bims-moremu Biomed News
on Molecular regulators of muscle mass
Issue of 2025–06–29
47 papers selected by
Anna Vainshtein, Craft Science Inc.
  1. Skeletal Muscle Mitochondria Contain Nuclear-Encoded RNA Species Prior to and Following Adaptation to Exercise Training in Rats.
  2. Stem Cell Aging and Rejuvenation in the Skeletal Muscle System.
  3. The role of the circadian clock in regulating mitochondrial dynamics and their impact on skeletal muscle function and metabolism.
  4. Metabolic analysis of sarcopenic muscle identifies positive modulators of longevity and healthspan in C. elegans.
  5. Microgravity accelerates skeletal muscle degeneration: Functional and transcriptomic insights from an ISS muscle lab-on-chip model.
  6. Elucidating the potential mechanism and therapeutic targets of chronic stress-induced muscle atrophy.
  7. Muscle Stem Cell Microenvironment and Functions in Muscle Regeneration.
  8. Sex-dependent and muscle-specific progression of the MYBPC1 E248K Myotrem myopathy in response to aging.
  9. Enhancing Skeletal Muscle Fiber Type Transition Through Substrate Coating Alteration in Myoblast Cell Culture.
  10. Amino acid neurotransmitters in sarcopenia and healthy aging.
  11. Multi-Omics Identification of Fos as a Central Regulator in Skeletal Muscle Adaptation to Long-Term Aerobic Exercise.
  12. Exhaustive exercise abolishes REV-ERB-α circadian rhythm and shifts the kynurenine pathway to a neurotoxic profile in mice.
  13. Chronic systemic inflammation by peptidoglycan-polysaccharide induces skeletal muscle atrophy in male and ovariectomized C57BL/6J mice.
  14. Restoration of myogenesis in ALS-myocytes through miR-26a-5p-mediated Smad4 inhibition and its impact on motor neuron development.
  15. Ablation of LAT2 Transporter Causes Intramuscular Glutamine Accumulation and Inhibition of Fasting-Induced Proteolysis.
  16. Exercise-induced mitochondrial protection in skeletal muscle of ovariectomized mice: A myogenic E2 synthesis-independent mechanism.
  17. In vivo self-renewal and expansion of quiescent stem cells from a non-human primate.
  18. Fbxl3 deletion mitigates myopathy in mdx mice through upregulation of myogenin.
  19. Regulation of Myogenesis by MechanomiR-200c/FoxO3 Axis.
  20. Sarcospan protects against LGMD R5 via remodeling of the sarcoglycan complex composition in dystrophic mice.
  21. Potential cytotoxicity of truncated slow skeletal muscle troponin T (ssTnT) in a loss of function TNNT1 myopathy mouse model.
  22. Polyalanine Expansion in PABPN1 Alters the Structure and Dynamics of Its Nuclear Aggregates in Differentiated Muscle Cells.
  23. Patterns of Circulating piRNAs in the Context of a Single Bout of Exercise: Potential Biomarkers of Exercise-Induced Adaptation?
  24. Silencing PIM1 inhibits ENO1-induced AKT activation and attenuates fibrillogenesis during spinal cord injury-induced skeletal muscle atrophy.
  25. Ghrelin ameliorates sepsis induced acute skeletal muscle wasting via hypothalamic JAK2/STAT3 -AgRP pathway.
  26. OXA1L deficiency causes mitochondrial myopathy via reactive oxygen species regulated nuclear factor kappa B signalling pathway.
  27. Assessing the composition of myofibrillar and muscle connective protein fractions within skeletal muscle tissue.
  28. Multi-Modal Analysis of Satellite Cells Reveals Early Impairments at Pre-Contractile Stages of Myogenesis in Duchenne Muscular Dystrophy.
  29. From 2D Myotube Cultures to 3D Engineered Skeletal Muscle Constructs: A Comprehensive Review of In Vitro Skeletal Muscle Models and Disease Modeling Applications.
  30. GW8510 alleviates muscle atrophy and skeletal muscle dysfunction in mice through AMPK/PGC1α signaling.
  31. Concurrent Physical Activity Protects Against C26 Adenocarcinoma Tumor-Mediated Cardiac and Skeletal Muscle Dysfunction and Wasting in Males.
  32. Senescent macrophages induce ferroptosis in skeletal muscle and accelerate osteoarthritis-related muscle atrophy.
  33. Power and Endurance: Polar Opposites or Willing Partners?
  34. Oxidative Stress in Neurodegenerative Disorders: A Key Driver in Impairing Skeletal Muscle Health.
  35. Skeletal muscle atrophy in pulmonary arterial hypertension: potential mechanisms and effects of physical exercise.
  36. Effects of 810 nm treatments in acute myofiber contraction of C2C12 myotubes.
  37. DWORF expression is reduced in a large animal model of Duchenne muscular dystrophy.
  38. Exosomal miRNAs in muscle-bone crosstalk: Mechanistic links, exercise modulation and implications for sarcopenia, osteoporosis and osteosarcopenia.
  39. Hallmarks of stem cell aging.
  40. Changes in serial sarcomere number of five hindlimb muscles across adult aging in rats.
  41. Myostatin Modulation in Spinal Muscular Atrophy: A Systematic Review of Preclinical and Clinical Evidence.
  42. Can a pill replace exercise? Swigging this molecule gives mice benefits of working out.
  43. Sarcosine decreases in sarcopenia and enhances muscle regeneration and adipose thermogenesis by activating anti-inflammatory macrophages.
  44. Stepping up to inspire in muscular dystrophy.
  45. The Human Exersome Initiative (HEI): Rationale, study design, and protocol.
  46. Vascular collapse leads to muscle wasting in cancer cachexia.
  47. Altered Expression of Cell Cycle Regulators and Factors Released by Aged Cells in Skeletal Muscle of Patients with Bone Fragility: A Pilot Study on the Potential Role of SIRT1 in Muscle Atrophy.
  1. FASEB J. 2025 Jul 15. 39(13): e70702
    Skeletal Muscle Mitochondria Contain Nuclear-Encoded RNA Species Prior to and Following Adaptation to Exercise Training in Rats.
    Jessica L Silver, Séverine Lamon, Stella Loke, Gisella Mazzarino, Larry Croft, Mark Ziemann, Megan Soria, Glenn D Wadley, Adam J Trewin.
      Skeletal muscle mitochondria adaptation to exercise training is mediated by molecular factors that are not fully understood. Mitochondria import over 1000 proteins encoded by the nuclear genome, but the RNA population resident within the organelle is generally thought to be exclusively encoded by the mitochondrial genome. However, recent in vitro evidence suggests that specific nuclear-encoded miRNAs and other noncoding RNAs (ncRNAs) can reside within the mitochondrial matrix. Whether these are present in mitochondria of skeletal muscle tissue, and whether this is affected by endurance training-a potent metabolic stimulus for mitochondrial adaptation-remains unknown. Rats underwent 4 weeks of moderate-intensity treadmill exercise training, then were humanely killed and tissues were collected for molecular profiling. Mitochondria from gastrocnemius skeletal muscle were isolated by immunoprecipitation, further purified, and then the resident RNA was sequenced to assess the mitochondrial transcriptome. Exercise training elicited typical transcriptomic responses and functional adaptations in skeletal muscle, including increased mitochondrial respiratory capacity. We identified 24 nuclear-encoded coding or noncoding RNAs in purified mitochondria, in addition to 50 nuclear-encoded miRNAs that met a specified abundance threshold. Although none were differentially expressed in the exercise vs. control group at FDR < 0.05, exploratory analyses suggested that the abundance of 3 miRNAs was altered (p < 0.05) in mitochondria isolated from trained compared with sedentary skeletal muscle. We report the presence of a specific population of nuclear-encoded RNAs in the mitochondria isolated from rat skeletal muscle tissue, which could play a role in regulating exercise adaptations and mitochondrial biology.
    Keywords:  exercise; mitochondria; skeletal muscle; transcriptome
    DOI:  https://doi.org/10.1096/fj.202500157R
  2. Rejuvenation Res. 2025 Jun 24.
    Stem Cell Aging and Rejuvenation in the Skeletal Muscle System.
    Michela Libergoli, Albert E Almada.
      Aging is an unavoidable process associated with a progressive decline of muscle mass, strength, and regenerative ability. Satellite cells are a muscle stem cell (MuSC) population that plays a key role in mammalian muscle regeneration, by awakening from quiescence and then migrating to sites of damage, expanding in number to generate progenitor cells, and then either differentiating to rebuild the muscle tissue or self-renewing to repopulate the stem cell pool. Emerging evidence suggests that the aging process impairs the activation potential and the regenerative capacity of MuSCs. This review explores some of the recent discoveries of how mis-regulation of intrinsic and extrinsic mechanisms drive the decline of MuSC function in aging muscles, and we discuss new strategies to rejuvenate aged MuSC function for regenerative medicine. Understanding these processes will speed up the development of novel therapeutics for counteracting muscle loss and improve muscle healing in the elderly.
    Keywords:  aging; muscle regeneration; muscle stem cells; niche; rejuvenation; sarcopenia
    DOI:  https://doi.org/10.1089/rej.2025.0028
  3. J Physiol. 2025 Jun 25.
    The role of the circadian clock in regulating mitochondrial dynamics and their impact on skeletal muscle function and metabolism.
    Alfonso Carriel-Nesvara, Cristóbal Muñoz-Medina, Louise Deldicque, Mauricio Castro-Sepulveda.
      Disruptions in both circadian clock and mitochondrial dynamics in the skeletal muscle (SkM) have been associated with insulin resistance and sarcopenia. Emerging evidence, in resting conditions and in response to metabolic challenges like exercise, suggests the intricate interplay between the circadian clock, mitochondrial dynamics and SkM function. However the molecular mechanisms that connect the circadian clock to mitochondrial dynamics and SkM function remain poorly understood. This review focuses on the role of circadian clock proteins, particularly brain and muscle Arnt-like protein-1 (BMAL1), in regulating mitochondrial dynamics and examines how their dysregulation contributes to metabolic and SkM deterioration. By exploring their interaction we aim to identify potential therapeutic targets that could improve metabolic health and muscle function.
    Keywords:  circadian clock; insulin resistance; metabolism; mitochondrial dynamics; sarcopenia; skeletal muscle
    DOI:  https://doi.org/10.1113/JP289019
  4. Redox Biol. 2025 Jun 14. pii: S2213-2317(25)00245-9. [Epub ahead of print]85 103732
    Metabolic analysis of sarcopenic muscle identifies positive modulators of longevity and healthspan in C. elegans.
    Steffi M Jonk, Alan Nicol, Vicki Chrysostomou, Emma Lardner, Shu-Che Yu, Gustav Stålhammar, Jonathan G Crowston, James R Tribble, Peter Swoboda, Pete A Williams.
