.insight.191053
  6. Mol Cell Biochem. 2025 Aug 04.
    AMPK/mTOR balance during exercise: implications for insulin resistance in aging muscle.
    Xie Mingzheng, Weng You.
      Age-related reductions in skeletal muscle insulin responsiveness promote metabolic dysregulation and contribute to an elevated probability of type 2 diabetes onset. The malfunction of nutrient-responsive signaling routes, specifically AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR), constitutes a central component of this biological process. The integrated activity of these kinases in controlling energy dynamics, protein formation, and glucose processing is fundamental to ensure metabolic homeostasis in skeletal muscle tissue. Through its modulation of AMPK and mTOR pathways, exercise helps reinstate signaling equilibrium and supports better insulin efficacy in aging skeletal muscle. This review explores the molecular mechanisms by which different forms of exercise-endurance, resistance, and combined training-modulate the AMPK/mTOR axis in aging muscle. This analysis focuses on exercise-induced AMPK signaling as a catalyst for mitochondrial development, enhanced glucose processing, and intensified fatty acid breakdown, while also temporally coordinating mTOR activity to support muscle maintenance without exacerbating insulin resistance. By integrating insights from aging biology, exercise physiology, and molecular metabolism, this review highlights the therapeutic potential of targeting AMPK/mTOR signaling through physical activity to combat insulin resistance in the elderly.
    Keywords:  AMPK; Exercise intervention; Insulin resistance; Skeletal muscle aging; mTOR
    DOI:  https://doi.org/10.1007/s11010-025-05362-4
  7. Muscles. 2023 Sep 15. 2(3): 299-316
    Degradative Signaling in ATG7-Deficient Skeletal Muscle Following Cardiotoxin Injury.
    Fasih Ahmad Rahman, Troy Campbell, Darin Bloemberg, Sarah Chapman, Joe Quadrilatero.
      Skeletal muscle is a complex tissue comprising multinucleated and post-mitotic cells (i.e., myofibers). Given this, skeletal muscle must maintain a fine balance between growth and degradative signals. A major system regulating the remodeling of skeletal muscle is autophagy, where cellular quality control is mediated by the degradation of damaged cellular components. The accumulation of damaged cellular material can result in elevated apoptotic signaling, which is particularly relevant in skeletal muscle given its post-mitotic nature. Luckily, skeletal muscle possesses the unique ability to regenerate in response to injury. It is unknown whether a relationship between autophagy and apoptotic signaling exists in injured skeletal muscle and how autophagy deficiency influences myofiber apoptosis and regeneration. In the present study, we demonstrate that an initial inducible muscle-specific autophagy deficiency does not alter apoptotic signaling following cardiotoxin injury. This finding is presumably due to the re-establishment of ATG7 levels following injury, which may be attributed to the contribution of a functional Atg7 gene from satellite cells. Furthermore, the re-expression of ATG7 resulted in virtually identical regenerative potential. Overall, our data demonstrate that catastrophic injury may "reset" muscle gene expression via the incorporation of nuclei from satellite cells.
    Keywords:  apoptosis; autophagy; cardiotoxin; cell death; muscle injury; muscle regeneration; satellite cells
    DOI:  https://doi.org/10.3390/muscles2030023
  8. Mol Metab. 2025 Aug 04. pii: S2212-8778(25)00131-0. [Epub ahead of print] 102224
    Leukocyte-type 12/15-lipoxygenase is essential for timely inflammation-resolution and effective tissue regeneration following skeletal muscle injury.
    Binayok Sharma, Xinyue Lu, Hamood Rehman, Vandré C Figueiredo, Carol Davis, Holly Van Remmen, Shihuan Kuang, Susan V Brooks, Krishna Rao Maddipati, James F Markworth.
      Unlike traditional anti-inflammatory therapies which may interfere with musculoskeletal tissue repair, pharmacological administration of specialized pro-resolving lipid mediators (SPMs) can promote timely resolution of inflammation while stimulating skeletal muscle regeneration. Despite this, the potential role of endogenous inflammation-resolution circuits in skeletal muscle injury and repair remains unknown. Here, we investigated the effect of whole-body knockout of leukocyte-type 12/15-lipoxygenase (12/15-LOX) on acute inflammation and regeneration following skeletal muscle injury in mice. Prior to muscle injury, Alox15-/- mice displayed lower intramuscular concentrations of 12/15-LOX-derived lipid mediators than wild type (WT) mice, and this was associated with chronic low-grade muscle inflammation. Alox15-/- mice mounted an exaggerated acute immune response to sterile skeletal muscle injury which was associated with a local imbalance of pro-inflammatory vs. pro-resolving lipid mediators. During the regenerative phase, Alox15-/- mice displayed defects in myogenic gene expression, myofiber size, and myonuclear accretion. Mechanistically, bone marrow-derived macrophages (MФ) obtained from Alox15-/- mice produced less 12/15-LOX-derived lipid mediators and this was associated with impaired M2 polarization. Isolated myogenic progenitor cells also produced many LOX metabolites in response to long chain polyunsaturated fatty acid (LC-PUFA) supplementation, including bioactive SPMs. Alox15-/- myoblasts were both impaired in their ability to produce SPMs and were insensitive to the stimulatory effect of LC-PUFAs on in vitro myogenesis. These data show that the 12/15-LOX pathway is essential for timely resolution of acute inflammation and direct determination of myogenic progenitor cell fate following skeletal muscle injury.
    Keywords:  Inflammation; Lipid mediators; Lipoxygenase; Macrophage; Myogenesis; Regeneration; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.molmet.2025.102224
  9. Dev Cell. 2025 Jul 31. pii: S1534-5807(25)00444-7. [Epub ahead of print]
    Sympathetic innervation maintains the murine quiescent skeletal muscle stem cell pool via perivascular-derived Angpt1.
    Alessio Rotini, Juliette Berthier, Ester Martínez-Sarrà, Gwladys Berge, Teoman Ozturk, Zeynab Koumaiha, Nathalie Didier, Sara Salucci, Olivier Stettler, Marianne Gervais, Romain K Gherardi, Peggy Lafuste, Frédéric Relaix.
      Muscle stem cells rely on their niche for maintenance, yet how β-adrenergic innervation regulates these cells remains elusive. Here, we show that sympathetic fibers in skeletal muscle innervate the vascular stem cell niche, specifically targeting β-adrenergic receptors on perivascular cells. We observe that sympathetic denervation leads to vascular remodeling and, concomitantly, reduces the muscle stem cell pool, resulting in tissue repair defects. Mechanistically, we demonstrate that sympathetic denervation reduces perivascular-derived angiopoietin-1, a crucial factor in maintaining the quiescent state of post-natal muscle stem cells. Using pharmacologic and genetic tools, we identify that sympathetic signaling drives angiopoietin-1 production from murine perivascular cells through the stimulation of their β-adrenergic receptors, thereby preserving the quiescent stem cell pool. Collectively, our data identify the molecular and cellular axis coupling skeletal muscle tissue homeostasis and regeneration to sympathetic innervation and β-adrenergic signaling, which are thus key signaling pathways that contribute to satellite cell quiescence.
    Keywords:  angiopoietin-1; pericytes; perivascular cells; skeletal muscle; stem cells; sympathetic nervous system; vascular smooth muscle; β-adrenergic signaling
    DOI:  https://doi.org/10.1016/j.devcel.2025.07.006
  10. Physiol Rep. 2025 Aug;13(15): e70497
    Transcriptomic time course of skeletal muscle disuse and rehabilitation in middle-aged adults.
    Zachary D Von Ruff, Sean P Kilroe, Erik D Marchant, Emily J Arentson-Lantz, Steven Widen, Jill Thompson, Alejandro Villasante-Tezanos, Elena Volpi, Doug Paddon-Jones, Blake B Rasmussen.
      Disuse drives rapid muscle atrophy and metabolic dysfunction. This study aimed to characterize phenotypic and transcriptomic skeletal muscle changes in middle-aged individuals during disuse and rehabilitation. Eleven healthy middle-aged adults (6 males, 5 females; age; 57 ± 5 years) underwent 7 days of unilateral lower limb suspension (ULLS). Following disuse, participants participated in a rehabilitation program consisting of either a lower-body resistance exercise (RE) or walking control (WC) three times weekly for 2 weeks. Bilateral skeletal muscle biopsies were collected at Day 0 and Day 7 of disuse and 2 h post-exercise on Days 7, 9, 11, and 21. Strength testing was conducted, and RNA sequencing was performed on muscle samples. Seven days of disuse reduced knee extension strength (14%; p < 0.05) and isometric force (13%; p < 0.05). Over-representation analysis revealed a downregulation of mRNAs related to cellular respiration and NADH dehydrogenase complex assembly. Resistance exercise induced robust, but different, transcriptional changes in both disuse- and control-legs. Walking had minimal effect on the muscle transcriptome. We conclude that 7 days of disuse reduced leg strength, decreased mitochondrial gene expression, and increased inflammation and apoptosis-related genes. We also conclude that resistance exercise enhanced recovery from disuse by improving strength, associated with significant transcriptomic changes.
