bims-moremu Biomed News
on Molecular regulators of muscle mass
Issue of 2025–11–02
forty-one papers selected by
Anna Vainshtein, Craft Science Inc.
  1. Exercise, circadian rhythms, and muscle regeneration: a path to healthy aging.
  2. Intracellular and Extracellular Redox Signals During Exercise and Aging.
  3. Immunoproteasomes in Skeletal Muscle Pathologies: Emerging Roles, Conflicting Evidence, and Future Directions.
  4. PRDX5 Regulates Mitochondrial Function and Nuclear Spreading in Myogenesis and Acts With PRDX3 to Delay Muscle Aging.
  5. microRNA-22 Inhibition Stimulates Mitochondrial Homeostasis and Intracellular Degradation Pathways to Prevent Muscle Wasting.
  6. Epigenetic dysregulation in aged muscle stem cells drives mesenchymal progenitor expansion via IL-6 and Spp1 signaling.
  7. Molecular Framework of the Onset and Progression of Skeletal Muscle Aging.
  8. Brown adipose tissue and skeletal muscle coordinately contribute to thermogenesis in mice.
  9. Mavacamten facilitates myosin head ON-to-OFF transitions and shortens thin filament length in relaxed mouse skeletal muscle.
  10. The muscle protein density associates with radiodensity, strength, damage, unloading and disease: evidence from humans & mice.
  11. Muscle sparing through differential nutritional control of three muscle growth mechanisms: how zebrafish larvae deal with starvation.
  12. Voluntary wheel running promotes lymphangiogenesis in slow-twitch muscle in young mice.
  13. Exploring Desmin as a Potential Modifier in Duchenne Muscular Dystrophy-Associated Cardiomyopathy.
  14. Shining a Light on Skeletal Muscle Regeneration: Red Photobiomodulation Boosts Myoblast Differentiation In Vitro.
  15. Estrogen Receptor Regulates Male Satellite Cells in a Female, but Not Male, Environment.
  16. Targeting Cellular Senescence in Dystrophin-/-/Utrophin-/-Double Knockout Mice Improves Musculoskeletal Health and Increases Lifespan.
  17. The role and mechanisms of myokines in sarcopenia: new intervention strategies for the challenges of aging.
  18. Cytokinins Are Age- and Injury-Responsive Molecules That Regulate Skeletal Myogenesis.
  19. Modulation of the JAK2-STAT3 pathway promotes expansion and maturation of human iPSC-derived myogenic progenitor cells.
  20. TET exhibits enzymatic-independent and-dependent functions during Drosophila flight muscle development and aging.
  21. Magnesium Preserves Calcium Homeostasis and Contributes to Protect Myotubes from Inflammation-Induced Damage.
  22. R405W Desmin Knock-In Mice Highlight Alterations of Mitochondria, Protein Quality Control and Myofibrils in Myofibrillar Myopathy.
  23. Boldo Restores Vascularization and Reduces Skeletal Muscle Inflammation in Symptomatic Mice with Dysferlinopathy.
  24. Endocrine control of skeletal muscle regeneration and clinical applications.
  25. Urinary titin represents an exciting biomarker for assessment of muscle health.
  26. Effects of Exercise Training on Muscle Function.
  27. Circular rna Pde4dip regulates myogenesis by interacting with Zfp143 mRNA: a novel regulatory axis.
  28. Linking Elastin in Skeletal Muscle Extracellular Matrix to Metabolic and Aerobic Function in Type 2 Diabetes: A Secondary Analysis of a Lower Leg Training Intervention.
  29. Human three-dimensional engineered muscle tissue characterization and intramyocellular lipid modeling.
  30. Arsenic Exposure Alters Liver Metabolism and Accelerates Skeletal Muscle Atrophy in Female BALB/c Mice.
  31. Abdominal LIPUS ameliorates simulated microgravity induced skeletal muscle atrophy via the gut-muscle axis.
  32. Potential health benefits of cold-water immersion: the central role of PGC-1α.
  33. Sodium Tanshinone IIA Sulfonate Ameliorates Fibrosis of Skeletal Muscle Injury by Regulating Transforming Growth Factor-β1/Smad3 and Phosphoinositide 3-Kinase/protein Kinase B/Cyclooxygenase-2 Signaling Pathways.
  34. Nicotinamide nucleotide transhydrogenase dysfunction transcriptionally impacts mitochondrial β-oxidation and neuromuscular junction in M. Gastrocnemius of 24-day-old mice.
  35. Study on the Mechanism of Low-Intensity Pulsed Ultrasound in Ameliorating Glucose Metabolism Through Attenuation of Skeletal Muscle Atrophy in Mice with Type 1 Diabetes.
  36. NSAID ingestion augments training-induced muscle hypertrophy and differentially affects muscle mRNA expression, but not strength gains, in trained men.
  37. The effect of bed rest, unilateral limb immobilization and head-down tilt on muscle protein synthesis: A systematic review and meta-analysis.
  38. Editorial: Spotlight on aging: role of exercise and nutrition in healthy longevity.
  39. Morphological and functional phenotyping of skeletal muscle and bone in the zQ175 knock-in mouse model of Huntington's disease.
  40. Peripheral immune and metabolic regulation of Aβ and Tau by exercise in Alzheimer's disease.
  41. GLP-1R Agonists and Muscle Health: Potential Role in Sarcopenia Prevention and Treatment.
  1. Front Neurosci. 2025 ;19 1633835
    Exercise, circadian rhythms, and muscle regeneration: a path to healthy aging.
    Zhanguo Su, Lijuan Xiang.
      The circadian system regulates core physiological processes, including muscle regeneration, protein synthesis, and cellular homeostasis. Disruptions in circadian rhythms contribute to impaired muscle function in older adults, with age-related declines in muscle mass and regenerative capacity serving as major contributors to sarcopenia. Emerging evidence indicates that exercise-a powerful modulator of muscle adaptation-can also influence circadian regulation, offering a potential avenue to enhance muscle repair in aging populations. This review examines how physical activity interacts with circadian mechanisms in aged skeletal muscle, emphasizing key molecular and cellular pathways involved in muscle regeneration. Central circadian regulators such as Clock, BMAL1, and PER1 are discussed in the context of muscle protein turnover, satellite cell activity, and mitochondrial function. Aligning exercise timing with circadian rhythms is proposed as a promising strategy to enhance muscle recovery and functional capacity in older individuals. Furthermore, the review highlights the therapeutic potential of chrono-exercise to delay the onset of sarcopenia and promote healthy aging. By integrating insights from chronobiology, geroscience, and exercise physiology, this analysis underscores the importance of chrono-exercise in supporting muscle health during aging.
    Keywords:  aging; circadian rhythm; exercise timing; sarcopenia; skeletal muscle regeneration
    DOI:  https://doi.org/10.3389/fnins.2025.1633835
  2. Free Radic Biol Med. 2025 Oct 29. pii: S0891-5849(25)01308-5. [Epub ahead of print]
    Intracellular and Extracellular Redox Signals During Exercise and Aging.
    Daniela Caporossi, Malcolm J Jackson, Carlos Henriquez-Olguin.
      Regular physical activity enhances systemic health and resilience, partly through the generation of reactive oxygen species (ROS) that serve as key modulators of redox-sensitive signaling pathways. This review explores how redox signaling mediates both local and systemic responses to exercise, with particular focus on skeletal muscle and aging. We first examine the compartmentalized generation of ROS within myofibers, highlighting the distinct contributions of mitochondrial and NADPH oxidase systems and the context-dependent nature of oxidative eustress versus distress. We then detail how redox signals initiate adaptive responses that extend beyond muscle through the release of exerkines, cytokines, peptides, and metabolites, and their packaging within extracellular vesicles (EVs). These circulating factors facilitate interorgan communication and reinforce systemic redox homeostasis. Aging disrupts these processes, leading to impaired redox signaling, neuromuscular degeneration, and diminished responsiveness to exercise. Notably, animal models such as Sod1-deficient mice underscore the importance of neuronal redox control in sarcopenia. Finally, we highlight how exercise-induced EVs may counteract age-associated dysfunction by delivering redox-regulatory molecules to distant tissues. Understanding the molecular interplay between redox signals and systemic adaptation offers promising avenues for therapeutic strategies targeting metabolic and neuromuscular decline in aging.
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.10.283
  3. Cells. 2025 Oct 12. pii: 1586. [Epub ahead of print]14(20):
    Immunoproteasomes in Skeletal Muscle Pathologies: Emerging Roles, Conflicting Evidence, and Future Directions.
    Alexander Kalinkovich, Gregory Livshits.
      Skeletal muscle pathologies, including sarcopenia, inflammatory myopathies, and various muscular dystrophies, are strongly influenced by chronic low-grade inflammation and impaired proteostasis. Immunoproteasomes (IMPs), inducible proteolytic complexes activated by pro-inflammatory cytokines, are emerging as regulators linking immune signaling to protein quality control. Evidence suggests that IMPs have paradoxical, context-dependent roles in skeletal muscle. On one hand, they can support proteostasis and muscle regeneration under stress; on the other, persistent activation may sustain cytokine production, antigen presentation, and maladaptive immune-muscle interactions, promoting chronic inflammation and muscle wasting. Selective IMP inhibitors, such as ONX 0914 and KZR-616, display potent anti-inflammatory effects in preclinical models of autoimmune myositis and muscle atrophy. Yet, their use in skeletal muscle pathologies is controversial; while inhibition may dampen harmful immune activation, it could also impair muscle repair and proteostasis. This review summarizes current findings, highlights key contradictions, and explores unresolved questions about the role of IMPs in skeletal muscle pathologies. We emphasize the need for a deeper understanding of IMP-mediated mechanisms in skeletal muscle pathology and strategies combining selective inhibitors to enhance therapeutic efficacy while minimizing adverse effects. IMPs thus represent both a promising and potentially risky therapeutic target, with outcomes highly dependent on disease context.
    Keywords:  chronic inflammation; immunoproteasomes; sarcopenia; skeletal muscle
    DOI:  https://doi.org/10.3390/cells14201586
  4. J Cachexia Sarcopenia Muscle. 2025 Dec;16(6): e70098
    PRDX5 Regulates Mitochondrial Function and Nuclear Spreading in Myogenesis and Acts With PRDX3 to Delay Muscle Aging.
    Joonho Suh, Je-Hyun Eom, Jongmin Baik, Wonn Shim, Max A Tischfield, Hyun Ae Woo, Yun-Sil Lee.