      Sarcopenia is the age-related degeneration of skeletal muscle, resulting in loss of skeletal muscle tone, mass, and quality. Skeletal muscle is a source of systemic metabolites and macromolecules important for neuronal health, function, and healthy neuronal aging. Age-related loss of skeletal muscle might result in decreased metabolite and macromolecule availability, resulting in reduced neuronal function or increased susceptibility to unhealthy aging and neurodegenerative diseases. We aimed to identify muscle metabolite candidates that regulate healthy aging. C57BL/6J mice were aged to young adult (4 months) and old age (25 months) and skeletal muscle was collected. Age-related muscle loss was confirmed by reduced muscle mass, muscle fiber degeneration, reduced myosin intensity, in addition to a metabolic shift and increased DNA damage in skeletal muscle. Using a low molecular weight enriched metabolomics protocol, we assessed the metabolic profile of skeletal muscle from young adult and old age mice and identified 20 metabolites that were significantly changed in aged muscle. These metabolite candidates were tested in C. elegans assays of lifespan, healthspan, muscle, and mitochondrial morphology under normal and stressed conditions. We identified four metabolite candidates (beta-alanine, 4-guanidinobutanoic acid, 4-hydroxyproline, pantothenic acid) that, when supplemented in C. elegans provided robust gero- and mitochondrial protection. These candidates also affected life-, and health- span in C. elegans models of amyotrophic lateral sclerosis (ALS) and Duchenne muscular dystrophy (DMD). Our findings support that aging muscle can be used to identify novel metabolite modulators of lifespan and health and may show promise for future treatments of neurodegenerative and neuromuscular disorders.
    Keywords:  Aging; C. elegans; Metabolomics; Mitochondria; Sarcopenia
    DOI:  https://doi.org/10.1016/j.redox.2025.103732
  5. Stem Cell Reports. 2025 Jun 21. pii: S2213-6711(25)00154-7. [Epub ahead of print] 102550
    Microgravity accelerates skeletal muscle degeneration: Functional and transcriptomic insights from an ISS muscle lab-on-chip model.
    Maddalena Parafati, Zon Thwin, Legrand K Malany, Paul M Coen, Siobhan Malany.
      Microgravity accelerates skeletal muscle degeneration, mimicking aspects of aging, yet its effects on muscle cell function remain underexplored. Using a muscle lab-on-chip model onboard the International Space Station (ISS), we examined 3D-bioengineered myobundles derived from young and older adult donors under microgravity. Electrical stimulation applied intermittently to the myobundles revealed reduced contraction magnitude in microgravity and decreased protein levels of myosin heavy chain 7, a main isoform in slow-twitch muscle fibers. Transcriptomic profiling revealed active myogenesis across ground and spaceflight samples, but younger electrically stimulated myobundles displayed enhanced mitochondrial-related gene expression in microgravity, while older and non-electrically stimulated myobundles were less responsive. Comparative analysis between young and older derived myobundles identified 86 muscle-specific age-associated genes altered in microgravity, linked to inflammation, mitochondrial dysfunction, and cellular stress. These findings highlight a unique age-related molecular response in microgravity and underscores electrical stimulation as a potential countermeasure. These insights advance our understanding of muscle aging and degeneration in microgravity, guiding future therapeutic strategies.
    Keywords:  age-related muscle wasting; contractile magnitude; donor-derived primary myobundles; electrical stimulation; global transcriptomics; muscle microphysiological system; real microgravity
    DOI:  https://doi.org/10.1016/j.stemcr.2025.102550
  6. Int Immunopharmacol. 2025 Jun 20. pii: S1567-5769(25)01108-7. [Epub ahead of print]162 115118
    Elucidating the potential mechanism and therapeutic targets of chronic stress-induced muscle atrophy.
    Vipul Agarwal, Anugya Gupta, Rishabh Chaudhary, Anand Kumar.
      Skeletal muscle atrophy, while a long-standing health issue, is becoming more pressing concern in light of changing socioeconomic trends and current healthcare challenges. This shift reflects growing awareness of its widespread prevalence and significant impact on individual health. Demographic shifts like aging populations with rising sarcopenia rates, chronic diseases and sedentary lifestyles are major contributors. Skeletal muscle atrophy is characterized by increased protein breakdown and decreased protein anabolism. The incidence of skeletal muscle atrophy has increased recently. Chronic psychological or physiological stress is one of the primary lifestyle factor that causes muscle atrophy. Recent years have seen significant progress in understanding the molecular mechanisms of chronic stress and skeletal muscle atrophy. However, the specific mechanism linking chronic stress to muscle atrophy is not much explored. Literature suggests that chronic stress triggers inflammation, elevated cortisol levels, and fibrosis, causing elevated proteolysis and diminished protein synthesis, eventually leading to skeletal muscle atrophy. This review explores potential mechanisms underlying chronic stress-induced skeletal muscle atrophy. Moreover, considering severe economic and social consequences of skeletal muscle atrophy, it is critical to have effective prevention and treatment strategies, which are currently limited. Additionally, this review explores several safe and effective treatment options, for management of stress-induced muscle atrophy.
    Keywords:  Chronic Stress; Cortisol; Electroacupuncture; Exercise; Inflammation; Muscle atrophy
    DOI:  https://doi.org/10.1016/j.intimp.2025.115118
  7. Biomolecules. 2025 May 26. pii: 765. [Epub ahead of print]15(6):
    Muscle Stem Cell Microenvironment and Functions in Muscle Regeneration.
    Wenjing Li, Minyou Chen, Lingli Zhang.
      Muscle stem cells (MuSCs) are the key to muscle regeneration. The activation and maintenance of MuSCs require the precise regulation of their microenvironments. Myofibers and other cells including endothelial cells, fibroblasts, and immune cell populations constitute the cell components of the MuSC niche. The communication between these cell populations and MuSCs play an essential role in muscle repair. Furthermore, the physical and chemical stimulations around MuSCs also affect the cell behaviors of MuSCs. Extracellular matrix (ECM) and the factors stored in it generate a repair-promoting niche for efficient muscle regeneration. Understanding the mechanism of muscle stem cell regulation is the basis of clinically optimizing muscle repair. In this review, we discuss recent findings about the microenvironments of MuSCs and their functions in muscle regeneration, which would shed light on new targets and strategies for muscle injury treatment.
    Keywords:  function; microenvironment; muscle regeneration; muscle stem cells
    DOI:  https://doi.org/10.3390/biom15060765
  8. JCI Insight. 2025 Jun 26. pii: e182471. [Epub ahead of print]
    Sex-dependent and muscle-specific progression of the MYBPC1 E248K Myotrem myopathy in response to aging.
    Jennifer Megan Mariano, Humberto C Joca, Jacob G Kallenbach, Natasha Ranu, Julien Ochala, Christopher Ward, Aikaterini Kontrogianni-Konstantopoulos.
      Dominant missense mutations in MYBPC1, the gene encoding the essential sarcomeric slow Myosin Binding Protein-C (sMyBP-C), are associated with Myotrem, a new, early-onset congenital myopathy characterized by muscle weakness, hypotonia, skeletal deformities, and myogenic tremor. Importantly, the clinical manifestation of Myotrem in mid- and late adulthood is unknown. Using the Myotrem MYBPC1 E248K Knock-In (KI) murine model, we interrogated contractile performance of soleus, gastrocnemius, and Tibalis Anterior (TA) muscles in both male and female mice in mid- (12-months) and late (24-months) adulthood. Our findings showed that the phenotypic manifestation of E248K Myotrem differs across muscle-type, sex, and age. While KI soleus muscle consistently exhibited contractile impairment across both sexes and ages, KI gastrocnemius muscle displayed preserved force production. Interestingly, TA muscle showed a sex- and age-specific impact with preserved function through 12-months in both sexes and a sharp decline at 24-months solely in males. Quantitative analysis of TA sarcomeric organization uncovered structural deficits coinciding with contractile dysfunction, supporting the notion that sMyBP-C serves a primarily structural role in skeletal muscle. Collectively, our studies revealed that aging impacts the E248K Myotrem myopathy in a muscle- and sex-dependent fashion and show that sarcomeric disorganization accompanies contractile deterioration in affected muscles.
    Keywords:  Cell biology; Cytoskeleton; Muscle biology; Neuromuscular disease; Skeletal muscle
    DOI:  https://doi.org/10.1172/jci.insight.182471
  9. Int J Mol Sci. 2025 Jun 12. pii: 5637. [Epub ahead of print]26(12):
    Enhancing Skeletal Muscle Fiber Type Transition Through Substrate Coating Alteration in Myoblast Cell Culture.
    Yhusi Karina Riskawati, Chuang-Yu Lin, Akira Niwa, Hsi Chang.
      Skeletal muscle diseases often exhibit fiber-type-specific characteristics and pose substantial clinical challenges, necessitating innovative therapies. The extracellular matrix (ECM) plays a pivotal role in muscle physiology and regeneration, influencing cell differentiation. However, its specific role and mechanisms influencing muscle fiber type specification remain insufficiently understood. In this study, C2C12GFP myoblasts were differentiated into myofibers on plates coated with fibronectin, Collagen I, and Geltrex™. Differentiation occurred successfully across all ECM substrates, resulting in myofiber formation. Quantitative polymerase chain reaction (qPCR) analysis confirmed myogenic marker expression patterns, indicating decreased Pax7 and increased Myog levels by day 7. Protein analysis through Western blot and immunofluorescence assays along with transcriptomic profiling through RNA sequencing consistently indicated that Collagen I promoted slow-type fibers development, as evidenced by increased slow myofiber protein expression and the upregulation of slow fiber-associated genes, potentially mediated by pathways involving calcineurin/NFAT, MEF2, MYOD, AMPK, PI3K/AKT, and ERK1. In contrast, fibronectin and Geltrex™ led to fast-type fiber development, with elevated fast-type fiber protein levels and upregulation of fast fiber-associated genes, possibly through activation of HIF1A, FOXO1, NFKB, and ERK2. These findings elucidate ECM-mediated muscle fiber type differentiation mechanisms, informing future targeted therapies for muscle regeneration.
    Keywords:  Collagen I; Fibronectin; Geltrex™, C2C12 differentiation; muscle fiber type; transcriptomic
    DOI:  https://doi.org/10.3390/ijms26125637
  10. Brain Res Bull. 2025 Jun 20. pii: S0361-9230(25)00249-7. [Epub ahead of print]229 111437
    Amino acid neurotransmitters in sarcopenia and healthy aging.
    Steffi M Jonk, James R Tribble, Peter Swoboda, Pete A Williams.
      Sarcopenia is the age-related degeneration of skeletal muscle. Healthy skeletal muscle secretes metabolites and macromolecules that are systemically important for the immune system (e.g. myokines) and the central nervous system (e.g. BDNF). Exercise interventions to stimulate skeletal muscle are therapeutic for sarcopenia and limit risk and/or provide neuroprotection in neurodegenerative disease models. Metabolic analysis of aged skeletal muscle has identified altered skeletal muscle metabolomes at an old age. Many of the molecules identified are amino acids that also act as neurotransmitters. In this review, we summarize how 13 amino acids act as neurotransmitters or as precursor to neurotransmitters, and how these are involved in the skeletal muscle secretome, sarcopenia, and (healthy) aging.
    Keywords:  Amino acids; Metabolomics; Muscle; Neurotransmitters; Sarcopenia
    DOI:  https://doi.org/10.1016/j.brainresbull.2025.111437
  11. Biology (Basel). 2025 May 24. pii: 596. [Epub ahead of print]14(6):
    Multi-Omics Identification of Fos as a Central Regulator in Skeletal Muscle Adaptation to Long-Term Aerobic Exercise.
    Chaoyang Li, Xinyuan Zhu, Yi Yan.