    Keywords:  aging; disuse atrophy; resistance exercise; transcriptomics
    DOI:  https://doi.org/10.14814/phy2.70497
  11. bioRxiv. 2025 Jul 31. pii: 2025.07.28.667277. [Epub ahead of print]
    SkeletAge: Transcriptomics-based Aging Clock Identifies 26 New Targets in Skeletal Muscle Aging.
    Muhammad Ali, Fei Li, Manpreet Katari.
      Identifying the set of genes that regulate baseline healthy aging - aging that is not confounded by illness - is critical to understating aging biology. Machine learning-based age-estimators (such as epigenetic clocks) offer a robust method for capturing biomarkers that strongly correlate with age. In principle, we can use these estimators to find novel targets for aging research, which can then be used for developing drugs that can extend the healthspan. However, methylation-based clocks do not provide direct mechanistic insight into aging, limiting their utility for drug discovery. Here, we describe a method for building tissue-specific bulk RNA-seq-based age-estimators that can be used to identify the ageprint . The ageprint is a set of genes that drive baseline healthy aging in a tissue-specific, developmentally-linked fashion. Using our age estimator, SkeletAge, we narrowed down the ageprint of human skeletal muscles to 128 genes, of which 26 genes have never been studied in the context of aging or aging-associated phenotypes. The ageprint of skeletal muscles can be linked to known phenotypes of skeletal muscle aging and development, which further supports our hypothesis that the ageprint genes drive (healthy) aging along the growth-development-aging axis, which is separate from (biological) aging that takes place due to illness or stochastic damage. Lastly, we show that using our method, we can find druggable targets for aging research and use the ageprint to accurately assess the effect of therapeutic interventions, which can further accelerate the discovery of longevity-enhancing drugs.
    DOI:  https://doi.org/10.1101/2025.07.28.667277
  12. Sci Rep. 2025 Aug 07. 15(1): 28874
    Screening and identification of muscle pericyte selective markers.
    Jingsong Ruan, Minkyung Kang, Rong Wang, Wanling Xuan, Feng Cheng, Yao Yao.
      Pericytes, which share markers with smooth muscle cells (SMCs), are heterogenous cells. Pericytes in the brain and skeletal muscle have different embryonic origins, representing distinct subpopulations. One challenge in the field is that there are no subpopulation-specific pericyte markers. Here, we compared the transcriptomes of muscle pericytes and SMCs, and identified 741 muscle pericyte-enriched genes and 564 muscle SMC-enriched genes. Gene ontology analysis uncovered distinct biological processes and molecular functions in muscle pericytes and SMCs. Interestingly, the Venn diagram revealed only one gene shared by brain and muscle pericytes, suggesting that they are indeed distinct subpopulations with different transcriptional profiles. We further validated that GSN co-localized with PDGFRβ+SMA- cells in small and large blood vessels but not PDGFRβ+SMA+ cells, indicating that GSN predominantly marks pericytes and fibroblasts rather than SMCs in skeletal muscle. Negligible levels of GSN were detected in the brain. These findings indicate that GSN may serve as a selective marker for muscle pericytes.
    Keywords:  Genetic tool; PDGFRβ; Pericytes; SM22α; Smooth muscle cells
    DOI:  https://doi.org/10.1038/s41598-025-14225-3
  13. Redox Biol. 2025 Aug 05. pii: S2213-2317(25)00321-0. [Epub ahead of print]86 103808
    Age-related declines in mitochondrial Prdx6 contribute to dysregulated muscle bioenergetics.
    Jose Adan Arevalo, Dianna Xing, Roberto Garcia Leija, Max A Thorwald, Diana Daniela Moreno-Santillán, Kaitlin N Allen, Giovanna Selleghin-Veiga, Heidi C Avalos, Eva Utke, Justin L Conner, George A Brooks, José Pablo Vázquez-Medina.
      An age-related decline in mitochondrial function is a multi-factorial hallmark of aging, driven partly by increased lipid hydroperoxide levels that impair mitochondrial respiration in skeletal muscle, leading to atrophy. Although pharmacological and genetic manipulations to counteract increased lipid hydroperoxide levels represent a promising strategy to treat sarcopenia, the mechanisms driving such phenotypes remain understudied. Peroxiredoxin 6 (Prdx6) is a multifunctional enzyme that contributes to peroxidized membrane repair via its phospholipid hydroperoxidase and phospholipase A2 activities. Here, we show decreased mitochondrial Prdx6 levels, increased mitochondrial lipid peroxidation, and dysregulated muscle bioenergetics in aged mice and muscle cells derived from older humans. Mechanistically, we found that Prdx6 supports optimal mitochondrial function and prevents mitochondrial fragmentation by limiting mitochondrial lipid peroxidation via its membrane remodeling activities. Our results suggest that age-related declines in mitochondrial Prdx6 contribute to dysregulated muscle bioenergetics, thereby opening the door to therapeutic modulation of Prdx6 to counteract diminished mitochondrial function in aging.
    DOI:  https://doi.org/10.1016/j.redox.2025.103808
  14. Sci Rep. 2025 Aug 08. 15(1): 27825
    Combined stimuli of elasticity and microgrooves form aligned myotubes that characterize slow twitch muscles.
    Hiroki Hamaguchi, Tomoko G Oyama, Kotaro Oyama, Yasuko Manabe, Nobuharu L Fujii, Mitsumasa Taguchi.
      Skeletal muscles are classified into slow-twitch muscles composed primarily of type I and IIa fibers with high oxidative metabolism, and fast-twitch muscles composed of type IIx and IIb fibers with high glycolytic metabolism. Fiber-type shifts occur during development and aging; however, the stimuli that shift these types remain unclear. We analyzed the role of mechanical stimuli in myotube formation and shift to the characteristics of each fiber type using crosslinked gelatin gels with tunable elastic moduli (10-230 kPa) and microgrooves (3-50 µm). C2C12 myotubes on 10 kPa gel increased the expression of marker genes for type I and IIa fibers (MYH7 and MYH2) and oxidative metabolism (GLUT4 and myoglobin) than those on stiffer gels. Upregulation of PGC-1α on soft gel induced a shift toward slow-twitch muscle genetic characteristics. Microgrooves (3-10 µm) enhanced myoblast differentiation and myotube orientation, without affecting the gene expressions characterizing fiber types. This study demonstrated an approach to create highly oriented slow-twitch muscle models by controlling the elasticity and microgrooves.
    DOI:  https://doi.org/10.1038/s41598-025-12744-7
  15. Front Biosci (Landmark Ed). 2025 Jul 28. 30(7): 40141
    Cold Stress Regulates Muscle Development and Promotes Muscle Fiber Transformation by Regulating Mib1/Notch Pathway.
    Minxing Zheng, Jiahui Qi, Xuanjing Wang, Tingting Fu, Ziqi Chang, Tong Zhao, Yaqin Sun, Jiayin Lu, Yi Yan, Haidong Wang.
       BACKGROUND: In mammals, skeletal muscle typically constitutes approximately 55% of body weight. The thermogenesis of skeletal muscle increases with increased cold stress, and skeletal muscle maintains the animal's body temperature through the heat generated by shivering. However, less attention has been paid to investigating the impact of cold stress on the fiber type makeup of skeletal muscle, especially the gastrocnemius. Consequently, this research explored how cold stress regulates muscle development and fiber type composition.
    METHODS: A cold stress model was established by subjecting mice to a 4 °C environment for 4 hours daily. This model was combined with an in vitro siRNA-mediated knockdown model for joint validation. The impact of cold stress on skeletal muscle development and myofiber type transformation was assessed using experimental techniques, including immunofluorescence and western blotting.
    RESULTS: Following cold stress, the expression level of Myosin Heavy Chain 7 (MYH7) in the mouse gastrocnemius increased, while Myosin Heavy Chain 4 (MYH4) expression decreased. Concurrently, elevated expressions of Mindbomb-1 (Mib1) and the myogenic differentiation (MyoD) were observed. Subsequent knockdown of Mib1 in C2C12 cells resulted in increased MYH4 expression and decreased MYH7 expression.
    CONCLUSION: Cold stress induces skeletal muscle fibers to shift from fast-twitch to slow-twitch through the Mib1/Notch signaling pathway.