       BACKGROUND: Skeletal muscle aging is associated with oxidative stress and mitochondrial dysfunction. Peroxiredoxins (PRDXs), particularly PRDX3 and PRDX5, are antioxidant enzymes that are uniquely localized to mitochondria. While PRDX3 has been reported to play a role in maintaining mitochondrial function in muscle, the specific function of PRDX5 in muscle remains unclear. This study investigated the role of PRDX5 in mitochondrial function, myonuclear distribution and muscle aging.
    METHODS: Myoblasts were isolated from wild-type (WT), Prdx3-/-, Prdx5-/- and Prdx3-/-; Prdx5-/- mice crossed with mitochondria reporter (mt-GFP) mice. Nuclear and mitochondrial positioning were evaluated using confocal and super-resolution lattice structured illumination microscopy (SIM). Mitochondrial function was assessed by Seahorse oxygen consumption rates (OCR) assays. In vivo analyses included grip strength, treadmill performance and histological evaluation following venom-induced muscle injury.
    RESULTS: During myogenesis, Prdx5-/- and Prdx3-/-; Prdx5-/- myotubes exhibited impairments in nuclear spreading, characterized by clustered nuclei, unlike the even distribution observed in WT and Prdx3-/- myotubes (44.4% and 44.9% vs. 17.1% and 21.9%, respectively; p < 0.001). Mitochondrial ATP production was significantly reduced in Prdx3-/-, Prdx5-/- and Prdx3-/-; Prdx5-/- myotubes (p < 0.05). The expression of Rhot1 and Trak1, key regulators of mitochondrial transport, was significantly decreased in Prdx5-/- and Prdx3-/-; Prdx5-/- myotubes (p < 0.01). Knockdown of Rhot1 or Trak1 in WT myotubes led to myonuclear clustering similar to that observed in Prdx5-deficient myotubes, supporting that PRDX5 facilitates mitochondrial transport and nuclear positioning, at least in part, through transcriptional regulation of genes including Rhot1 and Trak1. In vivo, 48-week-old Prdx5-/- mice exhibited mitochondrial dysfunction and myonuclear clustering in myofibers, with reduced treadmill performance (p < 0.05). Muscle regeneration was impaired in Prdx5-/- mice, with decreased expression of regeneration and mitochondrial transport markers and increased nuclear clustering in regenerating myofibers (p < 0.05). Prdx3-/-; Prdx5-/- double-knockout mice displayed accelerated muscle aging, including decreased muscle mass and strength, and elevated expression of E3 ligases Atrogin1 and MuRF1 as early as 10 weeks of age (p < 0.05). These mice also exhibited increased mitochondrial H2O2 production, which upregulated the expression of Atrogin1 and MuRF1 (p < 0.05).
    CONCLUSIONS: Our findings reveal a previously unidentified role of PRDX5 in coordinating mitochondrial function and nuclear positioning during myogenesis and muscle regeneration. The combined deficiency of PRDX3 and PRDX5 accelerates muscle aging by exacerbating oxidative stress and mitochondrial dysfunction, suggesting that enhancing their activity may be a promising therapeutic strategy to prevent sarcopenia and age-related muscle degeneration.
    Keywords:  PRDX3; PRDX5; mitochondrial dysfunction; muscle aging; myonuclear distribution
    DOI:  https://doi.org/10.1002/jcsm.70098
  5. Int J Mol Sci. 2025 Oct 11. pii: 9900. [Epub ahead of print]26(20):
    microRNA-22 Inhibition Stimulates Mitochondrial Homeostasis and Intracellular Degradation Pathways to Prevent Muscle Wasting.
    Simone Tomasini, Emanuele Monteleone, Anna Altieri, Francesco Margiotta, Fereshteh Dardmeh, Hiva Alipour, Anja Holm, Sakari Kauppinen, Riccardo Panella.
      MicroRNA-22 (miR-22) is a negative regulator of mitochondrial biogenesis, as well as lipid and glucose metabolism, in metabolically active tissues. Silencing miR-22 holds promise as a potential treatment of obesity and metabolic syndrome, as it restores metabolic capacity-enhancing oxidative metabolism-and reduces ectopic fat accumulation in chronic obesity, a driver of impaired metabolic flexibility and muscle mass loss. Intramuscular adipose accumulation and defective mitochondrial function are features associated with obese-mediated muscle atrophy and hallmarks of neuromuscular disorders such as Duchenne muscular dystrophy. Therefore, miR-22 could represent a compelling molecular target to improve muscle health across various muscle-wasting conditions. This study describes a pharmacological strategy for the inhibition of miR-22 in skeletal muscle by employing a mixmer antisense oligonucleotide (ASO, anti-miR-22). Administration of the ASO in a mouse model of obesity positively modulated myogenesis while protecting dystrophic mice from muscle function decline, enhancing fatigue resistance, and limiting pathological fibrotic remodeling. Mechanistically, we show that anti-miR-22 treatment promotes derepression of genes involved in mitochondrial homeostasis, favoring oxidative fiber content regardless of the disease model, thus promoting a more resilient phenotype. Furthermore, we suggest that miR-22 inhibition increases autophagy by transcriptional activation of multiple negative regulators of mammalian target of rapamycin (mTOR) signaling to decrease immune infiltration and fibrosis. These findings position miR-22 as a promising therapeutic target for muscle atrophy and support its potential to restore muscle health.
    Keywords:  ASO; DMD; antimiRs; autophagy; fibrosis; miR-22; miRNA therapeutics; microRNA; muscle atrophy; oxidative metabolism
    DOI:  https://doi.org/10.3390/ijms26209900
  6. Nat Aging. 2025 Oct 29.
    Epigenetic dysregulation in aged muscle stem cells drives mesenchymal progenitor expansion via IL-6 and Spp1 signaling.
    Giulia Riparini, Morgan Mackenzie, Faiza Naz, Stephen Brooks, Kan Jiang, Anshu Deewan, Brittany Dulek, Shamima Islam, Kyung Dae Ko, Wanxia L Tsai, Massimo Gadina, Stefania Dell'Orso, Vittorio Sartorelli.
      Sarcopenia, the age-related decline in muscle mass, strength and function, is characterized by impaired muscle homeostasis, reduced regenerative potential of muscle stem cells (MuSCs) and increased fibrosis. Here we report that aged MuSCs can autonomously instruct fibro-adipogenic progenitors (FAPs) to proliferate and acquire a fibrogenic phenotype, independent of other cell types. Both the polycomb-deficient Ezh2-/- mouse model and aged mice exhibited defective regeneration, FAP expansion, fibrosis and elevated secretion of interleukin 6 (IL-6) and secreted phosphoprotein 1 (Spp1; osteopontin) by MuSCs. In aged MuSCs, reduction of the histone H3K27me3 repressive mark at the Nfbk1 gene correlated with its increased expression and enhanced chromatin recruitment to the IL6 and Spp1 genes, leading to their activation. Pharmacological inhibition of IL-6 and Spp1 signaling in co-culture systems or in aged mice reduced FAP proliferation and muscle fibrosis. These findings indicate that epigenetic dysregulation of aged MuSCs contributes to aged-related muscle fibrosis.
    DOI:  https://doi.org/10.1038/s43587-025-01002-0
  7. Int J Mol Sci. 2025 Oct 18. pii: 10145. [Epub ahead of print]26(20):
    Molecular Framework of the Onset and Progression of Skeletal Muscle Aging.
    Thomas Horlem, Stephanie Rubianne Silva Carvalhal, Sandro José Ribeiro Bonatto, Luiz Cláudio Fernandes.
      Aging is a multifactorial process that progressively disrupts cellular and tissue homeostasis, affecting all organ systems at distinct rates and predisposing individuals to chronic diseases such as cancer, type II diabetes, and sarcopenia. Among these systems, skeletal muscle plays a central role in healthspan decline, yet the precise onset of its deterioration remains unclear. Most studies emphasize late-life models, overlooking the transitional phase of middle age, when initial alterations emerge. Evidence indicates that middle-aged muscle exhibits aberrant metabolism, impaired insulin sensitivity, and an early, gradual reduction in mass, suggesting that decline begins long before overt sarcopenia. This narrative review synthesizes current findings on linear and non-linear molecular biomarkers associated with the onset of skeletal muscle aging, aiming to improve early detection of muscular alterations and support the development of interventions that delay or prevent functional decline.
    Keywords:  aging; metabolism; middle age; narrative review; skeletal muscle
    DOI:  https://doi.org/10.3390/ijms262010145
  8. Elife. 2025 Oct 27. pii: RP99982. [Epub ahead of print]13
    Brown adipose tissue and skeletal muscle coordinately contribute to thermogenesis in mice.
    Yuna Izumi-Mishima, Rie Tsutsumi, Tetsuya Shiuchi, Saori Fujimoto, Momoka Taniguchi, Mizuki Sugiuchi, Manaka Tsutsumi, Yuko Okamatsu-Ogura, Takeshi Yoneshiro, Masashi Kuroda, Kazuhiro Nomura, Hiroshi Sakaue.
      Endotherms increase the rate of metabolism in metabolic organs as one strategy to cope with a decline in the temperature of the external environment. However, an additional major contributor to maintenance of body temperature in a cold environment is contraction-based thermogenesis in skeletal muscle. Here, we show that impairment of hind limb muscle contraction by cast immobilization induced a loss of function of skeletal muscle and activated brown adipose tissue (BAT) thermogenesis as a compensatory mechanism. BAT utilizes free branched-chain amino acids (BCAAs) derived from skeletal muscle as an energy substrate for thermogenesis, and interleukin-6 released by skeletal muscle stimulates BCAAs production in muscle for support of BAT thermogenesis. Additionally, this thermoregulatory system between BAT and skeletal muscle may also play an important role in response to cold temperatures or acute stress. Our findings suggest that BAT and skeletal muscle cooperate to maintain body temperature in endotherms.
    Keywords:  amino acids; biochemistry; brown adipose tissue; chemical biology; inter-organ metabolic network; mouse; skeletal muscle; thermogenesis
    DOI:  https://doi.org/10.7554/eLife.99982
  9. Physiol Rep. 2025 Oct;13(20): e70606
    Mavacamten facilitates myosin head ON-to-OFF transitions and shortens thin filament length in relaxed mouse skeletal muscle.