      Skeletal muscle health and function are closely linked to long-term aerobic exercise, particularly in enhancing muscle metabolism and regulating gene expression. Regular endurance training can significantly ameliorate metabolic dysfunction and prevent chronic diseases. However, the precise molecular mechanisms underlying skeletal muscle adaptations to long-term aerobic exercise require further clarification. To address this, we integrated transcriptomic and single-cell omics datasets from multiple long-term aerobic exercise models retrieved from the GEO database. After merging and batch correction, differential expression analysis identified 204 DEGs, including 110 upregulated and 94 downregulated genes. Key feature genes were screened using Lasso regression, SVM-RFE, and Random Forest machine learning algorithms, validated by RT-qPCR, and refined through PPI network analysis. Among them, Fos and Tnfrsf12a were significantly downregulated following long-term aerobic exercise. Notably, Fos exhibited a more pronounced decrease than Tnfrsf12a, and was strongly associated with inflammation and muscle regeneration. PPI network analysis indicated that Fos interacted with genes such as Casp3, Egr1, Aft3, Hspa5, Src, and Igf2. GO, KEGG, and GSEA enrichment analyses revealed that Fos is involved in skeletal muscle differentiation, tissue remodeling, and the NF-κB inflammatory pathway. ssGSEA analysis further showed that samples with low Fos expression had significantly elevated Th1/Th2 and Treg cell infiltration. Single-cell analysis confirmed preferential Fos expression in muscle fiber/adipocyte progenitors, satellite cells, and tenocytes, all critical for myogenesis. In summary, our findings suggest that long-term aerobic exercise downregulates Fos, potentially alleviating inflammation and enhancing satellite cell-mediated muscle regeneration. Fos may serve as a central regulator of skeletal muscle remodeling during long-term aerobic exercise.
    Keywords:  Fos; RNA-seq; Tnfrsf12a; long-term aerobic exercise; machine learning; scRNA-seq; skeletal muscle
    DOI:  https://doi.org/10.3390/biology14060596
  12. J Physiol. 2025 Jun 24.
    Exhaustive exercise abolishes REV-ERB-α circadian rhythm and shifts the kynurenine pathway to a neurotoxic profile in mice.
    Alisson Luiz da Rocha, Ana Paula Pinto, Ivo Vieira de Sousa Neto, Vitor Rosetto Muñoz, Bruno Brieda Marafon, Lilian Eslaine Costa Mendes da Silva, José Rodrigo Pauli, Dennys Esper Cintra, Eduardo Rochete Ropelle, Fernando Moreira Simabuco, Leandro Pereira de Moura, Ellen Cristini de Freitas, Donato Americo Rivas, Adelino Sanchez Ramos da Silva.
      The circadian-regulated transcriptional repressor REV-ERB-α is a key mediator of skeletal muscle oxidative capacity, enhancing exercise performance when activated. Conversely its global genetic ablation leads to impaired performance. Simultaneously the kynurenine (KYN) pathway, involved in tryptophan degradation, produces neurotoxic metabolites under stress and inflammation, contributing to CNS dysfunction and fatigue. These mechanisms may underlie the fatigue and performance impairments caused by exhaustive exercise (EE). This study investigated the interplay between REV-ERB-α and the KYN pathway in acute and chronic EE models. Time course analyses revealed that EE downregulated REV-ERB-α in skeletal muscle, correlated with KYN pathway alterations. Notably KYN metabolism shifted towards a neurotoxic profile, characterized by reduced KYN aminotransferase 1 (KAT1) and increased KYN 3-monooxygenase (KMO) expression in skeletal muscle, with increased KYN levels in the hippocampus. In vitro experiments using C2C12 myoblasts showed that REV-ERB-α knockout upregulated KAT1 and KMO, whereas overexpression selectively reduced KMO. Pharmacological activation of REV-ERB-α with SR9009 upregulated KAT1 in skeletal muscle and reduced KMO in the hippocampus of mice. These findings reveal a dynamic relationship between REV-ERB-α and the KYN pathway, linking peripheral and central responses to EE. This study highlights REV-ERB-α and the KYN pathway as critical regulators of exercise-induced fatigue and suggests potential therapeutic targets to mitigate its effects, offering novel insights into the molecular basis of performance impairments associated with EE. KEY POINTS: Excessive exercise can impair performance and induce fatigue; however the underlying biological mechanisms remain incompletely understood. Although REV-ERB-α activation enhances skeletal muscle oxidative capacity and exercise performance, its deletion impairs both parameters. This study demonstrates that excessive exercise decreases REV-ERB-α levels in skeletal muscle and disrupts the kynurenine (KYN) pathway by downregulating KYN aminotransferase 1 (KAT1), an enzyme involved in a neuroprotective branch of the pathway. These alterations affect both skeletal muscle and the brain, suggesting a potential link between physical fatigue and brain function. REV-ERB-α suppresses KYN 3-monooxygenase (KMO), a key enzyme in the KYN pathway that promotes the formation of potentially neurotoxic metabolites, thereby revealing a novel mechanism and a potential therapeutic target.
    Keywords:  SR9009; exhaustive exercise; fatigue; kynurenine; neuromodulation
    DOI:  https://doi.org/10.1113/JP288290
  13. Physiol Rep. 2025 Jun;13(12): e70431
    Chronic systemic inflammation by peptidoglycan-polysaccharide induces skeletal muscle atrophy in male and ovariectomized C57BL/6J mice.
    Ryoga Kinoshita, Jay Jung, Sakura Hattori, Tatsuhiro Yamaguchi, Takaya Kotani, Karina Kouzaki, Yuki Tamura, Koichi Nakazato.
      Chronic systemic inflammation (CSI) induces skeletal muscle atrophy. The severity of tissue damage caused by CSI varies according to sex. However, there are still many unknowns regarding the sex differences in skeletal muscle atrophy in patients with CSI. This study aimed to determine the sex differences in CSI-induced muscle atrophy using male and female C57BL/6J mice. 12-week-old mice were divided into peptidoglycan-polysaccharide (PG-PS) (each sex, n = 9) and control groups (each sex, n = 10). In the ovariectomy (OVX) study, 8-week-old female C57BL/6J mice were divided into sham, OVX + Saline, and OVX + PG-PS groups (each group; n = 6). A single intraperitoneal injection of PG-PS or saline was administered to the mice. After 3 weeks, blood and lower leg skeletal muscles were collected. Plasma inflammatory cytokine levels were significantly increased in both sexes following PG-PS treatment. However, only male mice showed soleus muscle atrophy, decreased muscle protein synthesis (MPS), and increased apoptosis. In the OVX study, the OVX + PG-PS group exhibited soleus muscle atrophy caused by PG-PS-induced CSI. In atrophic muscles, PG-PS activated p65 and c-Jun. These findings suggest that ovarian function regulates muscle protein metabolism and suppresses CSI-induced skeletal muscle atrophy in female mice.
    Keywords:  inflammation; sex difference; skeletal muscle
    DOI:  https://doi.org/10.14814/phy2.70431
  14. Mol Ther Nucleic Acids. 2025 Sep 09. 36(3): 102581
    Restoration of myogenesis in ALS-myocytes through miR-26a-5p-mediated Smad4 inhibition and its impact on motor neuron development.
    Caterina Peggion, Raphael Severino Bonadio, Roberto Stella, Silvia Scalabrin, Laura Pasetto, Caterina Millino, Laura Camporeale, Beniamina Pacchioni, Valentina Bonetto, Alessandro Bertoli, Stefano Cagnin, Maria Lina Massimino.
      Amyotrophic lateral sclerosis (ALS) is the most common adult-onset paralytic disorder, characterized primarily by a progressive loss of motor neurons (MNs) in which degeneration skeletal muscle involvement has been demonstrated. Skeletal muscle is a plastic tissue that responds to insults through proliferation and differentiation of satellite cells. Skeletal muscle degeneration and regeneration are finely regulated by signals that regulate satellite cell proliferation and differentiation. It is known that satellite cell differentiation is impaired in ALS, but little is known about the involvement of microRNAs (miRNAs) and their role in intercellular communication in ALS. Here we demonstrated impaired differentiation of satellite cells derived from ALS mice related to the impairment of myogenic p38MAPK and protein kinase A (PKA)/pCREB signaling pathways that can be regulated by miR-882 and -134-5p. These miRNAs participate in autocrine signaling in association with miR-26a-5p that, secreted from wild-type (WT) and captured by ALS myoblasts, enhances ALS-related myoblast differentiation by repressing Smad4-related signals. Moreover, miR-26a-5p and -431-5p work in a paracrine way ameliorating motoneuron differentiation. These findings emphasize the need to better understand intercellular communication and its role in ALS pathogenesis and progression. They also suggest that miRNAs could be targeted or used as therapeutic agents for myofiber and MN regeneration.
    Keywords:  MT: non-coding RNAs; amyotrophic lateral sclerosis; cell communication; miRNA; myogenesis; neurogenesis; neuromuscular disorders; primary stem cells; skeletal muscle
    DOI:  https://doi.org/10.1016/j.omtn.2025.102581
  15. J Cachexia Sarcopenia Muscle. 2025 Jun;16(3): e13847
    Ablation of LAT2 Transporter Causes Intramuscular Glutamine Accumulation and Inhibition of Fasting-Induced Proteolysis.
    Meritxell Espino-Guarch, Susie Shih Yin Huang, Clara Vilches, Esther Prat, Rana El Nahas, Ghalia Missous, Susanna Bodoy, Abbirami Sathappan, Mohammad Ameen Al-Aghbar, Clara Mayayo, Montse Olivé, Silvia Busquets-Rius, David Sebastián, Antonio Zorzano, Manuel Palacin, Nicholas van Panhuys, Virginia Nunes.
       BACKGROUND: The neutral amino acid transporter SLC7A8 (LAT2) has been described as a key regulator of metabolic adaptation. LAT2 mutations in human populations have been linked to the early onset of age-related hearing loss and cataract growth. As LAT2 was previously found to be highly expressed in skeletal muscle, here we characterised its role in the regulation of skeletal muscle amino acid flux and metabolic adaptation to fasting.
    METHODS: Wild-type (WT) and LAT2 knock-out (LAT2KO) mice were exposed to short- and long-periods of fasting (16 and 48 h). The impact of the absence of LAT2 on amino acid content, gene expression, proteolysis activity, muscle tone, and histology was measured. To characterise the impact on muscle degradation, we tested LAT2 KO mice in cancer-associated cachexia, streptozocin-induced Type-1 diabetes, and ageing models.
    RESULTS: LAT2KO mice experienced a notable reduction in body weight during fasting (WT:14% and LAT2KO:18%, p = 0.02), with a greater reduction in fat mass (0.5-fold, p = 0.013) and a higher relative retention of muscle mass (1.3-fold, p = 0.0003) compared with WT. The absence of LAT2 led to increased intramuscular glutamine (Gln) accumulation (6.3-fold, p < 0.0001), accompanied by a reduction in skeletal muscle proteolysis during fasting (0.61-fold, p = 0.0004) primarily due to decreased proteasomal and autophagic activity (0.45-fold, p = 0.016 and 0.7-fold, p = 0.002, respectively). Ex vivo incubation of LAT2KO muscle with rapamycin recovered proteolysis function, demonstrating a mTORC1-dependent pathway. Decreased proteolysis in LAT2KO animals was associated with increased mTORC1 translocation to the lysosome (mTORC1-Lamp1 colocalization in fasted LAT2KO muscles was 1.23-fold, p < 0.0001). Of the three muscle loss models tested, differences were observed only during ageing. Young LAT2KO mice (3 M) exhibited muscle tone and MurF1 expression levels comparable to those of older WT mice (12 M) (0.44-fold, p = 0.02 and 0.48-fold, p = 0.04, respectively).
    CONCLUSION: LAT2 has a critical role in regulating Gln efflux from skeletal muscle. The absence of LAT2 led to elevated intracellular Gln levels, impairing muscle proteolysis by inducing mTORC1 recruitment to the lysosome. Further, chronic Gln accumulation and decreased proteolysis were found to induce the early onset of an age-related muscle phenotype.