    Keywords:   Mib1 gene; Notch signaling pathway; cold stress; muscle development; muscle fiber types; skeletal muscle
    DOI:  https://doi.org/10.31083/FBL40141
  16. J Cachexia Sarcopenia Muscle. 2025 Aug;16(4): e70031
    Voluntary Activity Wheel Running Improves Hyperammonaemia-Induced Skeletal Muscle Molecular and Metabolic Perturbations in Mice.
    Annette Bellar, Avinash Kumar, Khaviyaa Chandramohan, Saurabh Mishra, Muaz Alsabbagh-Alchirazi, Artem Astafev, Pugazhendhi Kannan, Amy Attaway, Roman Kondratov, Thomas Jaramillo, Lopa Mishra, Takhar Kasumov, Nicole Welch, Srinivasan Dasarathy.
       AIM: Voluntary exercise improves clinical outcomes in healthy subjects, but increased muscle ammoniagenesis may limit beneficial responses during hyperammonaemia in chronic diseases. Responses to 4-weeks voluntary wheel running (VWR) were compared with usual activity (UA) to determine if hyperammonaemia alters VWR responses and if VWR alters muscle responses to hyperammonaemia.
    METHODS: Eight- to 10-week-old male C57BL/6J mice were treated with 6 weeks of subcutaneous infusion of 2.5 mmol kg-1 day-1 ammonium acetate (AmAc) or vehicle (PBS) via an osmotic pump. Two weeks after the start of infusion, mice were assigned to the intervention (VWR or UA). Wheel runs were measured, and weekly average rotations, distance, and circadian patterns were analysed. Indirect calorimetry was performed pre- and post-intervention. Mice were euthanized 4 weeks after the start of VWR/UA, and organs (including muscles) were harvested, weighed, and muscle histomorphometry performed for fibre diameter/type. Protein synthesis by ex vivo puromycin incorporation, autophagy markers, expression of signalling proteins (mTORC1 pathway, eukaryotic initiation factor-2-α phosphorylation), and ammonia disposal enzymes were quantified by immunoblots. Mitochondrial oxidative function was measured by high-sensitivity respirofluorometry using substrate, uncoupler, inhibitor, and titration protocols. Fluorometric assays were done for ammonia measurements.
    RESULTS: Gastrocnemius muscle mass (p < 0.01), muscle fibre area (p < 0.01), and grip strength were lower in AmAc-UA than in PBS-UA mice and higher with VWR than UA in AmAc mice (p < 0.001). Expression of electron transport chain proteins and some components of mitochondrial oxidative function were less (p < 0.05 or less) in AmAc-UA than PBS-UA, and these perturbations were reversed in the AmAc-VWR mice (p < 0.05 or less). Global muscle protein synthesis (p < 0.05) and components of the mTORC1 pathway expression (p < 0.05) were higher, while myostatin expression was lower with VWR than UA in AmAc mice (p < 0.05). Expression of autophagy markers P62 and LC3-II was not different with VWR or UA in AmAc mice, while Beclin1 was higher in VWR compared with UA, regardless of treatment group (p < 0.001). Expression of muscle ammonia disposal pathway enzymes, including glutamate dehydrogenase and pyrroline-5-carboxylate synthase, was higher (p ≤ 0.05) in AmAc-UA versus PBS-UA and increased in only PBS-VWR mice (p < 0.05).
    CONCLUSION: VWR reverses hyperammonaemia-induced sarcopenia, protein synthesis/autophagy signalling perturbations, and mitochondrial oxidative dysfunction. Muscle mass, grip strength, signalling, and mitochondrial responses to VWR were not affected by hyperammonaemia. Increased expression of enzymes involved in the ammonia disposal pathway in skeletal muscle may be an adaptive response to hyperammonaemia. These data provide the rationale for exercise programmes in chronic diseases, including cirrhosis, even with hyperammonaemia.
    Keywords:  exercise; hyperammonaemia; mitochondrial function; sarcopenia; voluntary wheel running
    DOI:  https://doi.org/10.1002/jcsm.70031
  17. Cell Rep. 2025 Aug 05. pii: S2211-1247(25)00868-X. [Epub ahead of print]44(8): 116097
    Multi-dimensional metabolomic remodeling under diverse muscle atrophic stimuli in vivo.
    Mamoru Oyabu, Tomoki Sato, Runa Kawaguchi, Kiyoshi Yoshioka, Naoki Ito, Takahiro Eguchi, Hitoshi Gotoh, Tatsuya Yoshizawa, Yoshihiro Ogawa, Yusuke Ono, Shinji Miura, Yasutomi Kamei.
      Muscle wasting leads to reduced activities of daily living, an increased number of care-dependent individuals, and increased mortality. However, the metabolomic adaptations underlying muscle wasting remain poorly understood. Here, by comparing physiological, genetically induced, pathological, and age-related muscle atrophy, we identify the metabolites modulated by muscle atrophic stimuli, which we term "atrometabolites." Integrated metabolomics reveal that dysfunctional polyamine synthesis is a common feature of muscle atrophy. Mechanistically, we identify that adenosylmethionine decarboxylase 1 (Amd1) and Amd2 are important for maintaining polyamine metabolism and that downregulation of Amd1 and Amd2 is a trigger of myotube atrophy. Using skeletal muscle-specific FoxO triple-knockout mice, we find that FoxOs are required for immobilization-induced metabolomic remodeling and identify FoxO-dependent atrometabolites. This study comprehensively elucidates the molecular basis of muscle metabolomic adaptation and provides the datasets that will lead to the discovery of mechanisms underlying tissue adaptation to maintain homeostasis.
    Keywords:  Amd; CE-TOFMS; CP: Metabolism; FoxO triple knockout; atrometabolite; cancer cachexia; metabolic elasticity; metabolomic analysis; muscle atrophy; polyamine; sarcopenia
    DOI:  https://doi.org/10.1016/j.celrep.2025.116097
  18. Exp Physiol. 2025 Aug 08.
    In vitro muscle contraction: A technical review on electrical pulse stimulation in C2C12 cells.
    Mark R C van de Meene, Anita M van den Hoek, Roeland Hanemaaijer, Lars Verschuren, Jelle C B C de Jong.
      Electrical pulse stimulation (EPS) of skeletal muscle cells is increasingly used to model exercise In vitro. The murine C2C12 myotube system has become a common platform for such studies, yet wide variability in EPS protocols hampers reproducibility and cross-study comparisons. In this technical review, we analysed 54 peer-reviewed studies that employed EPS in C2C12 and extracted used EPS protocols to provide an overview of the most commonly used settings for the EPS parameters (pulse duration, frequency, voltage and stimulation duration). Additionally, we summarized the biological processes investigated in these studies to illustrate the range of research topics typically addressed using this model. The majority of studies used 2 ms pulses at 1 Hz and moderate voltages (10-20 V), often over 24 h of stimulation. Glucose uptake was the most commonly assessed endpoint, followed by AMPK activation, inflammation and mitochondrial adaptations. Correlation analyses revealed interdependence between pulse duration, voltage and EPS duration, indicating that these parameters are often balanced to avoid excessive or suboptimal stimulation. While frequency was largely standardized, voltage and pulse duration showed greater variation. Our findings underscore the need for more detailed parameter reporting and deliberate protocol design aligned with specific experimental objectives, such as mimicking endurance- or resistance-type exercise stimuli. This review serves as a resource for selecting EPS parameters tailored to specific biological processes and encourages standardization to improve translational relevance.
    Keywords:  EPS settings; contraction; electrostimulation; exercise; in vitro model; muscle; myotubes; translational
    DOI:  https://doi.org/10.1113/EP092677
  19. bioRxiv. 2025 Jul 27. pii: 2025.07.23.666188. [Epub ahead of print]
    Response of UBR-box E3 ubiquitin ligases and protein quality control pathways to perturbations in protein synthesis and skeletal muscle size.
    Leslie M Baehr, Luis Gustavo Oliveira de Sousa, Craig A Goodman, Adam P Sharples, David S Waddell, Sue C Bodine, David C Hughes.