    Michel N Kuehn, Nichlas M Engels, Devin L Nissen, Johanna K Freundt, Weikang Ma, Samantha P Harris, Thomas C Irving, Wolfgang A Linke, Anthony L Hessel.
      The first-in-its-class cardiac drug mavacamten shifts myosin heads towards a structurally inactive position where they lay along the helical tracks of the thick filament. However, mavacamten is not completely specific to cardiac myosin and can also affect skeletal muscle myosin, an important consideration since mavacamten is administered orally and so will also be present in skeletal tissue. Indeed, emerging clinical reports indicate mavacamten-induced generalized skeletal myopathy in elderly patients. These findings raise important safety considerations for vulnerable populations, while also highlighting the drug's potential as a novel basic research tool to probe thick filament regulation and myosin head availability in skeletal muscle mechanics experiments. Using small-angle X-ray diffraction (MyoXRD), we tracked these structural changes in the thick filaments of relaxed muscle before and after mavacamten incubation and found that mavacamten treatment reduced the proportion of myosin heads in an active state but did not eliminate length-dependent structural changes in passive muscle that are linked to changes in contraction performance upon activation, demonstrating similar effects to those observed in cardiac muscle. These findings provide valuable insights for the potential use of mavacamten as a tool to study skeletal muscle contraction across striated muscle.
    Keywords:  X‐ray diffraction; mouse; myosin inhibitors; ultrastructure
    DOI:  https://doi.org/10.14814/phy2.70606
  10. J Appl Physiol (1985). 2025 Oct 31.
    The muscle protein density associates with radiodensity, strength, damage, unloading and disease: evidence from humans & mice.
    Moniek Schouten, Ruud Van Thienen, Sebastiaan Dalle.
      Skeletal muscle remodeling affects muscle functionality, quality and mass. The protein density is an important determinant of muscle quality, that can be readily assessed, but which is rarely reported. This study assessed how muscle protein density responds to challenges such as exercise, injury, immobilization and disease, and associated this with measures of lean mass, radiodensity, functionality and damage. The protein density was determined in human muscle biopsies from older adults (65-83 years) and young males (18-35 years), and in murine muscles. The protein density was compared between challenged conditions (disease, injury, eccentric exercise, immobilization) and a control condition, and/or associated with i) measures of muscle volume and radiodensity (via computed tomography), ii) molecular measures of damage and iii) measures of strength. Protein density correlated with upper leg lean mass (r=0.4468; p=0.0371) and radiodensity (r=0.5085; p=0.0157) in older adults. Eccentric exercise decreased the protein density with 9% (p=0.0248) in young adults, which correlated with decreases in strength (r>0.79; p<0.01). In murine disease and injury models, muscle loss (-12%; -90%; p<0.01) was accompanied by a loss of protein density (-3; -21%), in a muscle- and time-dependent way. Interestingly, the immobilization-induced muscle loss (-16%; p=0.0069) was accompanied by a higher protein density (+8%; p=0.0293) compared to the non-immobilized leg. In conclusion, muscle protein density associates with muscle mass and muscle function. Muscle protein density can be a valuable biomarker that provides more insights into the mechanisms that underlie muscle adaptations due to disease, aging, injury and exercise.
    Keywords:  cachexia; exercise; muscle edema; muscle quality; neurodegeneration
    DOI:  https://doi.org/10.1152/japplphysiol.00407.2025
  11. Dev Biol. 2025 Oct 27. pii: S0012-1606(25)00306-9. [Epub ahead of print]
    Muscle sparing through differential nutritional control of three muscle growth mechanisms: how zebrafish larvae deal with starvation.
    Jeffrey J Kelu, Jing Zhang, Tapan G Pipalia, Akos Berthold, Andrew S Brack, Angela Cheung, Simon M Hughes.
      How vertebrate skeletal muscle size is regulated and balanced with body size over the life-course is unclear, but is important for human health and quality of life. Muscle growth occurs by increase in myofibre number (hyperplasia) and enlargement of existing fibres (hypertrophy). Fibre enlargement reflects either hypernucleation, an increase in myofibre nuclei, and/or hyperoidy, an increase in nuclear domain size (NDS), the volume of myofibre per myonucleus. Quantitative time lapse imaging of muscle cellularity indicates that myotome growth in early larval zebrafish is dominated by hyperoidy, with lesser contribution by hypernucleation. Addition of small new myofibres makes a quantitatively even smaller contribution to growth. During neonatal mouse muscle growth a distinct balance of different growth mechanisms occurs, but yields quantitively similar hyperoidy. In zebrafish, the number of myofibres and myonuclei continue to increase in the absence of independent feeding, whereas NDS shrinks and whole body growth falters without adequate food intake from 5 days post-fertilisation, despite the continued availability of yolk. The persistent accrual of myonuclei while fibres undergo atrophy in response to starvation we term muscle sparing. Myofibre volume increases more than myofibril content during growth. During atrophy, in contrast, cytoplasmic puncta containing sarcolemmal markers become associated with autophagosomes, and lysosomes and myofibrils fill a larger fraction of the remaining sarcoplasm. These observations lead us to propose a 'shopping bag' hypothesis for myofibre hyperoidy and atrophy, whereby change in sarcolemmal area and myofibre volume (the 'bag') precede, and may be required for, changes in the myofibril content (the 'shopping'). The distinct regulation of three muscle growth mechanisms in developing vertebrate models predict similar controls on human muscle growth which, given the importance of skeletal muscle for whole body metabolic health, are of potential relevance to the developmental origins of human health and disease.
    DOI:  https://doi.org/10.1016/j.ydbio.2025.10.020
  12. Front Physiol. 2025 ;16 1654445
    Voluntary wheel running promotes lymphangiogenesis in slow-twitch muscle in young mice.
    Yuma Tamura, Takafumi Kawashima, Aoi Kodama, Rui-Cheng Ji, Yuta Itoh, Nobuhide Agata, Keisuke Kawakami.
       Introduction: Lymphatic vessels contribute to tissue homeostasis. Although the lymphatic vessels in skeletal muscle are known to undergo structural changes under certain conditions, such as atrophy and injury, effects of exercise on intramuscular lymphatic vessels remain unclear.
    Methods: This study was aimed at investigating whether 8 weeks of voluntary wheel running (VWR) induces histological changes in lymphatic and blood capillaries, and whether these responses are related to age and myofiber type. Young (3-month-old) and aged (18-month-old) male C57BL/6 mice were assigned to sedentary or VWR groups. The soleus (SOL; slow-twitch) and plantaris (PLAN; fast-twitch) muscles were analyzed using immunohistochemistry and quantitative polymerase chain reaction.
    Results: In young mice, VWR increased the quantity of type I myofibers and significantly enhanced the density of lymphatic vessels and blood capillaries in the SOL, besides upregulating the expression of vascular endothelial growth factors, VEGF-C and VEGF-D. These changes were not observed in aged mice or in the PLAN of mice in either age group.
    Discussion: Although aged mice showed a similar increase in the quantity of type I myofibers, they did not exhibit corresponding vascular remodeling, which suggests that aging reduces responsiveness to exercise-induced angiogenic and lymphangiogenic signals. Overall, these findings indicate that VWR promotes lymphangiogenesis and angiogenesis in slow-twitch muscle in young mice, probably as an adaptive response to meet the increased oxygen demand. Exercise-induced vascular and lymphatic remodeling in skeletal muscle is significantly influenced by age and myofiber type, highlighting a reduced adaptive capacity of aged muscle that may impact strategies for promoting vascular health through physical activity.
    Keywords:  aged mice; blood capillary; lymphatic vessels; skeletal muscle; voluntary wheel running
    DOI:  https://doi.org/10.3389/fphys.2025.1654445
  13. Acta Physiol (Oxf). 2025 Dec;241(12): e70117
    Exploring Desmin as a Potential Modifier in Duchenne Muscular Dystrophy-Associated Cardiomyopathy.
    Brice-Emmanuel Guennec, Yeranuhi Hovhannisyan, Gaëlle Revet, Sila Polat, Medhi Hassani, Nathalie Mougenot, Inès Barthelemy, Stephane Blot, Caroline Cieniewski-Bernard, Arnaud Ferry, Ekaterini Kordeli, Zhenlin Li, Onnik Agbulut.
       AIM: Duchenne muscular dystrophy (DMD), a rare X-linked genetic disorder, is affecting skeletal and cardiac muscles due to the loss of the dystrophin protein. Modifier proteins, whose expression is altered in DMD patients, may influence disease progression. Desmin, a muscle-specific intermediate filament protein, is increased in the skeletal muscle of mdx mice, a murine model of DMD with a mild phenotype. Here, we inquired whether desmin acts as a modifier in DMD-associated cardiomyopathy.
    METHODS: Soluble and insoluble desmin levels were quantified in the hearts of two mdx mouse models (B10.mdx and D2.mdx), and GRMD dystrophic dogs. The expression of desmin-regulatory proteins was also assessed in mdx mice. To assess the impact of desmin levels on the phenotype, we generated mdx mice either desmin-deficient (mdx-Des-/-) or with reduced levels of desmin by introducing a heterozygous desmin knock-out allele (mdx-Des+/-). Phenotypic analyses included cardiac function assessment and histological evaluation.
    RESULTS: In mdx mice, desmin was elevated in its insoluble, phosphorylated, and presumably filamentous form, while GRMD dogs with a severe DMD-like phenotype showed no such increase. Desmin deficiency in mdx mice led to severely aggravated dystrophic features, including cardiac dysfunction and increased fibrosis. Moreover, partial desmin reduction in mdx-Des+/- mice led to the abrogation of insoluble desmin increase and worsened the mild mdx dystrophic phenotype.
    CONCLUSION: Increased filamentous desmin appears to be protective in mdx mouse hearts and may modulate the severity of DMD cardiomyopathy. These findings support a modifier role for desmin and highlight this protein as a potential therapeutic target for DMD.
    Keywords:  Duchenne muscular dystrophy; cardiomyopathy; desmin intermediate filament; disease‐modifier proteins; mdx mice
    DOI:  https://doi.org/10.1111/apha.70117
  14. FASEB J. 2025 Nov 15. 39(21): e71107
    Shining a Light on Skeletal Muscle Regeneration: Red Photobiomodulation Boosts Myoblast Differentiation In Vitro.