    Keywords:  LAT2; ageing; glutamine; mTORC1; proteolysis; skeletal muscle
    DOI:  https://doi.org/10.1002/jcsm.13847
  16. Redox Biol. 2025 Jun 21. pii: S2213-2317(25)00248-4. [Epub ahead of print]85 103735
    Exercise-induced mitochondrial protection in skeletal muscle of ovariectomized mice: A myogenic E2 synthesis-independent mechanism.
    Xu Tian, Yi Hu, Tao Li, Fangfang Yu, Tingting Li, Xiangyang Tian, Yiwei Feng, Qiuling Zhong, Yifan Meng, Wei Chen, Rengfei Shi.
       BACKGROUND: Skeletal muscle, a 17β-estradiol (E2)-sensitive tissue, is prone to accelerated aging due to postmenopausal E2 deficiency and subsequent mitochondrial dysfunction. While exogenous E2 treatment has been shown to protect against mitochondrial damage in ovariectomized rodents, the impact of exercise-induced local E2 production in skeletal muscle on mitochondrial function remains to be determined. This study investigated exercise-mediated mitochondrial protection in ovariectomized mice and the contribution of myogenic E2.
    METHODS: Female C57BL/6J mice (8-week-old) were divided into Sham, OVX, and OVX + ET groups (N = 12). OVX mice underwent bilateral ovariectomy, with the OVX + ET group performing 8 weeks of treadmill exercise starting 10 weeks post-surgery. Functional tests (grip strength, fatigue resistance) and gastrocnemius analyses (morphology, mitochondrial function, E2/antioxidant levels, and protein expression) were conducted. Parallel experiments in muscle-specific aromatase knockout (MS-ARO-CKO) mice included E2 supplementation via subdermal pellets.
    RESULTS: 18 weeks after ovariectomy (OVX), C57BL/6J mice exhibited significant reductions in grip strength (∼30 %), rotarod performance (∼57 %), and grid hanging performance (∼92 %). Concomitantly, OVX led to marked decreases in mitochondrial respiration (p < 0.05) and antioxidant capacity (p < 0.05) in the gastrocnemius muscle, accompanied by alterations in mitochondrial quality control and antioxidant signaling proteins (p < 0.05). Exercise intervention effectively attenuated these OVX-induced deficits, accompanied by a 66 % increase in E2 levels and upregulation of aromatase (ARO) activity and expression (p < 0.05). In MS-ARO-CKO mice model, exercise failed to improve the impaired antioxidant capacity induced by OVX. However, exercise, similar to estrogen supplementation, restored mitochondrial function and related protein expression abnormalities induced by OVX (p < 0.05).
    CONCLUSIONS: Our findings demonstrate that the protective effects of exercise on skeletal muscle mitochondria involve multiple mechanisms, independent myogenic E2 Synthesis, providing novel insights for improving skeletal muscle health in postmenopausal women.
    Keywords:  Exercise training; Mitochondrial function; Muscle weakness; Myogenic 17β-estradiol
    DOI:  https://doi.org/10.1016/j.redox.2025.103735
  17. Nat Commun. 2025 Jun 24. 16(1): 5370
    In vivo self-renewal and expansion of quiescent stem cells from a non-human primate.
    Jengmin Kang, Abhijnya Kanugovi, M Pilar J Stella, Zofija Frimand, Jean Farup, Andoni Urtasun, Shixuan Liu, Anne-Sofie Clausen, Heather Ishak, Summer Bui, Soochi Kim, Camille Ezran, Olga Botvinnik, Ermelinda Porpiglia, Mark A Krasnow, Antoine de Morree, Thomas A Rando.
      The development of non-human primate models is essential for the fields of developmental and regenerative biology because those models will more closely approximate human biology than do murine models. Based on single cell RNAseq and fluorescence-activated cell sorting, we report the identification and functional characterization of two quiescent stem cell populations (skeletal muscle stem cells (MuSCs) and mesenchymal stem cells termed fibro-adipogenic progenitors (FAPs)) in the non-human primate Microcebus murinus (the gray mouse lemur). We demonstrate in vivo proliferation, differentiation, and self-renewal of both MuSCs and FAPs. By combining cell phenotyping with cross-species molecular profiling and pharmacological interventions, we show that mouse lemur MuSCs and FAPs are more similar to human than to mouse counterparts. We identify unexpected gene targets involved in regulating primate MuSC proliferation and primate FAP adipogenic differentiation. Moreover, we find that the cellular composition of mouse lemur muscle better models human muscle than does macaque (Macaca fascicularis) muscle. Finally, we note that our approach presents as a generalizable pipeline for the identification, isolation, and characterization of stem cell populations in new animal models.
    DOI:  https://doi.org/10.1038/s41467-025-58897-x
  18. Biochem Biophys Res Commun. 2025 Jun 17. pii: S0006-291X(25)00935-0. [Epub ahead of print]776 152220
    Fbxl3 deletion mitigates myopathy in mdx mice through upregulation of myogenin.
    Min Chen, Wei He, Lei Si, Yanming Wu, Hua You, Yangxin Li, Yao-Hua Song, Yan Xu.
      Duchenne muscular dystrophy (DMD) is a severe X-linked neuromuscular disorder with limited therapeutic options, highlighting the urgent need for novel treatment strategies. In this study, we investigated the role of FBXL3 in DMD pathogenesis and assessed its potential as a gene therapy target. Using mdx mice, a well-established preclinical model of DMD, we found that satellite cell-specific deletion of FBXL3 significantly improved muscle pathology and functional performance. FBXL3-deficient mdx mice exhibited increased body and muscle mass, along with enhanced grip strength and endurance capacity. Histological analyses demonstrated a marked increase in both the number and cross-sectional area of centrally nucleated fibers, indicative of enhanced regenerative activity. These changes were associated with elevated myogenin expression and reduced inflammation and fibrosis, suggesting that FBXL3 functions as a negative regulator of muscle repair. Moreover, targeted FBXL3 silencing via adeno-associated virus (AAV) delivery to the gastrocnemius muscle resulted in increased muscle mass and further upregulation of myogenin, supporting its therapeutic relevance. Together, these findings identify FBXL3 as a key modulator of muscle regeneration via repression of myogenin and provide compelling evidence for its inhibition as a promising gene therapy strategy in DMD.
    Keywords:  FBXL3; Muscular dystrophy; Satellite cells; mdx
    DOI:  https://doi.org/10.1016/j.bbrc.2025.152220
  19. Cells. 2025 Jun 09. pii: 868. [Epub ahead of print]14(12):
    Regulation of Myogenesis by MechanomiR-200c/FoxO3 Axis.
    Junaith S Mohamed, Aladin M Boriek.
      Cyclic mechanical stretch has been shown to inhibit myoblast differentiation while promoting proliferation. However, the underlying molecular mechanisms are not well understood. Here, we report that mechanical stretch inhibits the differentiation of mouse primary myoblasts by promoting the cell cycle program and by inhibiting the expression of the myogenic regulator MyoD. Stretch alters the miRNA expression profile as evidenced by miRNA microarray analysis. We identified miR-200c as one of the highly downregulated mechanosensitive miRNAs (mechanomiRs) whose expression level was increased during differentiation. This suggests that mechanomiRs-200c is a myogenic miRNA. Overexpression of mechanomiR-200c revoked the effect of stretch on myoblast differentiation, and the introduction of the mechanomiR-200c antagomir restored the stretch effect. This suggests that stretch blocks differentiation, in part, through mechanomiR-200c. The gene encoding the transcription factor FoxO3 is a known direct target of mechanomiR-200c. Interestingly, MyoD binds to the mechanomiR-200c promoter in differentiating myoblasts, whereas stretch appears to reverse such binding. Our data further demonstrate that the levels of mechanomiR-200c are robustly elevated during the early stage of the muscle repair process in young mice, but not in the injured muscle of aged mice. Overall, we identified a novel pathway, MyoD/mechanomiR-200c/FoxO3a, and the potential mechanism by which stretch inhibits myoblast differentiation.
    Keywords:  MyoD; differentiation; mechanical stretch; microRNAs; myoblasts
    DOI:  https://doi.org/10.3390/cells14120868
  20. J Clin Invest. 2025 Jun 19. pii: e187868. [Epub ahead of print]
    Sarcospan protects against LGMD R5 via remodeling of the sarcoglycan complex composition in dystrophic mice.
    Ekaterina I Mokhonova, Daniel Helzer, Ravinder Malik, Hafsa Mamsa, Jackson Walker, Mark Maslanka, Tess S Fleser, Mohammad H Afsharinia, Shiheng Liu, Johan Holmberg, Z Hong Zhou, Eric J Deeds, Kirk C Hansen, Elizabeth M McNally, Rachelle H Crosbie.
      The dystrophin-glycoprotein complex (DGC) is composed of peripheral and integral membrane proteins at the muscle cell membrane that link the extracellular matrix with the intracellular cytoskeleton. While it is well-established that genetic mutations that disrupt the structural integrity of DGC result in numerous muscular dystrophies, the three-dimensional structure of the complex has remained elusive. Two recent elegant cryoEM structures of DGC illuminate its molecular architecture and reveal the unique structural placement of sarcospan (SSPN) within the complex. SSPN, a 25-kDa tetraspanin-like protein, anchors beta-dystroglycan to the beta-, gamma- and delta-sarcoglycan trimer, supporting biochemical studies that SSPN is a core element for DGC assembly and stabilization. Here, we advance these studies by revealing that SSPN provides scaffolding in gamma-sarcoglycanopathies enabling substitution of gamma-sarcoglycan by its homolog, zeta-sarcoglycan, leading to the structural integrity of the DGC and prevention of limb-girdle muscular dystrophy R5. Three-dimensional modeling reveals that zeta-sarcoglycan preserves protein-protein interactions with the sarcospan, sarcoglycans, dystroglycan, and dystrophin. The structural integrity of the complex maintains myofiber attachment to the extracellular matrix and protect the cell membrane from contraction-induced damage. These findings demonstrate that sarcospan prevents limb-girdle muscular dystrophy R5 by remodeling of the sarcoglycan complex composition.
    Keywords:  Cell biology; Muscle biology; Skeletal muscle
    DOI:  https://doi.org/10.1172/JCI187868
  21. FEBS J. 2025 Jun 26.
    Potential cytotoxicity of truncated slow skeletal muscle troponin T (ssTnT) in a loss of function TNNT1 myopathy mouse model.
    Han-Zhong Feng, Kevin A Strauss, Jian-Ping Jin.
      A nonsense mutation in codon Glu180 of the TNNT1 gene, which encodes the slow skeletal muscle isoform of troponin T (ssTnT), causes a recessively inherited myopathy (the Amish Nemaline Myopathy, ANM). A ssTnT knockout (ssTnT-KO) mouse model produced the loss of ssTnT function phenotypes of ANM with slow fiber atrophy and decreased fatigue resistance of soleus muscle. We further developed a Tnnt1 p.Glu180* knock-in (ANM-KI) mouse model to precisely mimic the human mutation. In addition to reproducing the loss of function phenotypes, ANM-KI mice exhibit more severe myopathy than that of ssTnT-KO mice. Compared with wild-type controls, ANM-KI and ssTnT-KO soleus muscles show different changes in gene expression profiles, of which gene ontology analysis indicated inflammatory activation in ANM-KI soleus muscle. The mutant Tnnt1 mRNA was readily detectable in ANM-KI soleus muscle. However, the truncated ssTnT1-179 fragment cannot be detected in western blot, indicating its very low level due to the active proteolytic clearance of non-myofilament-incorporated TnT in muscle cells. Nonetheless, the more severe myopathic impacts of the ANM-KI allele with more fiber number loss and muscle activity/injury-caused hypertrophy support a potent cytotoxicity of the ssTnT fragment, as shown in previous cell culture studies, which is further supported by activity-dependent and age-progressing myopathy with more active regeneration. The notion that non-myofilament-incorporated ssTnT fragments may potentially contribute to the pathogenesis and progression of myopathy merits further investigation.