      The N-degron pathway contributes to proteolysis by targeting N-terminal residues of destabilized proteins via E3 ligases that contain a UBR-box domain. Emerging evidence suggests the UBR-box family of E3 ubiquitin ligases (UBR1-7) are involved in the positive regulation of skeletal muscle mass. The purpose of this study was to explore the role of UBR-box E3 ubiquitin ligases under enhanced protein synthesis and skeletal muscle growth conditions. Cohorts of adult male mice were electroporated with constitutively active Akt (Akt-CA) or UBR5 RNAi constructs with a rapamycin diet intervention for 7 and 30 days, respectively. In addition, the UBR-box family was studied during the regrowth phase post nerve crush induced inactivity. Skeletal muscle growth with Akt-CA or regrowth following inactivity increased protein abundance of UBR1, UBR2, UBR4, UBR5 and UBR7. This occurred with corresponding increases in Akt-mTORC1/S6K and MAPK/p90RSK signaling and protein synthesis. The increases in UBR-box E3s, ubiquitination, and proteasomal activity occurred independently of mTORC1 activity and were associated with increases in markers related to autophagy, ER-stress, and protein quality control pathways. Finally, while UBR5 knockdown (KD) evokes atrophy, it occurs together with hyperactivation of mTORC1 and protein synthesis. In UBR5 KD muscles, we identified an increase in protein abundance for UBR2, UBR4 and UBR7, which may highlight a compensatory response to maintain proteome integrity. Future studies will seek to understand the role of UBR-box E3s towards protein quality control in skeletal muscle plasticity.
    New and Noteworthy: Novel UBR-box E3 ubiquitin ligases are responsive to heightened protein synthesis and alterations in skeletal muscle mass and fiber size, in order to maintain proteome integrity.
    DOI:  https://doi.org/10.1101/2025.07.23.666188
  20. Sci Rep. 2025 Aug 05. 15(1): 25770
    P-Rex2 suppresses glucose uptake into liver and skeletal muscle through different adaptor functions.
    Elpida Tsonou, Julia Y Chu, Polly A Machin, Anna G Roberts, Anne Segonds-Pichon, David Baker, David C Hornigold, Heidi C E Welch.
      P-Rex2 is a Rac guanine-nucleotide factor (Rac-GEF) that controls glucose homeostasis. This role is thought to be mediated through its adaptor function inhibiting Pten rather than through its Rac-GEF activity, but this remains to be demonstrated. To examine this question, we have investigated the roles of P-Rex2 in glucose homeostasis using Prex2-/- and catalytically-inactive Prex2GD mice. We show that P-Rex2 is required for insulin sensitivity but limits glucose clearance, suppressing glucose uptake into liver and skeletal muscle independently of its catalytic activity. In hepatocytes, P-Rex2 suppresses Glut2 cell surface levels, mitochondrial membrane potential and mitochondrial ATP production. We identify the orphan GPCR Gpr21 as a P-Rex2 target and propose that P-Rex2 limits hepatic glucose clearance by controlling Gpr21 trafficking. In skeletal muscle cells, P-Rex2 suppresses glucose uptake through a separate adaptor function, independently of Gpr21. Additionally, P-Rex2 suppresses insulin secretion by pancreatic islets and plasma insulin levels. Finally, P-Rex2 plays distinct Rac-GEF activity dependent and independent roles in PIP3 production in liver and skeletal muscle, respectively. Together, our study identifies complex roles of P-Rex2 in glucose homeostasis, mediated through largely GEF-activity independent mechanisms which include the GPCR Gpr21 in hepatocytes and but are not obviously linked to the regulation of Pten.
    Keywords:  G protein-coupled receptor (GPCR); Glucose homeostasis; Gpr21; Guanine-nucleotide exchange factor (GEF); Liver; Mitochondria; P-Rex1; P-Rex2; Skeletal muscle
    DOI:  https://doi.org/10.1038/s41598-025-01720-w
  21. Front Immunol. 2025 ;16 1575712
    FBXL3 serves as a suppressor of regenerative myogenesis.
    Wei He, Shiyuan Han, Yanming Wu, Min Chen, Ting Xue, Hua You, Ying Chang, Song-Bai Liu, Yi Sun, Yinjiang Tang, Xinghong Shi, Xingyu Han, Zixin Ma, Panting Qian, Sha Geng, Chaofan Wu, Yating Liang, Yangxin Li, Yan Xu, Yao-Hua Song.
      Muscle regeneration hinges on the proliferation and differentiation of satellite cells. FBXL3, a member of the F-box protein family known for its role as a negative regulator of the circadian clock, is implicated in myogenesis. In this study, we demonstrate the expression of FBXL3 in satellite cells of adult mice, where it acts as a negative regulator of myogenic regeneration. This regulation occurs through the promotion of ubiquitination and degradation of TCF12, a transcription factor crucial for differentiation. Loss of FBXL3 activates MyoD and myogenin, thereby augmenting myogenic differentiation and regeneration. The role of FBXL3 in muscle regeneration was also confirmed using the tamoxifen-inducible Pax7-CreER recombination system. To unravel the regulatory mechanism of MyoD and myogenin by FBXL3, we conducted RNA sequencing on Fbxl3+/+ and Fbxl3-/- primary myoblasts. Gene set enrichment analysis (GSEA) revealed that FBXL3 deficiency enriches the gene set associated with striated muscle cell development, including MEF2C, a regulator of myogenin expression. Through a search in the ChEA3 database, TCF12 emerged as the downstream candidate gene regulated by FBXL3 to modulate MEF2C. ChIP-PCR assays confirmed the enrichment of TCF12 on MEF2C promoter at three consensus sites. Dual-luciferase reporter assay validated that TCF12 activates the MEF2C promoter. This comprehensive study underscores the crucial role of FBXL3 in satellite cell-mediated myogenic regeneration and provides insights into the intricate regulatory network involving TCF12 and MEF2C.
    Keywords:  FBXL3; differentiation; muscle; regeneration; satellite cell
    DOI:  https://doi.org/10.3389/fimmu.2025.1575712
  22. J Appl Physiol (1985). 2025 Aug 04.
    Altered Acute Metabolic Response to Muscle Stimulation in Muscular Dystrophic Mice Observed by Phosphorus-31 Magnetic Resonance Spectroscopy and Fingerprinting.
    Kihwan Kim, Yudu Li, Lauren G Koch, Zhi-Pei Liang, Xin Yu.
      Duchenne muscular dystrophy (DMD) is a genetic disorder characterized by progressive muscle degeneration. Impaired muscle metabolism has been implicated in DMD, and interventions aimed at normalizing and enhancing metabolic function, such as exercise, have been proposed as potential therapeutic strategies. However, the metabolic response to exercise in DMD remains incompletely understood. This study aimed to investigate the acute metabolic response to muscle stimulation mimicking high-intensity exercise. Using phosphorus-31 magnetic resonance spectroscopy (31P-MRS) and fingerprinting (31P-MRSF), changes in phosphocreatine (PCr) recovery rate and creatine kinase (CK) shuttle activity following repeated muscle stimulation were quantified in mdx mice, a well-established mouse model of DMD. The impact of muscle degeneration and aging was assessed by comparing mdx and control mice in two age groups: young (10-12 weeks) and adult (20-22 weeks). Young control mice exhibited a significant increase in PCr recovery rate and CK rate constant following muscle stimulation, indicating a positive acute metabolic adaptation. In contrast, mdx mice showed no increase in PCr recovery rate and an attenuated increase in CK rate constant, suggesting compromised mitochondrial function and CK shuttle efficiency. These findings indicate that muscle degeneration in DMD impairs acute metabolic response to high-intensity muscle contractions, potentially limiting exercise-induced metabolic benefits. Furthermore, this study demonstrates the utility of 31P-MRS and 31P-MRSF as noninvasive tools to assess muscle metabolism and exercise response in vivo.
    Keywords:  Duchenne muscular dystrophy; creatine kinase; exercise; metabolic function; phosphorus-31 magnetic resonance spectroscopy
    DOI:  https://doi.org/10.1152/japplphysiol.00185.2025
  23. Sci Rep. 2025 Aug 07. 15(1): 28988
    The impact of exercise on skeletal muscle proteome of prediabetic subjects analyzed with data independent mass spectrometry.
    Anna Czajkowska, Łukasz Szczerbiński, Marcin Czajkowski, Anna Citko-Rojewska, Paulina Konopka, Agnieszka Blachnio-Zabielska, Adam Krętowski, Piotr Zabielski.