    Martina Parigi, Alessia Tani, Francesco Palmieri, Rachele Garella, Aurora Longhin, Gabriella Teti, Daniele Nosi, Daniele Guasti, Caterina Licini, Alessandra La Contana, Mirella Falconi, Monica Mattioli Belmonte, Roberta Squecco, Flaminia Chellini, Chiara Sassoli.
      Although photobiomodulation (PBM) therapy (i.e., the application of light with a 600-1100 nm wavelength using laser or light-emitting diode devices, a power density of less than 100 mW/cm2, and an energy density of less than 10 J/cm2 at the target) is emerging as a significant noninvasive strategy of promoting regeneration of damaged skeletal muscle tissue, its actual benefits remain debated. In particular, operating parameters exhibiting positive effects on regenerative muscle satellite stem cells need to be clearly identified. Hence, we investigated the effects of red PBM carried out by a laser diode (635 ± 10 nm; 0.4, 4, and 8 J/cm2; 4 mW/cm2; non-contact mode; continuous wave; single exposure) on murine myoblasts undergoing differentiation and on mature myotubes by combining morphological, biochemical, and functional analyses. Red PBM, especially with a 4 J/cm2 energy density, did not alter cell viability but successfully promoted the expression of myogenic transcription factors as myoblast determination protein 1 (MyoD) and myogenin, as well as myotube formation, mitochondrial metabolism, and biogenesis. Consistently, electrophysiological analyses of cell membrane passive properties and inward ion currents indicated the acquisition of a more differentiated phenotype in PBM-treated cells. Moreover, we found that PBM was able to enhance the release of extracellular vesicles (EVs) during cell differentiation according to a promyogenic phenotype. Red PBM treatment did not alter mature myotube viability and dimension while increasing their secretion of promyogenic EVs. Overall, this study provides experimental evidence supporting promyogenic effects of red PBM and the essential groundwork for further preclinical and clinical studies in the field of skeletal muscle regenerative medicine.
    Keywords:  HSP70; IL6; extracellular vesicles; ion currents; laser; myogenesis; photobiomodulation; satellite cells; skeletal muscle
    DOI:  https://doi.org/10.1096/fj.202502477R
  15. Cells. 2025 Oct 16. pii: 1606. [Epub ahead of print]14(20):
    Estrogen Receptor Regulates Male Satellite Cells in a Female, but Not Male, Environment.
    Ahmed S Shams, Brian P Sullivan, Erik A Toso, Dawn A Lowe, Michael Kyba.
      Skeletal muscle homeostasis is dependent on the satellite cell pool, which is regulated by numerous signaling pathways. Estradiol (E2) function via estrogen receptor alpha (ERα, Esr1) plays an important role in satellite cell regulation in females, being necessary for satellite cell maintenance, proliferation and differentiation. Here we investigate this signaling axis in male satellite cells. Male satellite cells express Esr1 mRNA at similar levels to female satellite cells, and E2 enhances the proliferation of male satellite cell-derived myoblasts in vitro. Deletion of Esr1 specifically in male satellite cells has no effect on satellite cell number, nor on their ability to self-renew after injury, during regeneration, or when transplanted into male hosts. However, Esr1 deletion severely reduces self-renewal of male satellite cells when transplanted into female hosts. These data suggest that male satellite cells are competent for E2-ERα signaling, but that this signaling is not efficacious in the male environment, though E2-ERα signaling does become necessary when the male cells are transplanted into a female environment.
    Keywords:  17β-estradiol; estrogen; estrogen receptor; regeneration; satellite cells; sex hormones; skeletal muscle; transplantation
    DOI:  https://doi.org/10.3390/cells14201606
  16. Pharmacol Res. 2025 Oct 29. pii: S1043-6618(25)00441-4. [Epub ahead of print] 108016
    Targeting Cellular Senescence in Dystrophin-/-/Utrophin-/-Double Knockout Mice Improves Musculoskeletal Health and Increases Lifespan.
    Xueqin Gao, Joseph J Ruzbarsky, Matthieu Huard, S Amir H Sajedi, Peter T Shyu, Zuokui Xiao, Britney S Force, Sarah White, Jessica Ayers, Bing Wang, X Edward Guo, Johnny Huard.
      Duchenne muscular dystrophy (DMD) is a severe genetic muscle disease caused by mutations of the dystrophin gene. Previous studies have detected senescent cells in the skeletal muscle of human DMD, dystrophin-deficient mice (Mdx), and rats. This study aimed to use a more severe dystrophin-/-/utrophin-/- (dKO-Hom) mouse model to identify which cells become senescent and if targeting cellular senescence can improve bone quality and muscle pathology in dKO-Hom mice. Immunohistochemistry of P21 and GLB1 revealed significantly more senescent cells in the skeletal muscle tissues of 4-week-old Mdx and dKO-Hom mice compared to WT mice, but not in the bone tissue. The senescent cells were predominantly macrophages (GLB1+/CD68+). Treatment of dKO-Hom mice with ruxolitinib improved spine L5 trabecular bone microarchitecture and ameliorated skeletal muscle histopathology by decreasing senescent macrophages (GLB1+CD68+, FUCA1+/CD68+ or P21+/CD68+) and senescent-associated phenotypes (SASP) such as macrophage migration inhibitory factor (MIF) in skeletal muscle. Ruxolitinib treatment also improved heart muscle pathology by decreasing senescent macrophages. Additionally, ruxolitinib treatment increased muscle grip strength and treadmill endurance of Mdx mice. Moreover, ruxolitinib significantly extended the lifespan of dKO-Hom mice after 12 days of treatment. Furthermore, treatment of dKO-Hom mice with ruxolitinib and deflazacort synergistically improved bone microarchitecture of the spine L5 vertebrate and the proximal tibia trabecular bone (BV/TV, Tb.N, Tb.Th) by increasing osteoblast cells and decreasing osteoclasts. Co-administration of ruxolitinib and deflazacort also synergistically ameliorated skeletal muscle and heart pathology. Therefore, targeting senescent cells with ruxolitinib represents a promising approach for treating DMD patients but warrants further studies in humans.
    Keywords:  Muscular dystrophy; bone health; cellular senescence; deflazacort; dystrophin(-/-)/Utrophin(-/-) mice; ruxolitinib
    DOI:  https://doi.org/10.1016/j.phrs.2025.108016
  17. Front Med (Lausanne). 2025 ;12 1665708
    The role and mechanisms of myokines in sarcopenia: new intervention strategies for the challenges of aging.
    Xiangran Cui, Hongfei Liu, Yantong Liu, Zhitong Yu, Deyu Wang, Wei Wei, Shixuan Wang.
      Sarcopenia is a major health issue among the global aging population, with a prevalence of 10 to 30% in those over 60 years old. As age advances, the gradual decline in muscle mass and function leads to reduced ability to perform daily activities and significantly increases the risks of falls, fractures, disability, and mortality. Recent studies have shown that skeletal muscle is not only a locomotive organ but also an important endocrine organ that affects systemic metabolism by secreting a series of bioactive molecules known as myokines. The secretion patterns of myokines undergo significant changes during aging and the progression of sarcopenia. Protective factors such as IL-15 and IGF-1 decrease, while pathological factors like myostatin and Activin A increase. This imbalance subsequently leads to the continued decline in muscle mass and function, reflected in multiple mechanisms including disruption of protein synthesis and degradation, mitochondrial dysfunction, and chronic inflammatory states. This article systematically reviews the role of myokines in sarcopenia, clarifies their molecular mechanisms, and explores clinical application prospects, aiming to provide a theoretical basis and new intervention targets for the prevention and treatment of sarcopenia. Future research should focus on the dynamic changes, interactions, and targeted intervention strategies of myokines to address the challenges of global aging and improve the quality of life for the elderly population.
    Keywords:  muscle aging; muscle metabolism; myokines; sarcopenia; therapeutic interventions
    DOI:  https://doi.org/10.3389/fmed.2025.1665708
  18. Int J Mol Sci. 2025 Oct 18. pii: 10136. [Epub ahead of print]26(20):
    Cytokinins Are Age- and Injury-Responsive Molecules That Regulate Skeletal Myogenesis.
    Farnoush Kabiri, Zeynab Azimychetabi, Dev Seneviratne, Lorna N Phan, Hannah M Kavanagh, Hannah C Smith, R J Neil Emery, Craig R Brunetti, Janet Yee, Stephanie W Tobin.
      Myogenesis is a tightly regulated process essential for embryonic development, postnatal growth, and muscle regeneration. We recently identified that cytokinins (CTKs), a class of adenine-derived signaling molecules originally characterized in plants, are present in cultured skeletal muscle cells. The most abundant type of cytokinins detected within cultured muscle cells was isopentenyladenine (iP) in its nucleotide, riboside, and free base derivatives. The purpose of this study was to determine whether CTKs are also present in regenerating muscle tissue in vivo and to characterize the effects of iP and its riboside form, isopentenyladenosine (iPR), on muscle cell proliferation and differentiation. These effects were observed relative to adenine and adenosine, and to a second class of cytokinins with a large aromatic side chain, kinetin (the free base), and kinetin riboside. Cardiotoxin was used to induce muscle injury and repair processes in the gastrocnemius of 3- and 12-month-old mice. Samples were collected 3- and 7 days post-injury for ultra high-performance liquid chromatography tandem mass spectrometry with electrospray ionization (UHPLC-(ESI+)-HRMS/MS). Four CTKs (N6-benzyladenine (BA), dihydrozeatin-9-N-glucoside (DZ9G), isopentenyladenosine (iPR), and 2-methylthio-isopentenyladenosine (2-MeSiPR) were detected. 2-MeSiPR levels were significantly influenced by aging, as this CTK was increased in response to injury only in the younger mice. Treatment of C2C12 myoblasts with 10 µM of isopentenyladenosine (iPR) or kinetin riboside reduced cell proliferation, whereas iP (the free base) increased proliferation in a biphasic response. During differentiation, both iPR and kinetin riboside impaired myotube formation, while the free-base forms of iP and kinetin had no effect. Our data establishes that CTKs are present within muscle tissue and highly responsive to injury and aging. Furthermore, the biological activities of CTKs in muscle cells are influenced by structural modifications, including riboside conjugation and side chain composition. Understanding these differences provides insight into the distinct roles of CTKs in muscle cell metabolism and differentiation, offering potential implications for the use of exogenous CTKs in muscle biology and regenerative medicine.