    Keywords:  Amish Nemaline Myopathy; slow skeletal muscle troponin T; slow type muscles; transgenic mice
    DOI:  https://doi.org/10.1111/febs.70165
  22. FASEB J. 2025 Jun 30. 39(12): e70748
    Polyalanine Expansion in PABPN1 Alters the Structure and Dynamics of Its Nuclear Aggregates in Differentiated Muscle Cells.
    Sander D Mallon, Erik Bos, Vahid Sheikhhassani, Milad Shademan, Lenard M Voortman, Alireza Mashaghi, Thomas H Sharp, Vered Raz.
      Intracellular protein aggregation is a hallmark of aging and contributes to pathology in some age-associated diseases. In hereditary adult-onset neuromuscular diseases (NMDs), protein aggregates play a key role in disease onset and progression. The wild-type Poly(A) binding protein nuclear 1 (PABPN1) forms benign nuclear aggregates, whereas a short trinucleotide expansion leads to the formation of pathogenic aggregates, a hallmark of Oculopharyngeal Muscular Dystrophy (OPMD). In OPMD, the mutant PABPN1 causes skeletal muscle weakness. So far, the structural differences between benign and pathogenic protein aggregates and their effects on muscle cell biology remain poorly understood. We employed an array of advanced imaging modalities to explore the morphological differences between nuclear aggregates formed by non-pathogenic and pathogenic PABPN1 variants. Through analyses spanning micro- to nanoscale, we identified distinct structural features of aggregates formed by wild-type and expanded PABPN1. We demonstrate that these differences were more pronounced in differentiated muscle cells compared to proliferating cells. We further linked the structural features of PABPN1 aggregates to muscle cell biology, namely alterations in mitochondrial function and proteasomal activity. Our findings provide new insights into the structural distinctions between pathogenic and non-pathogenic aggregates and their implications for cellular dysfunction in NMDs.
    Keywords:  OPMD; aggregates structure; imaging; muscle; protein aggregates
    DOI:  https://doi.org/10.1096/fj.202501097R
  23. Noncoding RNA. 2025 Jun 16. pii: 46. [Epub ahead of print]11(3):
    Patterns of Circulating piRNAs in the Context of a Single Bout of Exercise: Potential Biomarkers of Exercise-Induced Adaptation?
    Caroline Eva Riedel, Javier Ibáñez, Annunziata Fragasso, Angelika Schmitt, Manuel Widmann, Felipe Mattioni Maturana, Andreas M Niess, Barbara Munz.
       BACKGROUND: Physical activity induces a range of physiological and molecular adaptations, particularly affecting skeletal muscle and the cardiovascular system, regulating both tissue architecture and metabolic pathways. Emerging evidence suggests that PIWI-interacting RNAs (piRNAs) may serve as potential biomarkers for these adaptations. Here, we analyzed piRNA patterns in the context of exercise.
    METHODS: This study selected eight participants of the iReAct study (DRKS00017446) for piRNA analysis. Baseline assessments included demographic profiling and fitness evaluation, particularly maximal oxygen uptake (V̇O2max) assessment. In addition, blood samples were collected pre- and (for six of the eight participants) post- standard reference training sessions. Subsequently, subjects underwent 6-week training protocols, employing standardized high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) regimens. Next, RNA sequencing was conducted to identify differentially expressed piRNAs, and correlation analyses were performed between piRNA expression patterns and training-associated changes in V̇O2max. Finally, to identify piRNAs potentially of interest in the context of exercise, different screening procedures were applied.
    RESULTS: There were unique and specific changes in individual piRNA expression levels in response to exercise. In addition, we could define correlations of piRNA expression patterns, namely of piR-32886, piR-33151, piR-12547, and piR-33074, with changes in V̇O2max. These correlations did not reach significance in the small sample size of this pilot study, but might be verified in larger, confirming studies.
    CONCLUSIONS: This hypothesis-generating study identifies characteristic piRNA patterns in the context of exercise. Their significance as biomarkers is yet to be determined.
    Keywords:  endurance training; epigenetics; exercise biomarkers; piRNA; training adaptation
    DOI:  https://doi.org/10.3390/ncrna11030046
  24. J Biol Chem. 2025 Jun 19. pii: S0021-9258(25)02248-3. [Epub ahead of print] 110398
    Silencing PIM1 inhibits ENO1-induced AKT activation and attenuates fibrillogenesis during spinal cord injury-induced skeletal muscle atrophy.
    Xiao Yu, Jiang Cao, Binyu Wang, Jiaju Fu, Jingcheng Liu, Tao Sui, Zi Wang, Chaoqin Wu, Jie Chang, Xiaojian Cao, Shaohua Zhang.
      Spinal cord injury (SCI) induces rapid and extensive skeletal muscle atrophy. During skeletal muscle atrophy, numerous extracellular matrix (ECM) and fibroblasts accumulate, impairing muscle function. The pro-viral Integration site for moloney murine leukaemia virus kinases-1(PIM1) is considered a positive regulator of inflammation. In our study, we found that PIM1 was overexpressed in the fibrotic regions of the skeletal muscle following SCI. We then explored the effects of the selective PIM1 inhibitor TP-3654 on fibrosis. TP-3654 decreased fibrosis by promoting fibroblast apoptosis, reducing proliferation and migration, and inhibiting tumor growth factor (TGF)-β classical and non-classical signaling pathways. In vivo PIM1 pharmacological inhibition with TP-3654 alleviates skeletal muscle fibrosis, mitigating skeletal muscle atrophy by decreasing ECM formation, enhancing the cross-sectional area of muscle fibers, and increasing muscle weight. Furthermore, we found a potential interaction between PIM1 and the enolase (ENO1)/protein kinase B (AKT) pathway. Downregulation of PIM1 expression in fibroblasts using drugs or siRNA leads to decreased ENO1 expression, concurrent with AKT phosphorylation reduction and suppressor of mothers against decapentaplegic (Smad)2/3 dephosphorylation within the TGF-β classical pathway. In summary, PIM1 might be an important target gene for future skeletal muscle atrophy treatments.
    Keywords:  ENO1/AKT; Fibrogenesis; Muscle atrophy; PIM1; Spinal cord injury
    DOI:  https://doi.org/10.1016/j.jbc.2025.110398
  25. Int J Surg. 2025 Jun 24.
    Ghrelin ameliorates sepsis induced acute skeletal muscle wasting via hypothalamic JAK2/STAT3 -AgRP pathway.
    Kaipeng Duan, Dongbao Li, Tao Chen, Weikang Li, Xiaotong Sun, Lixing Gu, Pengbo Wang, Xin Gao, Jin Zhou.
       BACKGROUND: Sepsis-induced acute skeletal muscle wasting would impede critical patients' recovery. The underlying mechanism for this metabolic disorder has not been fully elucidated. Here, we tested the hypothesis that circulating hormone ghrelin could regulate sepsis-induced acute skeletal muscle wasting via hypothalamic janus kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3) and agouti-related protein (AgRP) pathway.
    METHODS: Cecal ligation and puncture (CLP) was used to establish the model of sepsis-induced acute skeletal muscle wasting in rats. Ghrelin was administrated subcutaneously and in third ventricle (3 V) to evaluate its effect on muscle wasting and hypothalamic molecules. Regulated AgRP expression by adenovirus vector approach and modulated hypothalamic JAK2/STAT3 activation by AG490 and colivelin injection were employed to study their role on muscle wasting. The effects of enteral nutrition (EN) on muscle wasting and hypothalamic molecules were also tested.
    RESULTS: Both peripheral and 3 V ghrelin administration could decrease atrophy genes expression, increase hypothalamic growth hormone secretagogue receptor-1a (GHSR-1a) and AgRP gene expression, and lower hypothalamic JAK2/STAT3 pathway activation in septic model rats. Inhibiting AgRP expression has little effect on atrophy genes expression and hypothalamic JAK2/STAT3 pathway activity in sepsis, but it would mitigate the protective effect of ghrelin on muscle wasting. Inhibiting hypothalamic JAK2/STAT3 pathway partially restored AgRP expression, reduced hypothalamic IL-1β expression and attenuated muscle wasting caused by sepsis. Of note, activate hypothalamic JAK2/STAT3 pathway evoked hypothalamic inflammation and neuropeptides alteration, as well as muscle wasting in sham subjects. Although AgRP over-expression could mitigate sepsis-induced muscle wasting, it has little effect on hypothalamic JAK2/STAT3 pathway activity and inflammation. EN could ameliorate sepsis-induced muscle wasting, but requiring AgRP expression.
    CONCLUSION: Ghrelin could regulate sepsis-induced acute skeletal muscle wasting via hypothalamic JAK2/STAT3 and AgRP pathway. The protective effect of EN on muscle wasting was mediated by ghrelin and AgRP.
    Keywords:  JAK2/STAT3; agRP; enteral nutrition; ghrelin; muscle wasting; sepsis
    DOI:  https://doi.org/10.1097/JS9.0000000000002724
  26. Clin Transl Med. 2025 Jun;15(6): e70385
    OXA1L deficiency causes mitochondrial myopathy via reactive oxygen species regulated nuclear factor kappa B signalling pathway.
    Yongkun Zhan, Qian Wang, Ya Wang, Yanjie Fan, Dan Yan, Xianlong Lin, Yaoting Chen, Tingting Hu, Nan Li, Weiqian Dai, Hezhi Fang, Yongguo Yu.
       BACKGROUND: OXA1L is crucial for mitochondrial protein insertion and assembly into the inner mitochondrial membrane, and its variants have been recently linked to mitochondrial encephalopathy. However, the definitive pathogenic link between OXA1L variants and mitochondrial diseases as well as the underlying pathogenesis remains elusive.
    METHODS: In this study, we identified bi-allelic variants of c.620G>T, p.(Cys207Phe) and c.1163_1164del, p.(Val388Alafs*15) in OXA1L gene in a mitochondrial myopathy patient using whole exome sequencing. To unravel the genotype-phenotype relationship and underlying pathogenic mechanism between OXA1L variants and mitochondrial diseases, patient-specific human-induced pluripotent stem cells (hiPSC) were reprogrammed and differentiated into myotubes, while OXA1L knockout human immortalised skeletal muscle cells (IHSMC) and a conditional skeletal muscle knockout mouse model was generated using clustered regularly interspaced short palindromic repeats/Cas9 genomic editing technology.
    RESULTS: Both patient-specific hiPSC differentiated myotubes and OXA1L knockout IHSMC showed combined mitochondrial respiratory chain defects and oxidative phosphorylation (OXPHOS) impairments. Notably, in OXA1L-knockout IHSMC, transfection of wild-type human OXA1L but not truncated mutant form rescued the respiratory chain defects. Moreover, skeletal muscle conditional Oxa1l knockout mice exhibited OXPHOS deficiencies and skeletal muscle morphofunctional abnormalities, recapitulating the phenotypes of mitochondrial myopathy. Further functional investigations revealed that impaired OXPHOS resulting of OXA1L deficiency led to elevated reactive oxygen species production, which possibly activated the nuclear factor kappa B signalling pathway, triggering cell apoptosis.