      Physical exercise of even a moderate intensity is beneficial in both the prevention of prediabetes and management of Type 2 diabetes mellitus, as skeletal muscle is a primary tissue responsible for glucose uptake. Exercise-evoked proteomic alterations in muscle of subjects with prediabetes are of great importance for the study of relationships between insulin resistance and exercise. Although data-dependent (DDA) proteomic analysis is a cornerstone of deep proteome profiling employed in the elucidation of skeletal muscle biology, data-independent (DIA) approaches gain popularity in the studies focused on data reproducibility and throughput. We compared various ion-chromatogram libraries assembled with the use of off-line high-pH fractionation (HpH), gas-phase fractionation (GPF) and libraryless DirectDIA in LC/MS/HRMS DIA proteomic analysis of muscle from normoglycemic (NGT) and prediabetic (IGT) subjects after 3 months of supervised, mixed-mode exercise. In our hands, GPF-fractionated, hybrid DDA/DIA libraries yielded the best overall balance between the speed of preparation, data collection and protein identification among tested approaches. Analysis revealed, that despite 3-month exercise intervention skeletal muscle from IGT subjects displayed significant alterations in pathways and molecules relevant to muscle contraction, extracellular matrix composition and protein synthesis as compared to NGT counterparts. In conclusion, our study underlines the importance of the ion library assembly in the DIA analysis of clinical samples and confirms at molecular level changes connected with deficiency of muscle function in the prediabetic state.
    DOI:  https://doi.org/10.1038/s41598-025-13942-z
  24. J Hum Genet. 2025 Aug 06.
    Molecular genetics of skeletal muscle channelopathies.
    Tomoya Kubota, Masanori P Takahashi.
      Skeletal muscle channelopathies are genetic disorders associated with variants in genes encoding ion channels and related proteins expressed in skeletal muscle. Most commonly, these involve genes encoding voltage-gated ion channels (VGICs) that regulate sarcolemmal excitability, including CLCN1 for ClC-1, SCN4A for the Nav1.4 α subunit, CACNA1S for the Cav1.1 α subunit, and KCNJ2 for Kir2.1. Skeletal muscle channelopathies primarily manifest with two clinical symptoms: myotonia, characterized by delayed muscle relaxation, and paralysis and classified into two disease types: non-dystrophic myotonia and periodic paralysis. Recent advances in the clinical application of next-generation sequencing have improved diagnostic rate and provided epidemiological evidence of the diseases. Furthermore, atypical phenotypes have been identified, indicating that skeletal muscle channelopathies present a broad clinical spectrum. This review provides an updated overview of the clinical and genetic aspects of skeletal muscle channelopathies and discusses key issues that require further investigation.
    DOI:  https://doi.org/10.1038/s10038-025-01370-w
  25. Metabolism. 2025 Aug 07. pii: S0026-0495(25)00230-6. [Epub ahead of print]172 156361
    Exercise training increases skeletal muscle sphingomyelinases and affects mitochondrial quality control in men with type 2 diabetes.
    Mona Hendlinger, Lucia Mastrototaro, Marten Exterkate, Maria Apostolopoulou, Yanislava Karusheva, Geronimo Heilmann, Polina Lipaeva, Klaus Straßburger, Sofiya Gancheva, Sabine Kahl, Michael Roden.
      Lipotoxic ceramides (CERs) are implicated in the development of insulin resistance, type 2 diabetes (T2D) and related complications. Exercise training improves insulin sensitivity, potentially via reducing intracellular lipids or enhancing mitochondrial oxidation. Acid sphingomyelinase (ASM), which hydrolyzes sphingomyelin (SM) to CERs, is crucial for muscle repair and development, yet its role in insulin-resistant states and response to exercise remain unclear. We assessed ASM protein and activity, neutral sphingomyelinase (NSM) and sphingolipid species in skeletal muscle of insulin-sensitive (IS, n = 12), insulin-resistant (IR, n = 11) and T2D men (n = 20), before and after a 12-week high-intensity interval training (HIIT). Comprehensive phenotyping comprised hyperinsulinemic-euglycemic clamps, spiroergometry, targeted lipidomics and assessment of markers of mitochondrial quality control. ASM protein was lower at baseline and increased after HIIT only in T2D (p < 0.05), while ASM activity rose across all groups (IS p < 0.01; IR and T2D p < 0.001). HIIT also increased NSM protein in all groups (p < 0.05). Despite lower baseline SM levels in T2D, HIIT led to elevated CERs species in T2D (C16:0, C20:0, C22:0, C24:1, C24:0) and in IR (C16:0, C20:0) (all p < 0.05). Regression analysis suggested that changes in ASM protein and activity relate to changes in mitochondrial fusion and fission as well as AMP-activated protein kinase (AMPK)-mediated mitophagy. In conclusion, HIIT induces expression of both ASM and NSM and alters CER profiles in insulin-resistant skeletal muscle, independently of changes in insulin sensitivity. ASM could therefore rather contribute to exercise-induced mitochondrial remodeling than driving lipotoxicity, warranting further investigation of ASM as a potential target for exercise mimetic therapies.
    Keywords:  Ceramides; High-intensity interval training; Insulin resistance; Mitochondrial quality control; Sphingomyelinases; Type 2 diabetes
    DOI:  https://doi.org/10.1016/j.metabol.2025.156361
  26. Pflugers Arch. 2025 Aug 05.
    Ryanodine receptor stabilizer S-107 rescues slow-type rat soleus muscle function after 7-day hindlimb unloading.
    Daria A Sidorenko, Roman O Bokov, Gleb V Galkin, Natalia A Vilchinskaya, Sergey A Tyganov, Irina D Lvova, Boris S Shenkman, Timur M Mirzoev, Kristina A Sharlo.
      During periods of muscle disuse, calcium accumulates in the myoplasm of slow-tonic muscle fibers, leading to multiple negative consequences for muscle function. Leaky ryanodine receptors (RyRs) could contribute to this excessive accumulation of calcium. We hypothesized that the administration of S-107, a stabilizer of RyRs, would reduce the accumulation of calcium in the myoplasm/mitochondria and improve rat soleus muscle function during disuse. Male Wistar rats underwent 7 days of hindlimb suspension (HS), receiving S-107 in their food daily throughout the experiment. Seven days of HS led to cytosolic and mitochondrial calcium accumulation, enhanced mitochondrial respiration, and reduced mitochondrial biogenesis in the soleus muscle. This was accompanied by reductions in the proportion of slow-type myofibres, maximal isometric force, and fatigue resistance. Administering S-107 during HS prevented the accumulation of calcium in the mitochondria and the overactivation of mitochondrial respiration. It also attenuated the decline in markers of mitochondrial biogenesis and the decrease in fatigue resistance. S-107 treatment also partially prevented the decline in the soleus muscle force production but had only a minor effect on myoplasmic calcium accumulation. Our findings suggest that the destabilization of RyRs during muscle disuse leads to an accumulation of calcium in both the mitochondria and the myoplasm, which in turn causes a decline in muscle strength and resistance to fatigue.
    Keywords:  Calcium leakage; Hind limb suspension; Mitochondria; Muscle disuse
    DOI:  https://doi.org/10.1007/s00424-025-03108-1
  27. bioRxiv. 2025 Jul 29. pii: 2025.07.23.666431. [Epub ahead of print]
    MRI-based 3D Estimation of Skeletal Muscle Architecture and Strain during Contraction.
    Roberto A Pineda Guzman, Carly A Lockard, Xingyu Zhou, Evelyn Bombard, Crystal Coolbaugh, Mariana E Kersh, Bruce M Damon, Melissa T Hooijmans.
      Skeletal muscle generates forces that drive the motion of the human body. Three-dimensional (3D) quantification of whole-muscle architecture and strain, and their relationship during contraction is critical to understanding the mechanical function of skeletal muscle in health and disease. This has proven to be challenging, as brightness mode ultrasound is capable of measuring muscle architecture during contraction but cannot capture 3D changes in whole-muscle architecture, while Diffusion Tensor Imaging (DTI)-based tractography can measure 3D whole-muscle architecture but its use during contraction is precluded by long scan times (>5 minutes). In this study, we implement DTI-based tractography with an image registration-based approach, previously validated under passive deformation, to estimate 3D whole-muscle architecture of the tibialis anterior (TA) muscle during moderate intensity contractions (20-40% MVC). Moreover, this approach allows the measurement of whole-muscle strain during contraction, facilitating the evaluation of intramuscular relationships between architecture and strain. Our results show a decrease in the fiber-tract length, an increase in the pennation angle, and an increase in the fiber curvature of the TA during contraction. Intramuscular strain heterogeneity was observed between and within different regions of the muscle, with exploratory analyses suggesting that regional strain heterogeneity could be influenced by muscle architecture. Our results showcase the potential of MRI-based methods to obtain 3D estimates of whole-muscle architecture and strain during contraction, providing a breadth of new data that allows for new avenues of skeletal muscle biomechanical research.
    DOI:  https://doi.org/10.1101/2025.07.23.666431
  28. Muscles. 2025 Jan 09. pii: 1. [Epub ahead of print]4(1):
    Muscle Endurance Training in a Person with Friedreich's Ataxia.
    Nicole T McGarrell, Max E Green, Kevin K McCully.