    Keywords:  cytokinins (CTKs); i6A; isopentenyladenine (iP); isopentenyladenosine (iPR); kinetin; skeletal myogenesis
    DOI:  https://doi.org/10.3390/ijms262010136
  19. Stem Cell Reports. 2025 Oct 30. pii: S2213-6711(25)00296-6. [Epub ahead of print] 102692
    Modulation of the JAK2-STAT3 pathway promotes expansion and maturation of human iPSC-derived myogenic progenitor cells.
    Luca Caputo, Cedomir Stamenkovic, Matthew T Tierney, Alessandra Cecchini, Monica Nicolau, Gabriele Guarnaccia, Jesus R Barajas, Maria Sofia Falzarano, Rhonda Bassel-Duby, Alessandra Ferlini, Eric N Olson, Pier Lorenzo Puri, Alessandra Sacco.
      Generation of in vitro human induced pluripotent cell (hiPSC)-derived skeletal muscle progenitor cells (SMPCs) holds great promise for regenerative medicine for skeletal muscle wasting diseases, for example Duchenne muscular dystrophy (DMD). While multiple approaches have been described to obtain SMPCs in vitro, hiPSC-derived SMPCs generated using transgene-free protocols are usually obtained in a low amount and resemble a more embryonal/fetal stage of differentiation. Here, we demonstrate that modulation of the JAK2/STAT3 signaling pathway during an in vitro skeletal muscle differentiation protocol increases the yield of PAX7+ and CD54+ human SMPCs (hSMPCs) and drives them to a higher maturation stage, in both human embryonic stem (ES) and patient-derived induced pluripotent cells (iPSCs). Importantly, the obtained SMPCs are able to differentiate into multinucleated myotubes in vitro and engraft in vivo. These findings reveal that modulation of the JAK2/STAT3 signaling pathway is a potential therapeutic avenue to generate SMPCs in vitro with potential for cell therapy approaches.
    Keywords:  Duchenne muscular dystrophy; STAT3 pathway; hiPSC; myotubes; skeletal muscle progenitor cells, myogenic maturation, skeletal muscle regeneration, cell therapy
    DOI:  https://doi.org/10.1016/j.stemcr.2025.102692
  20. Skelet Muscle. 2025 Oct 27. 15(1): 30
    TET exhibits enzymatic-independent and-dependent functions during Drosophila flight muscle development and aging.
    Vincent Gerdy, Emilie Plantié, Romane Bertrand, Yoan Renaud, Guillaume Junion, Laurence Vandel, Lucas Waltzer.
       BACKGROUND: Enzymes of the Ten-Eleven Translocation family are responsible for 5-methylcytosine (5mC) oxidation and play a key role in regulating DNA demethylation during various developmental processes, including myogenesis. However, they also exhibit 5mC-independent functions whose importance for muscle development remains unexplored. As the Drosophila genome lacks the enzymes required for 5mC deposition but contains a single Tet gene essential for viability, we analyzed its role in flight muscle development.
    METHODS: Using a combination of genetics, imaging techniques, transcriptomic analysis and functional assays, we assessed the impact of Tet loss of function (using either Tet null or Tet catalytic inactive mutants, as well as Tet knockdown) on indirect flight muscle development from the larval to adult stages and during aging in Drosophila melanogaster.
    RESULTS: We found that Tet loss leads to a decrease in the number of adult muscle progenitors in the larva, dysregulation of the myogenic expression program in the pupa and disrupted flight muscle organization in the adult. Interestingly, our data reveal that these phenotypes are largely independent of TET enzymatic activity. However, analysis of TET-catalytic inactive flies also highlights the enzyme's critical role in adult fly mobility and its ability to prevent premature muscle aging. Further experiments demonstrate that TET expression in muscle progenitors and the central nervous system is essential for maintaining adult mobility.
    CONCLUSIONS: These results highlight the crucial role of TET beyond 5mC DNA oxidation, suggesting that both catalytic-dependent and catalytic-independent functions of TET are essential for muscle development and function in vivo.
    Keywords:   Drosophila ; Aging; Catalytic activity; Flight; Mobility; Muscles; Ten-eleven translocation
    DOI:  https://doi.org/10.1186/s13395-025-00399-x
  21. Int J Mol Sci. 2025 Oct 11. pii: 9912. [Epub ahead of print]26(20):
    Magnesium Preserves Calcium Homeostasis and Contributes to Protect Myotubes from Inflammation-Induced Damage.
    Giuseppe Pietropaolo, Sara Castiglioni, Jeanette A Maier, Federica I Wolf, Valentina Trapani.
      Magnesium (Mg2+) is a key regulator of cellular biochemical processes and an essential cofactor in skeletal muscle physiology. Although Mg2+ deficiency has been linked to reduced muscle strength, its role in the regulation of calcium (Ca2+) signaling and in inflammation remains incompletely understood. In this study, we examined the effects of Mg2+ availability using the murine myoblast cell line C2C12. Cells were differentiated under low, normal, or high Mg2+ conditions, and myotube formation, intracellular Ca2+ fluxes, and resistance to inflammatory stimuli were assessed. Mg2+ deficiency impaired myotube differentiation, while Mg2+ supplementation preserved Ca2+ response during stimulation and contributed to protect myotubes against inflammation-induced damage. Collectively, these findings highlight a dual role of Mg2+ in sustaining functional performance under repeated stress and protecting myotubes against inflammatory injury. This study supports the importance of adequate dietary Mg2+ intake as a potential strategy to mitigate muscle loss associated with aging and chronic inflammation.
    Keywords:  calcium signaling; inflammation; magnesium homeostasis; skeletal muscle C2C12 cells
    DOI:  https://doi.org/10.3390/ijms26209912
  22. J Cachexia Sarcopenia Muscle. 2025 Dec;16(6): e70094
    R405W Desmin Knock-In Mice Highlight Alterations of Mitochondria, Protein Quality Control and Myofibrils in Myofibrillar Myopathy.
    Sabrina Batonnet-Pichon, Florence Delort, Alain Lilienbaum, Carolin Berwanger, Dorothea Schultheis, Ursula Schlötzer-Schrehardt, Andreas Schmidt, Steffen Uebe, Yosra Baiche, Tom J Eisenack, Débora Broch Trentini, Markus Mallek, Leonid Mill, Ana Ferreiro, Bettina Eberhard, Thomas Lücke, Markus Krüger, Christian Thiel, Rolf Schröder, Christoph S Clemen.
       BACKGROUND: Mutations in the desmin gene cause skeletal myopathies and cardiomyopathies. The objective of this study was to elucidate the molecular pathology induced by the expression of R405W mutant desmin in murine skeletal muscle.
    METHODS: A comprehensive characterization of the skeletal muscle pathology in hetero- and homozygous R405W desmin knock-in mice was performed. This included grip strength, blood acylcarnitine and amino acid, histological, ultrastructural, immunofluorescence, immunoblot, ribosomal stalling, RNA sequencing and proteomic analyses.
    RESULTS: Both hetero- and homozygous R405W desmin knock-in mice showed classical myopathological features of a myofibrillar myopathy with desmin-positive protein aggregation, degenerative changes of the myofibrillar apparatus and mitochondrial alterations. Muscle weakness and increased blood concentrations of acylcarnitines and amino acids were only present in homozygous animals. During its translation, mutant desmin did not induce terminal ribosomal stalling. Analyses of RNA sequencing and proteomic data from soleus muscle of 3-month-old mice depicted 59 up- and 3 down-regulated mRNAs and 101 up- and 18 down-regulated proteins that were shared between the heterozygous and homozygous genotypes in the respective omics datasets compared to the wild-type genotype. Combined analysis of the omics data demonstrated 187 significantly dysregulated candidates distributed across four groups of regulation. A down-regulation on the mRNA and protein levels was observed for a multitude of mitochondrial proteins including essential proton gradient-dependent carriers. Up-regulation on both omics levels was present for the transcription factor Mlf1, which is a binding partner of protein quality control related Dnajb6. Down-regulated on mRNA but up-regulated on the protein level was the sarcomeric lesion marker Xirp2 (xin actin-binding repeat-containing protein 2), whereas Ces2c (acylcarnitine hydrolase) was regulated in the opposite way.
    CONCLUSIONS: The present study demonstrates that the expression of mutant desmin results in a myofibrillar myopathy in hetero- and homozygous R405W desmin knock-in mice. Combined morphological, transcriptomic and proteomic analyses helped decipher the complex pattern of early pathological changes induced by the expression of mutant desmin. Our findings highlight the importance of major mitochondrial alterations, including essential proton gradient-dependent carriers as well as Dnajb6-related protein quality control and Xin-related myofibrillar damage, in the molecular pathogenesis of desminopathies.
    Keywords:  intermediate filament desmin; myofibrillar myopathy; protein aggregation; proteomicsdesminopathy; secondary mitochondriopathy; transcriptomics
    DOI:  https://doi.org/10.1002/jcsm.70094
  23. Int J Mol Sci. 2025 Oct 13. pii: 9945. [Epub ahead of print]26(20):
    Boldo Restores Vascularization and Reduces Skeletal Muscle Inflammation in Symptomatic Mice with Dysferlinopathy.
    Walter Vásquez, Felipe Troncoso, Andrea Lira, Carlos Escudero, Juan C Sáez.
      Dysferlinopathies are progressive muscular dystrophies caused by DYSF mutations, leading to impaired membrane repair, chronic inflammation, lipid accumulation, and muscle degeneration. No approved therapies currently halt the progression of this disease. Here, we evaluated the effects of daily oral administration of pulverized Boldo (Peumus boldus) leaves, commonly used as a nutraceutical, to blAJ mice, a model of dysferlinopathy. Symptomatic bIAJ mice were treated for four weeks with Boldo and presented significantly improved grip strength and restored endothelial-dependent vasodilation. Muscle perfusion and capillary density in the gastrocnemius were both enhanced by treatment. Histological analyses revealed that Boldo prevented myofiber atrophy, reduced centrally nucleated fibers, and improved muscle tissue architecture. Lipid accumulation observed in blAJ muscles was absent in Boldo-treated mice. At the cellular level, Boldo normalized sarcolemma membrane permeability (dye uptake) and reduced mRNA levels of inflammasome components (NLRP3, ASC, and IL-1β), suggesting anti-inflammatory activity. These findings indicate that Boldo improves vascular and muscle integrity, supporting its potential as a complementary therapeutic strategy for dysferlinopathy.