    CONCLUSIONS: Together, our findings reinforce the genotype-phenotype association between OXA1L variations and mitochondrial diseases and further delineate the potential molecular mechanisms of how OXA1L deficiency causes skeletal muscle deficits in mitochondrial myopathy.
    KEYPOINTS: OXA1L gene bi-allelic variants cause mitochondrial myopathy. OXA1L deficiency results in combined mitochondrial respiratory chain defects and OXPHOS impairments. OXA1L deficiency leads to elevated ROS production, which may activate the NF-κB signalling pathway, disturbing myogenic gene expression and triggering cell apoptosis.
    Keywords:  NF‐κB signalling pathway; OXA1L; mitochondrial myopathy; oxidative phosphorylation; reactive oxygen species
    DOI:  https://doi.org/10.1002/ctm2.70385
  27. Crit Rev Food Sci Nutr. 2025 Jun 25. 1-12
    Assessing the composition of myofibrillar and muscle connective protein fractions within skeletal muscle tissue.
    Andrew M Holwerda, Thorben Aussieker, Joan Senden, Freek G Bouwman, Janneau van Kranenburg, Alexander Overman, Tim Snijders, Lex B Verdijk, Lars Holm, Luc J C van Loon.
      (195 WORDS)It has been suggested that different nutritional stimuli are required to augment myofibrillar versus muscle connective protein synthesis rates. To study such different aspects of skeletal muscle remodeling, researchers often isolate myofibrillar or connective protein fractions from muscle tissue samples. However, the composition of these muscle protein fractions remains poorly defined. Here, we evaluated the amino acid profiles and protein compositions of the myofibrillar and muscle connective protein fractions within skeletal muscle tissue. The muscle connective protein fraction was shown to contain ∼70% of the total mixed muscle collagen content, with 4.4 ± 0.9% collagen relative to total protein content. This was 3-4 fold greater than the collagen content in mixed muscle tissue (1.2 ± 0.2%; p < 0.05). Myofibrillar proteins, such as actin and myosin, accounted for 39% of the myofibrillar protein fraction and 32% of the muscle connective protein fraction. The muscle connective protein fraction contained a higher proportion (42%) of key scaffolding proteins compared to the myofibrillar protein fraction (11%). In conclusion, the muscle connective protein fraction contains an enriched proportion of collagen among a large proportion of intra- and extracellular scaffolding and cell adhesion proteins, all of which are far less abundant in the myofibrillar protein fraction.
    Keywords:  Connective protein synthesis; collagen; extracellular matrix; skeletal muscle
    DOI:  https://doi.org/10.1080/10408398.2025.2522363
  28. Cells. 2025 Jun 13. pii: 892. [Epub ahead of print]14(12):
    Multi-Modal Analysis of Satellite Cells Reveals Early Impairments at Pre-Contractile Stages of Myogenesis in Duchenne Muscular Dystrophy.
    Sophie Franzmeier, Shounak Chakraborty, Armina Mortazavi, Jan B Stöckl, Jianfei Jiang, Nicole Pfarr, Benedikt Sabass, Thomas Fröhlich, Clara Kaufhold, Michael Stirm, Eckhard Wolf, Jürgen Schlegel, Kaspar Matiasek.
      Recent studies on myogenic satellite cells (SCs) in Duchenne muscular dystrophy (DMD) documented altered division capacities and impaired regeneration potential of SCs in DMD patients and animal models. It remains unknown, however, if SC-intrinsic effects trigger these deficiencies at pre-contractile stages of myogenesis rather than resulting from the pathologic environment. In this study, we isolated SCs from a porcine DMD model and age-matched wild-type (WT) piglets for comprehensive analysis. Using immunofluorescence, differentiation assays, traction force microscopy (TFM), RNA-seq, and label-free proteomic measurements, SCs behavior was characterized, and molecular changes were investigated. TFM revealed significantly higher average traction forces in DMD than WT SCs (90.4 ± 10.5 Pa vs. 66.9 ± 8.9 Pa; p = 0.0018). We identified 1390 differentially expressed genes and 1261 proteins with altered abundance in DMD vs. WT SCs. Dysregulated pathways uncovered by gene ontology (GO) enrichment analysis included sarcomere organization, focal adhesion, and response to hypoxia. Multi-omics factor analysis (MOFA) integrating transcriptomic and proteomic data, identified five factors accounting for the observed variance with an overall higher contribution of the transcriptomic data. Our findings suggest that SC impairments result from their inherent genetic abnormality rather than from environmental influences. The observed biological changes are intrinsic and not reactive to the pathological surrounding of DMD muscle.
    Keywords:  DMD; dystrophin; force generation; muscle pathology; muscle stem cells; porcine model; proteomics; transcriptomics
    DOI:  https://doi.org/10.3390/cells14120892
  29. Cells. 2025 Jun 11. pii: 882. [Epub ahead of print]14(12):
    From 2D Myotube Cultures to 3D Engineered Skeletal Muscle Constructs: A Comprehensive Review of In Vitro Skeletal Muscle Models and Disease Modeling Applications.
    Tianxin Cao, Curtis R Warren.
      In recent years, the field of skeletal muscle tissue engineering has experienced significant advancements, evolving from traditional two-dimensional (2D) cell cultures to increasingly sophisticated three-dimensional (3D) engineered constructs. While 2D models have provided foundational insights into muscle cell biology, emerging 3D platforms aim to better recapitulate the complex native muscle environment, including mature muscle fibers, supportive vasculature, and native-like extracellular matrix (ECM) composition. Here, we provide a comprehensive review of current in vitro skeletal muscle models, detailing their design principles, structure, and functionalities as well as the advantages and limitations inherent to each approach. We put a special emphasis on 3D engineered muscle tissues (EMTs) developed through advanced bioengineering strategies and note that design criteria such as scaffold selection, perfusion system incorporation, and co-culture with supporting cell types have significantly enhanced tissue maturity and complexity. Lastly, we explore the application of these engineered models to disease studies, highlighting models of both mendelian muscle disorders and common polygenic diseases and the potential of these platforms for drug discovery and regenerative therapies. Although an ideal in vitro model that fully recapitulates native muscular architecture, vascularization, and ECM complexity is yet to be realized, we identify current challenges and propose future directions for advancing these bioengineered systems. By integrating fundamental design criteria with emerging technologies, this review provides a roadmap for next-generation skeletal muscle models poised to deepen our understanding of muscle biology and accelerate therapeutic innovation.
    Keywords:  3D engineered muscle tissue; disease modeling; skeletal muscle models
    DOI:  https://doi.org/10.3390/cells14120882
  30. Int J Mol Med. 2025 Sep;pii: 128. [Epub ahead of print]56(3):
    GW8510 alleviates muscle atrophy and skeletal muscle dysfunction in mice through AMPK/PGC1α signaling.
    Yutong Chen, Zurui Liu, Chen Liu, Daqian Yang, Mengmeng Xiao, Zhengqian Li, Zhengwei Xie.
      Preventing and restoring muscle loss and function is essential for elderly individuals. GW8510 may accelerate myotube differentiation. The present study aimed to investigate the protective effect of GW8510 (a CDK2 inhibitor) on muscle atrophy. Mouse models of muscle atrophy were induced by denervation, dexamethasone and glycerol. Muscle‑to‑body weight ratio, the cross‑sectional area of muscles, grip strength, fatigue and serum levels of superoxide dismutase and creatine kinase were assessed. In vitro, a dexamethasone‑induced C2C12 myotube atrophy model was used to evaluate mitochondrial function. Reverse transcription‑quantitative PCR, immunoblotting and small interfering RNA transfection were performed to explore the potential molecular mechanisms following treatment with GW8510. GW8510 resulted in a significant increase in the gastrocnemius and soleus muscle ratios in denervation mice (7 and 3%, respectively), alongside an increase in cross‑sectional area. Moreover, GW8510 significantly improved grip strength and superoxide dismutase activity, with similar protective effects in dexamethasone‑ and glycerol‑induced muscle atrophy models. GW8510 decreased reactive oxygen species production, increased mitochondrial DNA copy number, maintained mitochondrial dynamics and enhanced antioxidant activity in C2C12 myotubes. Mechanistically, GW8510 significantly inhibited the expression of atrophy‑associated markers F‑box protein 32 and tripartite motif‑containing 63 while activating AMPK (both P<0.01). The knockdown peroxisome proliferator‑activated receptor‑γ co‑activator‑1α (Pgc1α) negated the effects of GW8510. Overall, GW8510 mitigated muscle atrophy via the activation of the AMPK/PGC1α pathway. GW8510 could serve as a novel therapeutic agent for the prevention of muscle atrophy.
    Keywords:  AMPK; GW8510; Pgc1α; denervation; dexamethasone; muscle atrophy
    DOI:  https://doi.org/10.3892/ijmm.2025.5569
  31. Cells. 2025 Jun 18. pii: 924. [Epub ahead of print]14(12):
    Concurrent Physical Activity Protects Against C26 Adenocarcinoma Tumor-Mediated Cardiac and Skeletal Muscle Dysfunction and Wasting in Males.
    Louisa Tichy, Kimberly F Allred, Erika T Rezeli, Michael F Coleman, Clinton D Allred, Stephen D Hursting, Traci L Parry.
      Muscle loss unresponsive to nutritional supplementation affects up to 80% of cancer patients and severely reduces survival and treatment response. Exercise may help preserve muscle mass and function, yet the translatability of preclinical methods remains questionable. This study aimed to assess how voluntary wheel running, a clinically relevant physical activity, protects skeletal and cardiac muscle against cancer-mediated dysfunction and identify underlying molecular mechanisms.
    METHODS: BALB/c mice were assigned to sedentary nontumor-bearing (SED+NT), sedentary tumor-bearing (SED+T), wheel run nontumor-bearing (WR+NT), and wheel run tumor-bearing (WR+T). Tumor-bearing groups received 5 × 105 C26 cells; WR mice had wheel access for 4 weeks. Muscle function and tissue were analyzed for protective mechanisms.
    RESULTS: SED+T mice exhibited significant fat and lean mass loss, indicating cachexia, which was prevented in WR+T mice. SED+T also showed 15% reduced grip strength and cardiac dysfunction, while WR+T preserved function. WR+T mice had lower expression of muscle wasting markers (Atrogin1, MuRF1, GDF15, GDF8/11). Physical activity also reduced tumor mass by 57% and volume by 37%.
    CONCLUSION: Voluntary wheel running confers tumor-suppressive, myoprotective, and cardioprotective effects. These findings support physical activity as a non-pharmacological strategy to combat cancer-related muscle wasting and dysfunction.
    Keywords:  cancer; exercise; muscle wasting; physical activity; protection
    DOI:  https://doi.org/10.3390/cells14120924
  32. Nat Aging. 2025 Jun 27.
    Senescent macrophages induce ferroptosis in skeletal muscle and accelerate osteoarthritis-related muscle atrophy.
    Wei Xiang, Tongyi Zhang, Bingfei Li, Song Li, Bin Zhang, Shunzheng Fang, Lifeng Chen, Yunquan Gong, Bo Huang, Daibo Feng, Jinhui Wu, Jing Yuan, Yaran Wu, Xiaojing Yan, Runze Jin, Xiaoqi Zhang, Xiangqin Fang, Jiqin Lian, Lin Chen, Siru Zhou, Zhenhong Ni.