      Friedreich's ataxia (FRDA) results from a faulty mitochondrial protein known as Frataxin. The purpose of this case report was to test whether skeletal muscle in FRDA can adapt to an endurance-based training program using neuromuscular electrical stimulation (NMES). A 36-year-old female with FRDA completed twelve training sessions, each lasting 30 min over 30 days, focused on the forearm muscles using NMES. Pre- and post-training session measurements of contractions, muscle-specific endurance, and muscle mitochondrial capacity were taken per training session. Training contractions increased from 4200 to 9420. Muscle-specific endurance increased by 14% at 2 Hz and 17% at 4 Hz. Muscle endurance at 6 Hz increased from 0% to 51%. The rate constant of mitochondrial capacity was 0.95 min-1 pre- and 0.99 min-1 post-training session. In conclusion, one month of NMES increased training volume and muscle-specific endurance but did not change mitochondrial capacity. Muscle adaptations to endurance training were seen in FRDA, but increased training might be needed to test if mitochondrial capacity can improve.
    Keywords:  NIRS; near-infrared spectroscopy; neuromuscular disease; neuromuscular electrical stimulation
    DOI:  https://doi.org/10.3390/muscles4010001
  29. J Appl Physiol (1985). 2025 Aug 04.
    The contralateral repeated bout effect is not caused by adaptations in skeletal muscle.
    Nao Tokuda, Koichi Himori, Yuki Ashida, Azuma Naito, Nao Yamauchi, Ayaka Niibori, Takashi Yamada.
      The repeated bout effect (RBE) refers to the phenomenon whereby the recovery of maximal voluntary contraction, a parameter considered to reflect muscle damage, is enhanced in a subsequent bout of exercise following an initial damaging bout. To investigate whether the ipsilateral RBE (IL-RBE) and contralateral RBE (CL-RBE) involve peripheral skeletal muscle adaptations, we assessed strength recovery following damaging eccentric contractions (ECCs) using supramaximal electrical stimulation to recruit all muscle fibers. Male Wistar rats were randomly assigned to one of four groups: non-damaging control (CNT), damage (DMG), IL-RBE, and CL-RBE. The plantar flexors were exposed to 100 repeated ECCs with supramaximal electrical stimulation: once in the DMG group, and twice at 2-week intervals in the IL-RBE and CL-RBE groups. In the DMG group, the maximum isometric torque (MIT) at a stimulation frequency of 100 Hz remained 30% lower than the initial value even 4 days after ECCs. This was accompanied by an increased number of Evans Blue Dye-positive fibers, activation of calpain 1, and decreased expression of excitation-contraction coupling proteins. In the IL-RBE group, membrane damage and protein degradation were almost completely prevented, and MIT returned to baseline by one day after ECCs. Conversely, the CL-RBE group did not show these beneficial effects observed in the IL-RBE group. These findings suggest that protective peripheral muscle adaptations contribute to the IL-RBE, but similar adaptations are unlikely to play a role in the CL-RBE.
    Keywords:  calpain; contralateral; eccentric contractions; ipsilateral; repeated bout effect
    DOI:  https://doi.org/10.1152/japplphysiol.00495.2025
  30. Muscles. 2023 Nov 08. 2(4): 374-388
    A Straightforward Approach to Analyze Skeletal Muscle MRI in Limb-Girdle Muscular Dystrophy for Differential Diagnosis: A Systematic Review.
    Ryo Morishima, Benedikt Schoser.
      Skeletal muscle MRI studies in limb-girdle muscular dystrophy (LGMD) have increased over the past decades, improving the utility of MRI as a differential diagnostic tool. Nevertheless, the relative rarity of individual genotypes limits the scope of what each study can address, making it challenging to obtain a comprehensive overview of the MRI image of this splintered group. Furthermore, MRI studies have varied in their methods for assessing fat infiltration, which is essential in skeletal muscle MRI evaluation. It stayed problematic and impeded attempts to integrate multiple studies to cover the core MRI features of a distinct LGMD. In this study, we conducted a systematic review of LGMD in adults published until April 2023; 935 references were screened in PubMed and EMBASE, searches of the gray literature, and additional records were added during the screening process. Finally, 39 studies were included in our final analysis. We attempted to quantitatively synthesize the MRI data sets from the 39 individual studies. Finally, we illustrated ideal and simple MRI muscle involvement patterns of six representative LGMD genotypes. Our summary synthesis reveals a distinct distribution pattern of affected muscles by LGMD genotypes, which may be helpful for a quick first-tier differential diagnosis guiding genetic diagnostics.
    Keywords:  limb-girdle muscular dystrophy; muscle dystrophies; skeletal muscle MRI; systematic review
    DOI:  https://doi.org/10.3390/muscles2040029
  31. Cell Signal. 2025 Jul 31. pii: S0898-6568(25)00452-8. [Epub ahead of print] 112037
    Pro-inflammatory cytokines as regulators of protein tyrosine phosphatases and insulin signaling in murine skeletal muscle cells.
    Vanessa Stein, Peter Geserick, Katharina Friedrich, Björn Brinschwitz, Isabell Marie Musal, Jannis Ulke, Jens Fielitz, Kai Kappert.
      Inflammatory processes can disrupt tissue homeostasis and promote metabolic disturbances, including insulin resistance. Pro-inflammatory cytokines, such as tumor necrosis factor (TNF), interleukin-1 beta (IL-1β) and interleukin-6 (IL-6), mediate this process. Since skeletal muscle is one of the major insulin-sensitive tissues, it is crucial to search for molecular links that promote insulin resistance during inflammation. Protein tyrosine phosphatases (PTPs) negatively regulate insulin signaling in multiple organs and models. To gain insight into the potential interactions of cytokines and PTPs in skeletal muscle, we characterized the effects and kinetics of cytokine stimulation on insulin signaling in murine C2C12 muscle cells. The protein level and activities of PTP non-receptor type 1 (PTPN1/PTP1B) and type 2 (PTPN2/TCPTP) were evaluated after cytokine stimulation and addressed by pharmacological inhibition or siRNA-mediated knockdown (KD). TNF, IL-1β and IL-6 elicited different kinetics and expression patterns of the respective PTPs and insulin signaling molecules, while surprisingly, insulin action was preserved. Furthermore, PTPN1 and PTPN2 had only minor effects on insulin signaling in C2C12 cells with siRNA-mediated compensatory PTP regulation. However, pan-PTP inhibition by sodium orthovanadate confirms that PTPs are negative regulators of insulin signaling. In summary, our data provide insights into the balance of the physiological and pathophysiological effects of cytokines and targeting individual PTPs to regulate insulin signaling in C2C12 cells. Additionally, our findings highlight the complex dynamics and interplay of cytokines, PTPs and metabolic pathways. This should be acknowledged when new therapeutic tools are developed to address inflammation-induced diseases such as type 2 diabetes or related comorbidities.
    Keywords:  Insulin signaling; Muscle cells; Pro-inflammatory cytokines; Protein tyrosine phosphatase, non-receptor type 1 (PTPN1); Protein tyrosine phosphatase, non-receptor type 2 (PTPN2); Protein tyrosine phosphatases (PTPs)
    DOI:  https://doi.org/10.1016/j.cellsig.2025.112037
  32. Muscles. 2024 Aug 21. 3(3): 271-286
    Hormonal Influences on Skeletal Muscle Function in Women across Life Stages: A Systematic Review.
    Chandra Shikhi Kodete, Bharadwaj Thuraka, Vikram Pasupuleti, Saiteja Malisetty.
      Skeletal muscle function is vital for locomotion, posture, and metabolism, significantly impacting overall health and preventing falls, morbidity, and mortality, especially in elderly populations. This systematic review investigates the influence of hormonal fluctuations on skeletal muscle function across different life stages in women, including adolescence, the reproductive years, and menopause. A comprehensive literature search was conducted using databases such as PubMed, Scopus, and Web of Science to identify relevant studies. This review includes 45 studies that met the inclusion criteria, examining the roles of estrogen, progesterone, and other hormones in muscle metabolism, strength, and recovery. The findings highlight significant stage-specific hormonal impacts on muscle function, revealing how puberty, menstrual cycles, pregnancy, and menopause uniquely affect muscle health. Effective hormonal and non-hormonal interventions tailored to each life stage were identified, offering insights for optimizing muscle function and health management in women. This synthesis aims to bridge the gaps in understanding the hormonal regulation of muscle function, providing a foundation for future research and guiding clinical practices.
    Keywords:  estrogen; hormonal influence; menopause; menstrual cycle; skeletal muscle function; women’s health
    DOI:  https://doi.org/10.3390/muscles3030024
  33. Gene Ther. 2025 Aug 02.
    Dystrophin/mini-dystrophin expression analysis by immunoaffinity liquid chromatography-tandem mass spectrometry after gene therapy for DMD.