    Keywords:  dysferlinopathy; peumus boldus; skeletal muscle
    DOI:  https://doi.org/10.3390/ijms26209945
  24. Nat Rev Endocrinol. 2025 Oct 28.
    Endocrine control of skeletal muscle regeneration and clinical applications.
    Peggy Lafuste, Frederic Relaix.
      
    DOI:  https://doi.org/10.1038/s41574-025-01205-w
  25. J Muscle Res Cell Motil. 2025 Oct 28.
    Urinary titin represents an exciting biomarker for assessment of muscle health.
    Nicholas Melisi, Matthew J Gage.
      Titin is the largest known protein in the human body and operates as a signaling hub, contributes to passive force in the muscle, and as a molecular spring. Muscle tissue experiences damage and atrophy for many reasons including exercise, disease, or age. When muscle tissue is catabolized, a consistent biomarker can be found in the urine: urinary titin N-terminal fragment (UTF). This biomarker was first identified in 2014, but research into this biomarker began in earnest in 2016 when UTF was found to be elevated in both Duchenne muscular dystrophy patients and individuals post-exercise compared to the control groups. Subsequent research found that while Duchenne muscular dystrophy has increased UTF values, this symptom is common across many muscular dystrophy disorders. It's been postulated that UTF values could be an effective diagnostic tool for early muscular dystrophy disorders and certain forms of myopathy. Both muscle atrophy and eccentric exercise have both been shown to produce elevated UTF as well. This review highlights the key findings over the past 10 years in this field and identifies questions regarding production of UTF that should be the focus of the next 10 years of work in this area.
    Keywords:  ELISA; Eccentric exercise; Muscle damage; Muscular dystrophy; Sarcomere; Urinary titin fragment
    DOI:  https://doi.org/10.1007/s10974-025-09710-1
  26. Life (Basel). 2025 Oct 20. pii: 1632. [Epub ahead of print]15(10):
    Effects of Exercise Training on Muscle Function.
    Marco Duca, Athos Trecroci.
      Exercise training is a versatile and powerful tool to improve muscle function [...].
    DOI:  https://doi.org/10.3390/life15101632
  27. RNA Biol. 2025 Oct 31.
    Circular rna Pde4dip regulates myogenesis by interacting with Zfp143 mRNA: a novel regulatory axis.
    Suman Singh, Arundhati Das, Gaurahari Sahoo, Amaresh Chandra Panda.
      Many transcriptional and post-transcriptional regulators tightly regulate skeletal muscle myogenesis, including recently discovered circular RNAs (circRNAs). In this study, we used a crosslinking-based sequencing method called CLiPP-Seq, in which we performed AMT-mediated Cross-Linking of RNA-RNA duplexes followed by Poly(A) RNA Pulldown and sequencing to identify mRNA-interacting circRNAs in the mRNA samples of mouse C2C12 myoblasts and myotubes. BLAST analysis of the circRNAs with mRNAs identified their potential interacting partners. Interestingly, silencing of the circular RNA Pde4dip (circPde4dip) altered the target mRNA Zfp143 (zinc finger protein 143) expression and suppressed the differentiation of C2C12 myoblasts into myotubes. In summary, we identified unexplored mRNA-interacting circRNAs and their possible functions in muscle cell differentiation, specifically the circPde4dip-Zfp143 mRNA interaction regulating myogenesis.
    Keywords:  C2C12; RNA-RNA Interactions; circular RNA; mRNA regulation; microRNA; muscle cells; myogenesis
    DOI:  https://doi.org/10.1080/15476286.2025.2583576
  28. Metabolites. 2025 Oct 02. pii: 655. [Epub ahead of print]15(10):
    Linking Elastin in Skeletal Muscle Extracellular Matrix to Metabolic and Aerobic Function in Type 2 Diabetes: A Secondary Analysis of a Lower Leg Training Intervention.
    Nicholas A Hulett, Leslie A Knaub, Irene E Schauer, Judith G Regensteiner, Rebecca L Scalzo, Jane E B Reusch.
      Background: Type 2 diabetes (T2D) is associated with reduced cardiorespiratory fitness (CRF), a critical predictor of cardiovascular disease and all-cause mortality. CRF relies upon the coordinated action of multiple systems including the skeletal muscle where the mitochondria metabolize oxygen and substrates to sustain ATP production. Yet, previous studies have shown that impairments in muscle bioenergetics in T2D are not solely due to mitochondrial deficits. This finding indicates that factors outside the mitochondria, particularly within the local tissue microenvironment, may contribute to reduced CRF. One such factor is the extracellular matrix (ECM), which plays structural and regulatory roles in metabolic processes. Despite its potential regulatory role, the contribution of ECM remodeling to metabolic impairment in T2D remains poorly understood. We hypothesize that pathological remodeling of the skeletal muscle ECM in overweight individuals with and without T2D impairs bioenergetics and insulin sensitivity, and that exercise may help to ameliorate these effects. Methods: Participants with T2D (n = 21) and overweight controls (n = 24) completed a 10-day single-leg exercise training (SLET) intervention. Muscle samples obtained before and after the intervention were analyzed for ECM components, including collagen, elastin, hyaluronic acid, dystrophin, and proteoglycans, using second harmonic generation imaging and immunohistochemistry. Results: Positive correlations were observed with elastin content and both glucose infusion rate (p = 0.0010) and CRF (0.0363). The collagen area was elevated in participants with T2D at baseline (p = 0.0443) and showed a trend toward reduction following a 10-day SLET (p = 0.0867). Collagen mass remained unchanged, suggesting differences in density. Dystrophin levels were increased with SLET (p = 0.0256). Conclusions: These findings identify that structural proteins contribute to aerobic capacity and identify elastin as an ECM component linked to insulin sensitivity and CRF.
    Keywords:  collagen; elastin; extracellular matrix; insulin sensitivity; skeletal muscle
    DOI:  https://doi.org/10.3390/metabo15100655
  29. J Tissue Eng. 2025 Jan-Dec;16:16 20417314251382710
    Human three-dimensional engineered muscle tissue characterization and intramyocellular lipid modeling.
    Tianxin Cao, Eric Finnemore, Jon Hill, Shuo Wang, Chuanyu Wang, Heather Robinson, Jorge Villalona, Suzanne Segal, Curtis R Warren.
      Three-dimensional engineered muscle tissues (EMTs) are transformative tools for modeling skeletal muscle physiology and pathology in vitro. Here, we perform a comprehensive comparison of EMTs derived from primary human myoblasts (hP-Myo) and hiPS-derived myoblasts (hiPS-Myo) to evaluate their structural, functional, and transcriptional characteristics. Contractile performance was quantified using a magnetic force-sensing platform, revealing that hP-Myo EMTs generate ~2 fold higher twitch forces and enhanced tetanic responses compared to hiPS-Myo EMTs. Tissue architecture and maturation were assessed and demonstrated significant larger myofiber diameters in hP-Myo EMTs. Transcriptomic profiling highlighted that hP-Myo EMTs maintain a mature skeletal muscle-like signature, marked by enriched pathways linked to sarcomere organization and fast-/slow-twitch fiber specification. To model metabolic dysfunction, hiPS-Myo EMTs were subjected to lipid overload, recapitulating hallmarks of intracellular lipid (IMCL) accumulation, including impaired contractility, blunted force-frequency responses, and dysregulated lipid metabolism genes.
    Keywords:  3D tissue engineering; contractility; intramyocellular lipid; skeletal muscle
    DOI:  https://doi.org/10.1177/20417314251382710
  30. Biol Trace Elem Res. 2025 Oct 31.
    Arsenic Exposure Alters Liver Metabolism and Accelerates Skeletal Muscle Atrophy in Female BALB/c Mice.
    Deogade Sakshi Rajeshwar, Sree Vaishnavi Nalla, Itishree Dubey, Rohit Kumar Gautam, Shivani Bhardwaj, Richa Shrivastava, Sapana Kushwaha.
      The liver and skeletal muscle are metabolically interconnected organs vital for maintaining systemic homeostasis. Arsenic toxicity is known to adversely affect both organs individually, yet the mechanistic link between arsenic-induced liver dysfunction and skeletal muscle deterioration remains unclear. This study aimed to investigate whether arsenic-induced alterations in hepatic metabolism are associated with changes in skeletal muscle health. BALB/c mice were divided into four groups: Control, 0.2 ppm arsenic, 2 ppm arsenic, and 20 ppm arsenic. For 30 days, sodium arsenite was administered in the drinking water ad libitum. Arsenic exposure led to elevated serum ALT and AST levels, increased hepatic lipid accumulation, and dysregulated the expression of oxidative stress defense components (Nrf2/Keap1), lipid metabolism regulators (PPAR-γ and PPAR-α), β-oxidation and lipogenic enzymes (CPT-1, and SREBP-1), as well as hepatic energy sensors (p-mTOR and p-AMPK). These hepatic changes were accompanied by oxidative stress and elevated proinflammatory cytokines (TNF-α, IL-6) in the liver and serum. Concurrently, skeletal muscle exhibited functional decline, as evidenced by decreased grip strength and elevated serum creatine kinase levels. Histological and Succinate dehydrogenase (SDH) analysis further revealed atrophy, characterized by reduced fiber cross-sectional area and a fiber-type shift from fast-twitch (Type II) to slow-twitch (Type I) fibers respectively. At the molecular level, arsenic exposure upregulated the muscle-specific ubiquitin ligases MuRF1 and atrogin-1, accompanied by NF-κB activation, indicating increased proteolysis and inflammation. Additionally, decreased irisin expression in both liver and muscle and reduced serum insulin levels indicated systemic metabolic dysregulation. Correlation analysis of inflammatory markers with indices of liver and muscle injury, together with evidence of crosstalk between these tissues, revealed significant associations. Collectively, these findings suggest that arsenic-induced hepatic disturbances may indirectly contribute to skeletal muscle wasting via systemic inflammation, supporting the possible involvement of a liver-muscle axis in arsenic toxicity.
    Keywords:  Arsenic; Inflammation; Lipid metabolism; Liver; Skeletal muscle
    DOI:  https://doi.org/10.1007/s12011-025-04839-z
  31. NPJ Microgravity. 2025 Oct 27. 11(1): 73
    Abdominal LIPUS ameliorates simulated microgravity induced skeletal muscle atrophy via the gut-muscle axis.
    Yanan Yu, Yumei Zheng, Huiyuan Zhang, Xiushan Fan, Jianzhong Guo, Lijun Sun, Liang Tang, Dean Ta.