      Muscle atrophy around joints is a common issue for people with osteoarthritis (OA), but its causes are poorly understood. Here we demonstrate that chronic inflammation in quadriceps muscle coincides with OA in mice, characterized by an increase in macrophages, activation of inflammatory pathways and tissue vascularization. We show that, during OA progression, macrophages progressively exhibit increasing phenotypes of senescence and promote muscle atrophy through paracrine induction of ferroptosis. Mechanistically, iron overload-induced mitochondrial damage results in reduced asparagine metabolites, impairing coenzyme Q10 (CoQ10) synthesis by inhibiting mTORC1-HMGCR signaling. Ultimately, this cascade enhances lipid peroxidation and promotes ferroptosis in skeletal muscle cells. We show that the cardiac medication CoQ10 can attenuate muscle atrophy by inhibiting ferroptosis, thereby reducing pathological damage to OA joints. Our findings offer insights for the potential management of muscle atrophy in patients with OA.
    DOI:  https://doi.org/10.1038/s43587-025-00907-0
  33. Med Sci Sports Exerc. 2025 Jun 23.
    Power and Endurance: Polar Opposites or Willing Partners?
    Carrie Ferguson, Regula Furrer, Kevin A Murach, Russell T Hepple, Harry B Rossiter.
       ABSTRACT: Introduction. Peak neuromuscular power and endurance are distinct qualities of dynamic exercise performance. Dynamometry is used to assess peak neuromuscular power, often during performance across a single joint e.g., isotonic or isokinetic torque, while aptitude for endurance exercise may be inferred by measurement of critical power/speed or cardiopulmonary exercise testing to determine e.g., gas exchange threshold (GET), maximum oxygen uptake (V̇O2max) and exercise economy. Specificity is a critical component of any training program, but oversimplification of the specificity principle has contributed to the view that training adaptations to increase peak neuromuscular power or the ability to endure high power outputs are mutually exclusive, due to: (i) differences in the types of motor units recruited and their patterns of activation; and (ii) induction of distinct, antagonistic molecular signaling pathways in response to resistance and endurance exercise training (the "interference effect"). Methods, Results and Conclusion. This review explores evidence for reciprocation between peak neuromuscular power and endurance performance in sport, aging and among general and clinical populations. We also review the molecular events that mediate peak neuromuscular power and endurance training adaptations and their interactions. Finally, we describe the musculo-cardio-pulmonary exercise test (mCPET) to demonstrate that peak neuromuscular power and aerobic mediators of endurance performance are less polar opposites and more willing partners.
    Keywords:  AGING; CARDIOPULMONARY EXERCISE TESTING; CONCURRENT TRAINING; INTERFERENCE EFFECT; MCPET; PHYSIOLOGICAL RESILIENCE
    DOI:  https://doi.org/10.1249/MSS.0000000000003793
  34. Int J Mol Sci. 2025 Jun 16. pii: 5782. [Epub ahead of print]26(12):
    Oxidative Stress in Neurodegenerative Disorders: A Key Driver in Impairing Skeletal Muscle Health.
    Serena Castelli, Emily Carinci, Sara Baldelli.
      The fine regulation of antioxidant systems and intracellular production of reactive oxygen species (ROS) is responsible for cellular redox balance. The main organelles responsible for ROS production are mitochondria, and they complete this process through the electron transport chain. These potentially harmful molecules are buffered by enzymatic and non-enzymatic antioxidant systems. Oxidative stress is determined by an imbalance between the production and clearance of ROS in favor of the accumulation of these detrimental species, which generate cellular damage by interacting with macromolecules. In neurodegenerative diseases, oxidative stress has been demonstrated to be a crucial component, both causal and consequential to the disease itself. On the other hand, neurodegeneration disrupts neuromuscular junctions, leading to reduced muscle use and subsequent atrophy. Additionally, systemic inflammation and metabolic dysfunction associated with neurodegenerative diseases exacerbate muscle degeneration. Thus, sarcopenia and atrophy are common consequences of neurodegeneration and play a significant role in these disorders. Regarding this, ROS have been defined as promoting sarcopenia, stimulating the expression of genes typical of this condition. Overall, this review aims to contribute to filling the gap in the literature regarding the consequences at the muscular level of the relationship between oxidative stress and neurodegenerative diseases.
    Keywords:  atrophy; neurodegenerative disease; oxidative stress; sarcopenia; skeletal muscle
    DOI:  https://doi.org/10.3390/ijms26125782
  35. Heart Fail Rev. 2025 Jun 21.
    Skeletal muscle atrophy in pulmonary arterial hypertension: potential mechanisms and effects of physical exercise.
    Sebastião Felipe Ferreira Costa, Leôncio Lopes Soares, Luciano Bernardes Leite, Alexandre Martins Oliveira Portes, Antônio José Natali.
      Pulmonary arterial hypertension (PAH) is a rare and progressive disease characterized by pathological remodeling of the pulmonary arteries, resulting in increased pulmonary vascular resistance and right ventricular overload. This condition triggers common symptoms such as dyspnea and exercise intolerance, compromising thus the quality of life of individuals affected by this pathology. Skeletal muscle atrophy is one of the main determinants of these symptoms, which is mediated by an imbalance between protein synthesis and degradation, triggered by adverse systemic adaptations promoted by PAH, such as decreased blood perfusion and increased inflammation. This review addresses the main cellular and molecular mechanisms that potentially trigger or inhibit protein degradation pathways, and how they interact in the context of PAH. Furthermore, we focus on physical exercise as a non-pharmacological approach capable of modulating muscle atrophy induced by PAH.
    Keywords:  Exercise intolerance; Inflammation; PAH; Pathological remodeling; Protein degradation
    DOI:  https://doi.org/10.1007/s10741-025-10539-6
  36. PLoS One. 2025 ;20(6): e0327008
    Effects of 810 nm treatments in acute myofiber contraction of C2C12 myotubes.
    Nashwa Cheema, Linh Pham, Alexa Nazarian, Namrata Ghag, Emma Wise, Christiane Fuchs, Richard Rox Anderson, Joshua Tam.
      The muscoskeletal system can be irradiated with wavelengths in the red and near infrared regions which penetrate deep into the body and stimulate biological mechanisms. However, the activation of cellular responses in muscle, specifically actively contracting, is not clearly understood. Therefore, we investigated biological effects induced by irradiation with 810 nm wavelength of light in myotubes, resting or actively contracting in an acute model of exercise. In resting myotubes, cytosolic Ca2+ rose within 10 minutes post treatment with 810 nm at 2-4 J/cm2. ATP production was increased 4% ± 3 at 24 hrs post light treatment. In contracting myotubes, 810 nm treatment resulted in a significant ~30% increase in intracellular ATP levels and a 20% ± 12 reduction in lactate secretion into cell culture media. 810 nm treated myotubes also had a smaller change in myotube width during contractions, 5% ± 3, suggesting the myotubes were contracting with less force. Although the contractile motion was reduced, 810 nm treated myotubes had a higher frequency of spontaneous contractions after removal of electric pulse stimulation (EPS), 42% ± 21 and 1.3-2 - fold increase in mitochondrial proteins, Tom70, citrate synthase (CS) and succinate dehydrogenase (SDHA). This finding suggests that 810 nm treatment altered metabolic and contractile properties of myotubes due to mitochondrial activation. A more thorough understanding of these effects could lead to new treatment modalities that could improve physical performance.
    DOI:  https://doi.org/10.1371/journal.pone.0327008
  37. Dis Model Mech. 2025 Jun 01. pii: dmm052285. [Epub ahead of print]18(6):
    DWORF expression is reduced in a large animal model of Duchenne muscular dystrophy.
    Aaron M Gibson, Xiufang Pan, Omar Brito-Estrada, James A Teixeira, Lauren K Carl, Yongping Yue, Michael L Kamradt, Matthew J Burke, Caris A Wadding-Lee, Gang Yao, Roland W Herzog, Dongsheng Duan, Catherine A Makarewich.
      Duchenne muscular dystrophy (DMD) is a lethal muscle-wasting disease driven by cytosolic calcium overload, which leads to muscle degeneration. Sarco/endoplasmic reticulum calcium ATPase (SERCA), a key regulator of cytosolic calcium levels, exhibits reduced activity in animal models of DMD and human patients. Dwarf open reading frame (DWORF), a positive SERCA regulator, is downregulated in mdx DMD mice, and adeno-associated virus-mediated DWORF overexpression has been shown to ameliorate DMD cardiomyopathy. The canine DMD model provides a crucial bridge for translating findings from mice to humans. To investigate DWORF expression in this model, we developed a canine-specific anti-DWORF antibody, as the existing murine antibody is ineffective. This antibody detected DWORF in human, pig, cat and rabbit muscle, but not in mouse muscle. DWORF was absent in muscle tissues of neonatal normal dogs but highly expressed in those of adult dogs. In DMD-affected dogs aged 8 months or older, DWORF expression was significantly reduced in both cardiac and skeletal muscle. This study establishes a foundation for evaluating DWORF-based gene therapy in the canine DMD model, advancing the potential for clinical translation.
    Keywords:   DMD ; Canine model; DWORF; Duchenne muscular dystrophy; SERCA2a
    DOI:  https://doi.org/10.1242/dmm.052285
  38. Metabolism. 2025 Jun 21. pii: S0026-0495(25)00202-1. [Epub ahead of print]170 156333
    Exosomal miRNAs in muscle-bone crosstalk: Mechanistic links, exercise modulation and implications for sarcopenia, osteoporosis and osteosarcopenia.
    Bo Zhang, Yang Chen, Qiaojie Chen, Haijun Zhang.
      This review investigates the emerging role of exosomal microRNAs (miRNAs) as pivotal mediators of bidirectional communication between the skeletal muscle and bone tissue, with significant implications for age-related musculoskeletal disorders. In aging populations, sarcopenia often coexists with osteoporosis, forming osteosarcopenia, which markedly increases fracture risk, disability, and mortality. While traditional paradigms emphasize mechanical loading and endocrine pathways, emerging evidence has revealed that exosomes carrying bioactive miRNAs represent a novel class of paracrine factors in the muscle-bone axis. We examined how muscle-derived exosomal miRNAs (miR-34a and miR-27a-3p) influence bone metabolism, while bone-derived exosomal miRNAs (miR-486-5p) modulate muscle physiology. For each miRNA, we identified the target messenger RNAs (mRNAs) and signaling mechanisms. Importantly, exercise has emerged as a potent modulator of this crosstalk, altering exosomal miRNA profiles to promote anabolic outcomes in both tissues. This bidirectional communication contributes to osteosarcopenia pathophysiology, leading us to propose a novel "Exosomal miRNA Regulatory Network" for diagnosis and pathogenesis. Exosomal miRNAs show promise as early biomarkers for subclinical deterioration and therapeutic targets. However, methodological challenges in exosome isolation, incomplete characterization of miRNA networks, and aging complexity must be addressed before clinical implementation.
    Keywords:  Exercise; Exosomal miRNA regulatory network; Exosomal microRNAs; Muscle–bone crosstalk; Osteoporosis; Osteosarcopenia; Sarcopenia
    DOI:  https://doi.org/10.1016/j.metabol.2025.156333
  39. Cell Stem Cell. 2025 Jun 17. pii: S1934-5909(25)00226-7. [Epub ahead of print]
    Hallmarks of stem cell aging.
    Thomas A Rando, Anne Brunet, Margaret A Goodell.
      As organisms age, somatic stem cells progressively lose their ability to sustain tissue homeostasis and support regeneration. Although stem cells are relatively shielded from some cellular aging mechanisms compared with their differentiated progeny, they remain vulnerable to both intrinsic and extrinsic stressors. In this review, we delineate five cardinal features that characterize aged stem cells and examine how these alterations underlie functional decline across well-studied stem cell compartments. These hallmarks not only provide insight into the aging process but also serve as promising targets for therapeutic strategies aimed at rejuvenating stem cell function and extending tissue health span.