    Jason Walsh, Joe Palandra, Nicole Duriga, David Beidler, Avery McIntosh, Michael Binks, Hendrik Neubert.
      Adeno-associated virus (AAV)-based gene replacement therapies in Duchenne muscular dystrophy (DMD) aim to restore dystrophin function via the introduction of micro- or mini-dystrophins. We report dystrophin and mini-dystrophin concentrations generated by immunoaffinity liquid chromatography-tandem mass spectrometry (IA-LC-MS/MS) in skeletal muscle biopsies from ambulatory participants with DMD in a phase 1b study of fordadistrogene movaparvovec, an AAV9-based gene replacement construct. The assay performed robustly for 26 months, as demonstrated by limited variability in calibration standards for peptides LLQV (dystrophin and mini-dystrophin) and LEMP (mini-dystrophin only), quality control samples consisting of spiked mini-dystrophin in DMD skeletal muscle lysate, as well as unspiked, pooled, non-dystrophic skeletal muscle lysate (normal pool). Average values for LLQV in the normal pool tested as part of clinical sample and long-term stability runs were similar to validated values. Biopsy samples showed minor or absent LLQV and absent LEMP signals pre-treatment with fordadistrogene movaparvovec infusion, but signals substantially increased at Days 60 and 360, on average. There was strong concordance in LEMP and LLQV expression change between Days 60 and 360 (R2 = 0.91; p < 0.001). IA-LC-MS/MS enables reproducible, stable, and reliable quantification of dystrophin/mini-dystrophin following fordadistrogene movaparvovec infusion. ClinicalTrials.gov identifier: NCT03362502.
    DOI:  https://doi.org/10.1038/s41434-025-00554-5
  34. Int J Biol Macromol. 2025 Aug 04. pii: S0141-8130(25)07075-8. [Epub ahead of print]321(Pt 3): 146518
    Transcription factor MAFA regulates muscle growth via calcium ion channels and receptor tyrosine kinase activation.
    Cuiyu Lai, Yang Chen, Xuewen Han, Yu Fu, Jinlin Chen, Dandan Tan, Xuesong Shan, Huaizhi Jiang.
      MAFA, a member of the large Maf transcription factor family, is known primarily for its role in regulating insulin gene expression. However, its function in non-pancreatic tissues remains largely unexplored. This study aims to investigate the role of MAFA in skeletal muscle and to elucidate the underlying molecular mechanisms. Quantitative PCR analysis showed that MAFA is highly expressed in sheep skeletal muscle, and its expression level is positively correlated with muscle mass. By integrating ChIP-Seq and RNA-Seq data from longissimus dorsi muscle, we identified that MAFA preferentially binds and regulates genes enriched in calcium signaling and receptor tyrosine kinase (RTK)-related pathways. Functional studies were conducted in primary sheep myoblasts using MAFA overexpression and siRNA-mediated knockdown. These gain- and loss-of-function assays demonstrated that MAFA promotes myoblast proliferation and inhibits differentiation. Mechanistically, MAFA upregulates STIM1 and PPP3CA, promoting intracellular Ca2+ influx. In parallel, MAFA transcriptionally activates INSR and EGFR, thereby enhancing PI3K/Akt signaling and inducing phosphorylation-dependent nuclear exclusion of FOXO3, a key catabolic transcription factor. These findings suggest that MAFA may play an important regulatory role in skeletal muscle development through calcium- and RTK-mediated signaling pathways, offering new insights into muscle biology and potential targets for improving livestock production and muscle-related disorders.
    Keywords:  Calcium influx; EGFR; FOXO3; INSR; MAFA; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.ijbiomac.2025.146518
  35. Metabolism. 2025 Jul 31. pii: S0026-0495(25)00228-8. [Epub ahead of print]172 156359
    Symphony of regulated cell death: Unveiling therapeutic horizons in sarcopenia.
    Jie Peng, Mi Zou, Qianmingyue Zhang, Dongcan Liu, Shuanghong Chen, Ruiying Fang, Yuan Gao, Xiaohua Yan, Liang Hao.
      Sarcopenia is a progressive musculoskeletal condition associated with aging, marked by a decline in muscle mass, strength, and performance. This condition not only compromises functional independence in older individuals but also contributes to escalating healthcare and economic burdens. Although the underlying mechanisms are complex and multifaceted, recent discoveries have emphasized the regulatory influence of multiple forms of programmed cell death-including apoptosis, ferroptosis, necroptosis, and pyroptosis-on skeletal muscle degeneration. These cell death pathways contribute to key pathological features such as muscle fiber loss, proteostasis imbalance, neuromuscular dysfunction, mitochondrial deficits, and persistent inflammation. This review synthesizes current understanding of the molecular underpinnings of regulated cell death (RCD) in sarcopenia and discusses emerging therapeutic interventions aimed at modulating these pathways. These include pharmacological agents (e.g., ferroptosis inhibitors, polyphenols), structured exercise programs (notably resistance), targeted nutritional support (e.g., amino acids, vitamin D), cell-based therapies, and gene-targeted strategies. Despite growing evidence supporting RCD as a viable therapeutic target, the interplay among different cell death modalities and the translation of mechanistic insights into clinical practice remain insufficiently understood. Advancing sarcopenia treatment will require integrated multi-omics analyses, identification of predictive biomarkers, and rigorously designed clinical studies to support personalized and effective therapeutic approaches.
    Keywords:  Ferroptosis; Muscle degeneration; Regulated cell death; Sarcopenia; Therapeutic intervention
    DOI:  https://doi.org/10.1016/j.metabol.2025.156359
  36. Mol Metab. 2025 Aug 01. pii: S2212-8778(25)00137-1. [Epub ahead of print] 102230
    Inhibition of Unc119b improves insulin sensitivity through potentiation of Rac1 activation in skeletal muscle and brown adipose tissue.
    Ayushi Mittal, Paul Buscaglia, Dhiraj Srivastava, Nikolai O Artemyev, Julien A Sebag.
       OBJECTIVE: A hallmark of type II diabetes is an impairment of the glucose transporter GLUT4 translocation to the plasma membrane of specialized cells in response to insulin. Identifying mechanisms involved in this defect is critical to developing treatments that restore insulin sensitivity. We previously identified a small molecule insulin sensitizer, C59, which improves insulin-stimulated GLUT4 translocation through binding to Unc119b, however, the role and mechanism of Unc119b-mediated regulation of GLUT4 trafficking is unknown.
    METHODS: Here we use in vitro systems and rodent models of insulin resistance with genetic manipulations of Unc119b expression to uncover the role of this protein in the regulation of glucose homeostasis.
    RESULTS: We demonstrate that Unc119b is an endogenous inhibitor of GLUT4 translocation which contributes to the development of insulin resistance in obese individuals. We show that Unc119b interacts with Rac1 and inhibits its activation by insulin, resulting in reduced GLUT4 translocation. Both the prenylated C-terminus of Rac1 and C59 bind to the same site within Unc119b, thus suggesting that C59 enhances GLUT4 translocation by interfering with the action of Unc119b on Rac1.
    CONCLUSION: Overall, this study identifies Unc119b as a critical regulator of glucose homeostasis, uncovers its role in GLUT4 trafficking and identifies the mechanism of action of a new class of insulin sensitizers.
    Keywords:  Diabetes; GLUT4 translocation; Rac1; Unc119b; glucose tolerance; insulin sensitivity
    DOI:  https://doi.org/10.1016/j.molmet.2025.102230
  37. Muscles. 2024 Nov 26. 3(4): 393-403
    Noninvasive Assessments of Mitochondrial Capacity in People with Mitochondrial Myopathies.
    Kevin K McCully, Hannah M Bossie, Fran D Kendall.