      Study investigated if abdominal low-intensity pulsed ultrasound (LIPUS) alleviates simulated microgravity (hindlimb unloading, HU)-induced skeletal muscle atrophy by restoring gut microbiota. Mice were divided into control (NC), HU, and HU with daily abdominal LIPUS (HU + LIPUS) groups. Fecal microbiota transplantation (FMT) from LIPUS-treated mice to HU mice was also performed. After 28 days, abdominal LIPUS partially reversed HU-induced gut dysbiosis, restored intestinal barrier integrity, and increased short-chain fatty acid (SCFAs) levels. LIPUS downregulated muscle atrophy genes (MSTN, ActRIIB) and upregulated growth genes (Akt, mTOR) in HU mice, preventing muscle loss. SCFAs levels positively correlated with muscle function. HU mice receiving FMT from LIPUS-treated donors showed similar gut and muscle improvements as direct LIPUS treatment. Results demonstrate abdominal LIPUS ameliorates muscle atrophy by modulating the gut-muscle axis, offering a potential non-invasive strategy for astronauts and patients.
    DOI:  https://doi.org/10.1038/s41526-025-00514-8
  32. J Physiol. 2025 Oct 29.
    Potential health benefits of cold-water immersion: the central role of PGC-1α.
    Erich Hohenauer, Wafa Douzi, Johannes Burtscher.
      Cold-water immersion (CWI) elicits a coordinated thermoregulatory and stress-response programme that may converge on molecular pathways linked to peroxisome proliferator-activated receptor-γ co-activator-1α (PGC-1α), a master regulator of mitochondrial biogenesis and a coordinator of angiogenesis, antioxidant defence and metabolism. Through activation of peripheral cold receptors (e.g. TRPM8), CWI triggers sympathetic noradrenaline release and hypothalamic-pituitary-thyroid axis stimulation (TSH→D2→T3), driving β-adrenergic/cAMP-PKA-p38MAPK-CREB signalling that could robustly upregulate PGC-1α and uncoupling protein-1 in brown adipose tissue and skeletal muscle. Concurrent shivering-induced Ca2+ fluxes engage calcium/calmodulin-stimulated protein kinase II and calcineurin, enhancing PGC-1α expression in an AMP-activated protein kinase (AMPK)-independent manner. Elevated PGC-1α coactivates nuclear respiratory factors (NRF1/NRF2) and mitochondrial transcription factor A to expand mitochondrial content and oxidative capacity, while upregulating key antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase). Together with oestrogen-related receptor α, PGC-1α can co-activate vascular endothelial growth factor, a pathway compatible with angiogenesis and improved perfusion; however, in humans the link to CWI remains indirect and is largely limited to acute molecular responses. Downstream metabolic adaptations, including increased fatty acid oxidation (via carnitine palmitoyltransferase 1, peroxisome proliferator-activated receptors α/γ and AMPK) and fibroblast growth factor 21 secretion, enhance insulin sensitivity and energy expenditure. Most of the evidence currently rests on molecular signalling data, heterogeneous study designs, or acute gene expression responses. Direct evidence for increased mitochondrial content, improved mitochondrial function, or long-term health benefits in humans is scarce. Therefore, this article introduces a hypothetical dose-response relationship, linking immersion time to proposed health benefits and death, and provides practical recommendations for safe CWI protocols.
    Keywords:  angiogenesis; cold‐water immersion; extreme temperature adaptation; hormesis; mitochondrial biogenesis; peroxisome proliferator‐activated receptor γ co‐activator‐1α (PGC‐1α); redox regulation
    DOI:  https://doi.org/10.1113/JP289536
  33. Cell Biol Int. 2025 Oct 30.
    Sodium Tanshinone IIA Sulfonate Ameliorates Fibrosis of Skeletal Muscle Injury by Regulating Transforming Growth Factor-β1/Smad3 and Phosphoinositide 3-Kinase/protein Kinase B/Cyclooxygenase-2 Signaling Pathways.
    Fujun Ding, Jinghai Gong, Fei Yu, Pei Zhang, Hansheng Hu, Dan Guo.
      Sodium tanshinone IIA sulfonate exerts several pharmacological effects; however, its mechanism in skeletal muscle injuries remains unknown. We explored the biological function of sodium tanshinone IIA sulfonate in skeletal muscle injury and elucidated its underlying mechanisms. We established a skeletal muscle injury model following blunt trauma and transforming growth factor-β1-induced NIH/3T3 cell models. Morphological changes, collagen deposition, and fibrosis in the muscle tissues were evaluated, and cell proliferation was determined. The expression of myogenic differentiation markers in C2C12 cells, including myogenic differentiation 1 and myosin heavy chain, and the activity of the transforming growth factor-β1/Smad3 and phosphoinositide 3-kinase/protein kinase B/cyclooxygenase-2 signaling pathway were measured. Compared to the model group, the sodium tanshinone IIA sulfonate-treated group showed reduced inflammatory cell infiltration, collagen deposition, and fibrosis. Transforming growth factor-β1 and cyclooxygenase-2 expression and Smad3 and phosphoinositide 3-kinase/protein kinase B pathway activation were inhibited by sodium tanshinone IIA sulfonate. In vitro, sodium tanshinone IIA sulfonate treatment significantly reduced NIH/3T3 cell proliferation and downregulated p-Smad3, transforming growth factor-β1, and cyclooxygenase-2 expression in a dose-dependent manner. Moreover, sodium tanshinone IIA sulfonate enhanced myogenic differentiation 1 and myosin heavy chain expression in C2C12 cells. Furthermore, sodium tanshinone IIA sulfonate inhibited the activation of transforming growth factor-β1/Smad3 and phosphoinositide 3-kinase/protein kinase B/cyclooxygenase-2 signaling pathway in skeletal muscle fibrosis. Thus, sodium tanshinone IIA sulfonate exerted a suppressive effect on skeletal muscle fibrosis via the transforming growth factor-β1/Smad3 and phosphoinositide 3-kinase/protein kinase B/cyclooxygenase-2 signaling pathways, providing a new therapeutic approach for skeletal muscle fibrosis.
    Keywords:  PI3K/AKT/COX‐2 pathway; TGF‐β1/Smad3 pathway; fibrosis; skeletal muscle injury; sodium tanshinone IIA sulfonate
    DOI:  https://doi.org/10.1002/cbin.70099
  34. Int J Biol Macromol. 2025 Oct 28. pii: S0141-8130(25)09166-4. [Epub ahead of print]332(Pt 1): 148609
    Nicotinamide nucleotide transhydrogenase dysfunction transcriptionally impacts mitochondrial β-oxidation and neuromuscular junction in M. Gastrocnemius of 24-day-old mice.
    Jingyi Song, Jaap Keijer, Melissa Bekkenkamp-Grovenstein, Melanie Humphry, Claudia Carmone, Sander Grefte.
      Nicotinamide nucleotide transhydrogenase (NNT) is a key mitochondrial enzyme generating NADPH by utilizing the proton gradient produced by oxidative phosphorylation (OXPHOS), thereby linking redox homeostasis to mitochondrial energy metabolism. The commonly used C57BL/6 J mouse strain lacks functional NNT, yet its impact during early development remains unclear. This study aimed to characterize adaptive molecular responses in the gastrocnemius muscle of young mice with NNT deficiency. Congenic Nnt deficient (NntΔ; BL6JRcc.BL6J-NntC57BL/6J/Wuhap) and wild-type (Nntwt; B6JRcc(B6J)-Nnt+/Wuhap) mouse lines were newly created. Transcriptome profiling was performed on gastrocnemius muscles of 24-day-old male mice, followed by validation of key findings. Energy metabolism emerged as the most affected process, and NntΔ mice exhibited significant reduced OXPHOS-related genes, particularly within complex I and complex V showing a downregulation of 42.2 % and 50 % of their subunits, respectively. Additionally, expression of Cpt1b, Cpt2, and Slc25a20, involved in fatty acid transport, was reduced by 33 %, 19 % and 23 %, respectively. These results may explain the trend toward decreased oxygen consumption rates using palmitoylcarnitine (29 %; P-value = 0.068) and octanoylcarnitine (18 %; P-value = 0.081). CHRNA1, a protein critical for neuromuscular junction (NMJ) function, was also downregulated by 31 %. These results suggest that functional loss of NNT impairs mitochondrial energy pathways and β-oxidation, potentially influencing NMJ in the gastrocnemius muscle during development.
    Keywords:  Mitochondria; NNT; OXPHOS
    DOI:  https://doi.org/10.1016/j.ijbiomac.2025.148609
  35. Biology (Basel). 2025 Oct 01. pii: 1343. [Epub ahead of print]14(10):
    Study on the Mechanism of Low-Intensity Pulsed Ultrasound in Ameliorating Glucose Metabolism Through Attenuation of Skeletal Muscle Atrophy in Mice with Type 1 Diabetes.
    Zhanke Ma, Yanan Yu, Mengshu Cao, Fang Pang, Lijun Sun, Chenghui Wang, Xiushan Fan, Liang Tang.
      Diabetic skeletal muscle atrophy is one of the most serious complications among diabetes-related complications. LIPUS enhances muscle regeneration and repair in skeletal muscle injuries. However, whether LIPUS can improve skeletal muscle atrophy in mice with T1DM has not been studied. This study involves forty male C57BL/6 mice randomly divided into four groups: normal control group (NC), streptozocin (STZ)-induced T1DM mice (T1D), T1DM mice treated with LIPUS (DL), and T1DM mice treated with insulin (DI). The DL group was treated on the quadriceps of mice with LIPUS (1 MHz, 80 mW/cm2, 20 min/day) for 6 weeks. The results demonstrated that LIPUS significantly improved muscle function by increasing the cross-sectional area, mass, and strength of skeletal muscles. In addition, LIPUS significantly effectively lowered the blood glucose levels of T1DM mice. The knockout of myostatin (MSTN) (MSTN-/-) and knockin of MSTN (MSTN+/+) mice were employed to verify the underlying mechanism. The results indicated that LIPUS reduces blood glucose levels in T1DM mice by improving their muscle atrophy. This study demonstrated that LIPUS will become a novel therapy for the treatment of skeletal muscle atrophy caused by T1DM.
    Keywords:  low-intensity pulsed ultrasound (LIPUS); myostatin (MSTN); quadriceps; type 1 diabetes
    DOI:  https://doi.org/10.3390/biology14101343
  36. J Physiol. 2025 Oct 26.
    NSAID ingestion augments training-induced muscle hypertrophy and differentially affects muscle mRNA expression, but not strength gains, in trained men.