    Keywords:  aging; differentiation; hematopoietic stem cells; heterogeneity; muscle stem cells; neural stem cells; quiescence; stem cells
    DOI:  https://doi.org/10.1016/j.stem.2025.06.004
  40. Gerontology. 2025 Jun 22. 1-23
    Changes in serial sarcomere number of five hindlimb muscles across adult aging in rats.
    Avery Hinks, Geoffrey A Power.
       INTRODUCTION: The age-associated loss of muscle mass is partly accounted for by a reduction in muscle fascicle length (FL). Studies on rodents have confirmed this reduced FL is driven by a loss of sarcomeres aligned in series (serial sarcomere number; SSN) along a muscle. However, studies on rodents have focused primarily on rat plantar flexor SSN at two aging timepoints, leaving an incomplete view of age-related changes in SSN. Hence, this study investigated SSN as a contributor to the age-related loss of muscle mass in five hindlimb muscles across four aging timepoints in rats.
    METHODS: The soleus, medial gastrocnemius (MG), plantaris, tibialis anterior (TA), and vastus lateralis (VL) were obtained from 5 young (8 months), 5 middle-aged (20 months), 5 old (32 months), and 5 very old (36 months) male F344BN rats. After fixation of muscles in formalin and digestion in nitric acid, fascicles were teased out end-to-end to measure FL. SSN was determined by dividing FL by sarcomere length measured via laser diffraction. Muscle wet weight, anatomical cross-sectional area (ACSA), and physiological cross-sectional area (PCSA) were also determined for insight on age-related losses of whole-muscle mass and in-parallel muscle morphology.
    RESULTS: Age-related SSN loss was apparent after middle age for all muscles, with the plantaris showing the smallest (8%) and the VL the greatest (21%) differences between age groups. The MG and VL appeared to plateau in their SSN loss by 32 months, while the soleus and TA demonstrated continued decline from 32 to 36 months. In all muscles, an age-related lower SSN evidently contributed in part to the smaller muscle mass, alongside less contractile tissue in parallel (indicated by ACSA and PCSA).
    CONCLUSION: As SSN is closely tied to biomechanical function, these findings present SSN as a distinct target for improving muscle performance in older adults.
    DOI:  https://doi.org/10.1159/000546887
  41. Int J Mol Sci. 2025 Jun 18. pii: 5858. [Epub ahead of print]26(12):
    Myostatin Modulation in Spinal Muscular Atrophy: A Systematic Review of Preclinical and Clinical Evidence.
    Martina Gnazzo, Giulia Pisanò, Valentina Baldini, Giovanna Giacomelli, Silvia Scullin, Benedetta Piccolo, Emanuela Claudia Turco, Susanna Esposito, Maria Carmela Pera.
      Spinal Muscular Atrophy (SMA) is a genetic disorder characterized by the progressive loss of motor neurons and consequent muscle atrophy. Although SMN-targeted therapies have significantly improved survival and motor outcomes, residual muscle weakness remains a major clinical challenge, particularly in patients treated later in the disease course. Myostatin, a potent negative regulator of skeletal muscle mass, has emerged as a promising therapeutic target to address this gap. This review summarizes the preclinical and clinical evidence supporting the modulation of the myostatin pathway in SMA. Preclinical studies have demonstrated that inhibiting myostatin, especially when combined with SMN-enhancing agents, can increase muscle mass, improve motor function, and enhance neuromuscular connectivity in SMA mouse models. These findings provide a strong rationale for translating myostatin inhibition into clinical practice as an adjunctive strategy. Early clinical trials investigating myostatin inhibitors have shown favorable safety profiles and preliminary signs of target engagement. However, large-scale trials have yet to demonstrate widespread, robust efficacy across diverse patient populations. Despite this, myostatin pathway inhibition remains a compelling approach, particularly when integrated into broader treatment paradigms aimed at enhancing motor unit stability and function in individuals with SMA. Further clinical research is essential to validate efficacy, determine optimal timing, and define the patient subgroups most likely to benefit from myostatin-targeted therapies.
    Keywords:  SMN-targeted therapy; adjunctive treatment strategy; apitegromab; motor function restoration; muscle atrophy; myostatin inhibition; spinal muscular atrophy
    DOI:  https://doi.org/10.3390/ijms26125858
  42. Nature. 2025 Jun 25.
    Can a pill replace exercise? Swigging this molecule gives mice benefits of working out.
    Heidi Ledford.
      
    Keywords:  Ageing; Immunology; Metabolism
    DOI:  https://doi.org/10.1038/d41586-025-01994-0
  43. Nat Aging. 2025 Jun 23.
    Sarcosine decreases in sarcopenia and enhances muscle regeneration and adipose thermogenesis by activating anti-inflammatory macrophages.
    Yu Liu, Meiling Ge, Xina Xiao, Ying Lu, Wanyu Zhao, Kun Zheng, Kexin Yu, Yanting He, Qian Zhong, Lixing Zhou, Shan Hai, Xiaohui Liu, Na Jiang, Dan Du, Yan Zhang, Guo Cheng, Zhenmei An, Yi Zhao, Heng Xu, Biao Dong, Shuangqing Li, Binwu Ying, Huiyuan Zhang, Jirong Yue, Birong Dong, Lunzhi Dai.
      Age-related changes in circulating metabolites influence systemic physiology and may contribute to diseases such as sarcopenia. Although metabolic dysregulation is closely linked to sarcopenia, the roles of specific metabolites remain unclear. In this study, we performed comprehensive plasma metabolomic and lipidomic analyses across two cohorts comprising 1,013 individuals, uncovering the metabolic characteristics of sarcopenia, including a notable decline in plasma sarcosine levels in both aging patients and those with sarcopenia. Functional studies in mice showed that sarcosine helps maintain muscle mass homeostasis during aging, promotes adipose thermogenesis and enhances muscle regeneration. We demonstrate here that sarcosine activated the GCN2 signaling pathway to enhance anti-inflammatory macrophage polarization, promoting adipose thermogenesis and muscle regeneration. These effects may increase energy expenditure and restore metabolic balance to reduce chronic inflammation and improve insulin sensitivity, which are crucial for managing sarcopenia. This study underscores the potential of sarcosine supplementation as an adjunctive strategy via macrophage modulation for preventing sarcopenia in older adults.
    DOI:  https://doi.org/10.1038/s43587-025-00900-7
  44. J Physiol. 2025 Jun 26.
    Stepping up to inspire in muscular dystrophy.
    Carlos B Mantilla.
      
    Keywords:  diaphragm; muscular dystrophy; respiratory muscle
    DOI:  https://doi.org/10.1113/JP289311
  45. PLoS One. 2025 ;20(6): e0326149
    The Human Exersome Initiative (HEI): Rationale, study design, and protocol.
    Daria Neyroud, Julia Primavesi, Guia Tagliapietra, Chantal Daucourt, Hector Gallart-Ayala, Raphael Gottardo, Julijana Ivanisevic, Aaron L Baggish.
      Habitual physical activity and exercise training (PA/EX) confers numerous health-benefits. Phenotypic adaptations and clinical health outcomes attributable to PA/EX are well-established, and molecular markers and mediators of the PA/EX response have been described. To date, the majority of prior work focused on the biochemical response to PA/EX has leveraged convenience samples of trained athletes participating in events, patients undergoing clinically indicated exercise stress testing, or laboratory protocols comprised of a single dose of exercise. Accordingly, the impact of "exercise dose", defined by the product of intensity, duration, modality, and frequency, on the human biochemical response to PA/EX remains largely unexplored. The Human Exersome Initiative (HEI) was designed to fill this scientific knowledge gap. Specifically, the HEI will couple carefully controlled laboratory-based acute exercise testing with comprehensive systemic biochemical profiling to isolate the impact of PA/EX duration and intensity on human biochemistry. Herein, we describe the initial phase of the HEI which will aim to comprehensively define the impact of "exercise dose" on blood-based biochemistry in healthy young men and women. The overarching goal of the HEI is to elucidate how the human exercise response varies as a function of phenotypic variability. Using comparator data derived from young men and women, future iterations of this protocol will seek to determine how key sources of human variability (i.e., age, ethnicity, and the presence of comorbid disease) impact the biochemical response to PA/EX. We anticipate results from this work will facilitate biomarker discovery, the elucidation of molecular pathways and mechanisms associated with metabolic responses to exercise, and the identification of optimal exercise doses for future clinical interventions (i.e., tailoring preventive and therapeutic strategies).
    DOI:  https://doi.org/10.1371/journal.pone.0326149
  46. Nat Cancer. 2025 Jun 27.
    Vascular collapse leads to muscle wasting in cancer cachexia.
    Denis C Guttridge, Teresa A Zimmers.
      
    DOI:  https://doi.org/10.1038/s43018-025-01002-4
  47. Biomedicines. 2025 May 31. pii: 1350. [Epub ahead of print]13(6):
    Altered Expression of Cell Cycle Regulators and Factors Released by Aged Cells in Skeletal Muscle of Patients with Bone Fragility: A Pilot Study on the Potential Role of SIRT1 in Muscle Atrophy.
    Angela Falvino, Roberto Bonanni, Beatrice Gasperini, Ida Cariati, Angela Chiavoghilefu, Amarildo Smakaj, Virginia Veronica Visconti, Annalisa Botta, Riccardo Iundusi, Elena Gasbarra, Virginia Tancredi, Umberto Tarantino.
      Background/Objectives: Cellular aging represents a crucial element in the progression of musculoskeletal diseases, contributing to muscle atrophy, functional decline, and alterations in bone turnover, which promote fragility fractures. However, knowledge about expression patterns of factors potentially involved in aging and senescence at the tissue level remains limited. Our pilot study aimed to characterize the expression profile of cell cycle regulators, factors released by aged cells, and sirtuin 1 (SIRT1) in the muscle tissue of 26 elderly patients undergoing hip arthroplasty, including 13 with low-energy fracture and 13 with osteoarthritis (OA). Methods: The mRNA expression levels of cyclin-dependent kinase inhibitor 1A (CDKN1A), cyclin-dependent kinase inhibitor 1B (CDKN1B), cyclin-dependent kinase inhibitor 2A (CDKN2A), p53, tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), interleukin-15 (IL-15), chemokine (C-C motif) ligand 2 (CCL2), chemokine (C-C motif) ligand 3 (CCL3), growth differentiation factor 15 (GDF15), and SIRT1 were evaluated in muscle tissue by qRT-PCR. In addition, immunohistochemistry and Western blotting analysis were conducted to measure the protein levels of SIRT1. Results: A marked muscle atrophy was observed in fractured patients compared to the OA group, in association with an up-regulation of cell cycle regulators and factors released by the aged cells. The expression of matrix metallopeptidase 3 (MMP3), plasminogen activator inhibitor 1 (PAI-1), and fas cell surface death receptor (FAS) was also investigated, although no significant differences were observed between the two experimental groups. Notably, SIRT1 expression was significantly higher in OA patients, confirming its role in maintaining muscle health during aging. Conclusions: Further studies will be needed to clarify the role of SIRT1 in the senescence characteristic of age-related musculoskeletal disorders, counteracting the muscle atrophy that predisposes to fragility fractures.
    Keywords:  SIRT1; bone fragility; cellular aging; fragility fractures; muscle atrophy; osteoporosis; physiology; senescence
    DOI:  https://doi.org/10.3390/biomedicines13061350
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