      People affected by mitochondrial myopathies (MITOs) are thought to have impaired skeletal muscle oxygenation. The aims of this study were to measure skeletal muscle mitochondrial capacity in MITO participants and able-bodied (AB) participants and evaluate the influence of muscle-specific endurance training in one MITO participant. Participants (n = 7) with mitochondrial disease and controls (n = 9) were tested (ages 18-54 years). Mitochondrial capacity (mVO2max) was measured using the rate constant of recovery of oxygen consumption (mVO2) after exercise in the forearm flexor muscles with near-infrared spectroscopy (NIRS). One MITO participant was tested before and after performing 18 forearm exercise sessions in 30 days. There were no differences between MITO and AB participants in mVO2max (MITO: 1.4 ± 0.1 min-1; AB: 1.5 ± 0.3 min-1; p = 0.29), resting mVO2 (MITO: -0.4 ± 0.2%/min; AB: -0.3 ± 0.1%/min; p = 0.23), or initial post exercise oxygen consumption rates (MITO: 4.3 ± 1.2%/min; AB: 4.4 ± 1.4%/min; p = 0.9). Exercise oxygen desaturation was greater in MITO (39.8 ± 9.7% range) than in AB (28 ± 8.8% range) participants, p = 0.02. The MITO participant who trained increased her mitochondrial capacity (58%) and muscle-specific endurance (24%) and had reduced symptoms of muscle fatigue. We found no evidence supporting in vivo impairment of forearm muscle mVO2max in genetically confirmed MITO participants. This is consistent with studies that report increased mitochondrial content, which offsets the decrease in mitochondrial function. Positive muscle adaptations to endurance training appear to be possible in people with MITOs. Characterization of study populations will be important when interpreting the relationship between in vivo mitochondrial capacity and mitochondrial disease.
    Keywords:  Kearns–Sayre syndrome; MELAS; NIRS; near-infrared spectroscopy; skeletal muscle
    DOI:  https://doi.org/10.3390/muscles3040033
  38. Geroscience. 2025 Aug 06.
    EnsembleAge: enhancing epigenetic age assessment with a multi-clock framework.
    Amin Haghani, Ake T Lu, Qi Yan, Juan Carlos Izpisua Belmonte, Pradeep Reddy, Victor Cheng, X William Yang, Nan Wang, Khyobeni Mozhui, Kevin Murach, Alejandro Ocampo, Robert W Williams, Mathias Jucker, Carina Bergmann, Jesse R Poganik, Bohan Zhang, Vadim N Gladyshev, Steve Horvath.
      Several widely used epigenetic clocks have been developed for mice and other species, but a persistent challenge remains: different mouse clocks often yield inconsistent results. To address this limitation in robustness, we present EnsembleAge, a suite of ensemble-based epigenetic clocks. Leveraging data from over 200 perturbation experiments across multiple tissues, EnsembleAge integrates predictions from multiple penalized models. Empirical evaluations demonstrate that EnsembleAge outperforms existing clocks in detecting both pro-aging and rejuvenating interventions. Furthermore, we introduce EnsembleAge HumanMouse, an extension that enables cross-species analyses, facilitating translational research between mouse models and human studies. Together, these advances underscore the potential of EnsembleAge as a robust tool for identifying and validating interventions that modulate biological aging.
    Keywords:  Aging biomarkers; Biological age; DNA methylation; EnsembleAge; Epigenetic clocks; Healthspan; Lifespan interventions; MethylGauge dataset; Mouse models; Rejuvenation; Stress response
    DOI:  https://doi.org/10.1007/s11357-025-01808-1
  39. Diabetes. 2025 Aug 04. pii: db250405. [Epub ahead of print]
    ALY688 Attenuates Iron-Induced ER Stress and Insulin Resistance via Activation of ER-Phagy.
    Khang Nguyen, Jialing Tang, Damian Gatica, Ryan C Russell, Hye Kyoung Sung, Gary Sweeney.
       ARTICLE HIGHLIGHTS: This study adds mechanistic insight to the association between excess iron and insulin resistance and identifies an effective intervention strategy. Using a cellular skeletal muscle cell model and a preclinical animal model, we show that iron elicits endoplasmic reticulum (ER) stress and impairs insulin signaling. The adiponectin receptor agonist peptide ALY688 counteracts iron-induced ER stress and maintains insulin sensitivity. Loss-of-function approaches indicated that ALY688 acts via an autophagy-dependent, and specifically ER-phagy-dependent, mechanism.
    DOI:  https://doi.org/10.2337/db25-0405
  40. Stem Cell Res Ther. 2025 Aug 02. 16(1): 419
    hUC-MSCs and derived exosomes attenuate DEX-induced muscle atrophy through modulation of estrogen signaling pathway.
    Na Li, Xiaoqin Liu, Qiong Wang, Yushu Chen, Chao Han, Chao Qu, Xin Guan, Wei Zou, Xiaomin Wang, Ang Li, Yin Zhang, Liping Zhu, Ruoyutong Du, Jing Liu, Yanfu Wang.
       BACKGROUND: Sarcopenia, a multifactorial syndrome characterized by progressive loss of skeletal muscle mass and strength, combined with impaired physical function, is associated primarily with aging but also driven by chronic inflammation, immobility, and endocrine dysregulation. It leads to increased risks of frailty, falls, and loss of independence, posing a major public health challenge for aging populations. Although human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) and their derived exosomes (MSC-Exos) have demonstrated remarkable potential in regenerative medicine, their safety and efficacy in treating sarcopenia remain unclear. To address this issue, we conducted a preclinical study to systematically evaluate their therapeutic potential and safety.
    METHODS: Male C57BL/6 J mice were treated with dexamethasone (20 mg/kg, i.p.) to induce muscle atrophy. Subsequently, bilateral intramuscular injection of hUC-MSCs (1 × 10⁶ cells/kg), exosomes (100 μg), or intraperitoneal injected of SNG162 (40 mg/kg) for two weeks. Gastrocnemius muscles were excised for histological analysis, TUNEL staining, Western blotting, RNA sequencing, and qPCR. Differentiated C2C12 myotubes were treated with 10 μM dexamethasone and co-cultured with hUC-MSCs or exosomes for 24 h. Samples were collected for qPCR, Western blot analyses and flow cytometry. EdU labeling was used to assess cell proliferation, MyHC and MDC immunofluorescence staining were employed to assess myotube morphology and autophagy levels, respectively. ELISA was used to quantify inflammatory cytokines and estrogen levels.
    RESULTS: hUC-MSCs, MSC-Exos and SNG162 improved grip strength and endurance in mice, increased the Gast muscle-to-body weight ratio without adversely affecting overall body weight, and enhanced muscle fiber cross-sectional area (CSA). Concurrently, they upregulated the expression of MyHC, Beclin-1, Bcl-2/Bax, ERα46, ERα36, ERβ and estradiol, while reducing key atrophy and inflammatory markers, including FOXO3, MAFbX, MURF1, TNF-α, IL-6, IL-1β, P62, and Caspase-3 in vitro and in vivo models. Furthermore, hUC-MSCs and MSC-Exos attenuated DEX-induced apoptosis in Gast muscles and C2C12 myotubes. Notably, MSC-Exos outperformed hUC-MSCs in promoting the proliferation and differentiation of C2C12 myotubes. Mechanistically, RNA sequencing and Western blot analysis identified the PI3K/AKT/mTOR and ERK1/2 signaling pathways as pivotal mediators of these effects.
    CONCLUSIONS: This study underscores the potential of hUC-MSCs and their derived exosomes as a novel, safe, and effective therapeutic strategies for sarcopenia, offering promising avenues for clinical application.
    Keywords:  Apoptosis; Autophagy; Dexamethasone; Exosome; Human umbilical cord-derived mesenchymal stem cells; Muscle atrophy; Sarcopenia
    DOI:  https://doi.org/10.1186/s13287-025-04328-z
  41. bioRxiv. 2025 Jul 27. pii: 2025.07.25.666815. [Epub ahead of print]
    Transcriptomic Response to Neuromuscular Electrical Stimulation in Muscle, Brain and Plasma EVs in WT and Klotho-deficient Mice.
    Catherine Anne Cavanaugh, Amanda E Moore, Nicholas Francis Fitz, Iliya Lefterov, Radosveta Koldamova.
      Neuromuscular electrical stimulation (NMES) was shown to improve motor activities and daily living. Prior studies indicated extracellular vesicles (EVs) play a role in cellular communication. Here, we evaluated transcriptomic profiles of tibialis anterior muscle, brain, and plasma-derived EVs following NMES of WT and Klotho heterozygous (Kl HET ). Muscle RNA-seq data demonstrated that in both genotypes the most upregulated functional categories were related to glucose metabolism and response to insulin with pathways uniquely affected in each genotype. There was a similarity of non-coding RNA transcriptome of plasma EVs with functional patterns suggesting response to oxygen and insulin, and long-term synaptic potentiation. Brain transcriptome showed little functional overlap between WT and Kl HET mice. In WT, brain upregulation of genes were related to blood flow and cell adhesion processes while Kl HET shows upregulation of immune function. Results indicate that similar metabolic function is impacted in the location of stimulation, but the distal impact of stimulation on the brain is associated with Klotho deficiency.
    DOI:  https://doi.org/10.1101/2025.07.25.666815
  42. Nat Aging. 2025 Aug 08.
    Sarcosine shows promise in preventing sarcopenia.
      
    DOI:  https://doi.org/10.1038/s43587-025-00954-7
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