    Joanne E Mallinson, Tariq Taylor, Dumitru Constantin-Teodosiu, Despina Constantin, Martino V Franchi, Dorothee Auer, Paul L Greenhaff.
      Non-steroidal anti-inflammatory drugs (NSAIDs) are widely overused in sports. The temporal effects of combined NSAID consumption and resistance exercise training (RET) on muscle cross-sectional area (CSA), volume and targeted mRNA transcripts (n = 93) were quantified. Seventeen trained males (24.5 ± 1.1 years, body mass index (BMI) 24.2 ± 0.7 kg/m2) consumed either placebo (PLA; n = 8) or diclofenac (75 mg, NSAID; n = 9) daily for 12 weeks and performed 3×30 maximal, isokinetic knee extensions in the non-dominant leg (90°/s) thrice each week. Quadriceps muscle CSA and volume were measured at baseline, 28 days and 84 days (3T MRI). Vastus lateralis biopsies were obtained at baseline, 24 h, 7 days, 28 days and 84 days for mRNA abundance measurements (RT-PCR microfluidic cards). Work output throughout RET was no different between groups. Muscle CSA was increased from baseline in both groups at 28 days (PLA 4.3 ± 2.5%, P = 0.039; NSAID 4.6 ± 3.7%, P = 0.011), but only in the NSAID group at 84 days (PLA 3.9 ± 0.8%, NSAID 8.6 ± 5.3%; P < 0.001; NSAID vs. PLA, P = 0.038), and was paralleled by muscle volume changes. RET increased isometric strength (∼40%-50%), but gains were no different between groups. Based on mRNA expression changes several cellular functions associated with muscle mass and metabolic regulation were altered in both groups throughout RET and were greater in NSAID at 28 and 84 days. NSAID intervention produced greater muscle hypertrophy than PLA, which occurred between 28 and 84 days of RET and was paralleled by more pronounced muscle mRNA changes. These collective events were not accompanied by greater strength gains, suggesting that using NSAIDs alongside RET may not be optimal for enhancing sports performance. KEY POINTS: Non-steroidal anti-inflammatory drug (NSAID) ingestion over 84 days of resistance exercise training increased muscle cross-sectional area and volume gains compared to placebo ingestion in young, trained male volunteers, and this occurred predominantly from day 28 to day 84 of training. In parallel with this, alterations in gene networks associated with a number of cellular functions linked to regulation of muscle mass and muscle metabolism were detected in the NSAID group relative to placebo. This greater resistance training-induced hypertrophy associated with NSAID ingestion was not accompanied by greater gains in isometric knee extensor strength or isokinetic work output during training compared to resistance training alone.
    Keywords:  NSAID; hypertrophy; muscle strength; resistance exercise; skeletal muscle
    DOI:  https://doi.org/10.1113/JP289542
  37. Exp Physiol. 2025 Oct 30.
    The effect of bed rest, unilateral limb immobilization and head-down tilt on muscle protein synthesis: A systematic review and meta-analysis.
    Konstantinos Prokopidis, Paul T Morgan, Colleen S Deane, Oliver C Witard, David D Church.
      Muscle disuse leads to muscle atrophy and a decrease in muscle function that is primarily driven by reduced muscle protein synthesis (MPS). The aim of this systematic review and meta-analysis was to examine the effect of different models of muscle disuse on rates of MPS. A literature search was conducted in PubMed, Web of Science, Scopus and Cochrane Library. Eligible randomized and non-randomized controlled trials compared the effect of bed rest (BR), unilateral lower limb immobilization (ULLI), and 6° head-down tilt (HDT) on pre-post muscle disuse changes in MPS in adults. Using the random and fixed effects inverse-variance model, we calculated the mean difference (MD) in the effect of BR on mixed MPS and ULLI on myofibrillar MPS (MyoPS) (both expressed as fractional synthetic rate,%/h). The effect of HDT on MPS was examined through a narrative synthesis of data. A total of 16 studies were included in the systematic review and 13 in the meta-analysis. A significant reduction in mixed MPS was observed after BR (k = 4; MD: -0.017%/h, 95% CI: -0.023 to -0.011, I2 = 24%, P < 0.01) and a significant reduction in MyoPS was observed after ULLI (k = 9; MD: -0.015%/h, 95% CI: -0.021 to -0.008, I2 = 94%, P < 0.01). HDT led to reductions in both mixed MPS and MyoPS. A comparable reduction in mixed MPS and MyoPS was observed between different models of muscle disuse.
    Keywords:  fractional synthetic rate; muscle disuse; physical inactivity; skeletal muscle
    DOI:  https://doi.org/10.1113/EP092474
  38. Front Aging. 2025 ;6 1698219
    Editorial: Spotlight on aging: role of exercise and nutrition in healthy longevity.
    Antonio Paoli, Richard Siow, Tatiana Moro.
      
    Keywords:  aging; endurance exercise; healthy ageing; miRNA; microbiome; mind - body approaches; physical exercise; resistance trainig
    DOI:  https://doi.org/10.3389/fragi.2025.1698219
  39. J Huntingtons Dis. 2025 Oct 28. 18796397251387208
    Morphological and functional phenotyping of skeletal muscle and bone in the zQ175 knock-in mouse model of Huntington's disease.
    Behnaz Nateghi, Mohamed Lala Bouali, Zineb Bouredji, Anteneh Argaw, Soher Nagi Jayash, Colin Farquharson, Jérôme Frenette, Sébastien S Hébert.
      Background: Huntington's disease (HD) is a progressive neurodegenerative disorder primarily affecting the central nervous system (CNS). However, emerging evidence suggests that peripheral tissues, including skeletal muscle and bone, also undergo pathological changes contributing to disease burden. Objective: To characterize musculoskeletal impairments in the zQ175 knock-in (KI) mouse model of HD, through integrated behavioral, biomechanical, and imaging analyses. Methods: Motor function was assessed using grip strength, rotarod, and open field testing. Ex vivo contractility of the extensor digitorum longus (EDL) and Soleus (Sol) muscles was measured. Muscle fiber cross-sectional area (CSA) was quantified using semi-automated segmentation. Bone microarchitecture was analyzed using high-resolution micro-computed tomography (μCT). Results: Six-month-old homozygous zQ175 mice exhibited significantly reduced muscle strength and impaired contractile properties in both the EDL and Soleus muscles compared to wild-type (WT) controls. µCT analysis revealed decreased trabecular bone volume and alterations in bone structure. Conclusions: These findings provide a comprehensive musculoskeletal phenotyping of zQ175 mice, revealing early-onset muscle atrophy and skeletal fragility. Our study highlights the importance of targeting peripheral manifestations in HD and establishes zQ175 KI mice as a valuable additional model for investigating systemic disease mechanisms.
    Keywords:  Huntington's disease; bone microarchitecture; knock-in mousemodel; muscle atrophy; musculoskeletal dysfunction; zQ175
    DOI:  https://doi.org/10.1177/18796397251387208
  40. Front Immunol. 2025 ;16 1678526
    Peripheral immune and metabolic regulation of Aβ and Tau by exercise in Alzheimer's disease.
    Yuehan Yu, Kang Chen.
      Alzheimer's disease (AD), characterized by the pathological accumulation of amyloid-β (Aβ) and hyperphosphorylated Tau proteins, remains a major global health challenge with limited therapeutic options. Recent findings highlight that peripheral immune and metabolic pathways play a pivotal role in regulating brain Aβ and Tau homeostasis, particularly in response to physical exercise. In this review, we comprehensively examine current clinical and preclinical evidence on how exercise modulates peripheral immune responses, metabolic states, and systemic clearance mechanisms-including hepatic, renal, immune, and glymphatic pathways. We discuss how regular exercise suppresses peripheral inflammation, enhances immune cell-mediated phagocytosis, improves metabolic resilience, and promotes the elimination of neurotoxic proteins. Furthermore, exercise-induced peripheral mediators, such as myokines, non-coding RNAs, and lactate, are shown to mediate inter-organ communication and signaling pathway crosstalk and contribute to neuroprotection. This integrative perspective underscores the therapeutic promise of exercise as a non-pharmacological intervention that targets peripheral immune-metabolic networks to mitigate AD pathology.
    Keywords:  Alzheimer’s disease; Tau homeostasis; amyloid-β; exercise; myokines; peripheral clearance
    DOI:  https://doi.org/10.3389/fimmu.2025.1678526
  41. Eur J Endocrinol. 2025 Oct 30. pii: lvaf223. [Epub ahead of print]
    GLP-1R Agonists and Muscle Health: Potential Role in Sarcopenia Prevention and Treatment.
    Ainhoa González-Luis, Vicente Llinares-Arvelo, Carlos E Martínez-Alberto, Carolina Hernández-Carballo, Carmen Mora-Fernández, Juan F Navarro-González, Javier Donate-Correa.
      Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as a cornerstone therapy for weight loss and glycemic control in type 2 diabetes mellitus (T2DM) and obesity. Moreover, robust cardiometabolic benefits and favorable safety profiles have positioned GLP-1RAs at the forefront of modern obesity pharmacotherapy. However, findings from large-scale trials (e.g., SUSTAIN, STEP, SURPASS) have raised concerns that a significant proportion of the weight loss achieved with GLP-1RA treatment may derive from lean body mass-particularly skeletal muscle-which could be detrimental in populations already at risk for sarcopenia. However, emerging preclinical evidence suggests that GLP-1RAs may directly and indirectly influence skeletal muscle through anti-inflammatory, antioxidant, and mitochondrial-supportive mechanisms. These include modulation of key signaling pathways such as PI3K/Akt/mTOR and AMPK-PGC-1α, suppression of proteolytic activity, and promotion of myogenic differentiation. In experimental models of aging, sarcopenic obesity, and chronic disease, GLP-1RAs have shown muscle-preserving properties. Nevertheless, the balance between adipose tissue reduction and lean mass preservation remains incompletely understood in clinical settings. This review examines the existing experimental and clinical evidence and identify critical research directions to determine whether GLP-1RAs confer overall benefit or carry unintended risks for skeletal muscle integrity in the context of weight loss.
    Keywords:  GLP-1RAs; Sarcopenia; diabetes; muscle homeostasis; obesity
    DOI:  https://doi.org/10.1093/ejendo/lvaf223
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