bims-moremu Biomed News
on Molecular regulators of muscle mass
Issue of 2025–09–07
fifty-six papers selected by
Anna Vainshtein, Craft Science Inc.
  1. Skeletal muscle Rac1 mediates exercise training adaptations towards muscle glycogen resynthesis and protein synthesis.
  2. Mitochondrial Biogenesis in Skeletal Muscle.
  3. Transplantation of Cultured Myoblasts Into Intact Skeletal Muscle and Analysis of Muscle Contraction Force in Mice Model.
  4. Combating muscle atrophy: emerging therapeutic targets that are fiber-type-specific.
  5. Combined endurance and resistance exercise training alters the spatial transcriptome of skeletal muscle in young adults.
  6. Gene Manipulation of Muscle Phenotype.
  7. Endurance training increases a ubiquitylated form of histone H3 in the skeletal muscle, supporting Notch1 upregulation in an MDM2-dependent manner.
  8. SLC38A1 protects against aging-related oxidative stress and lipid peroxidation in C2C12 myoblasts: Implication of a ferroptosis-related regulator for skeletal muscle aging.
  9. Elucidating the role of human skeletal muscles in the pathogenesis of enterovirus D68 infection.
  10. Training-Induced Metabolic Adaptations in Skeletal Muscle.
  11. Hormesis and Muscle Plasticity.
  12. Rimonabant treatment partly attenuates skeletal muscle loss following immobilization in young and in old, sarcopenic male mice.
  13. Mitochondrial Quality Control.
  14. Circadian Rhythm and Muscle Function.
  15. Distribution of myogenic stem cell activator, hepatocyte growth factor, in skeletal muscle extracellular matrix and effect of short-term disuse and reloading.
  16. Mitochondrial DNA Deletion Mutations: A Molecular Cause of Age-Induced Skeletal Muscle Fiber Dysfunction and Fiber Death Contributing to Sarcopenia.
  17. CircularRNA and Musculoskeletal Diseases.
  18. Respiratory Resilience as Form Fades: Skeletal Muscle Mitochondrial Adaptation in Aging.
  19. The skeletal muscle of aged male mice exhibits sustained growth regulatory transcriptional profile following glucocorticoid exposure compared to young males.
  20. Mitochondrial diagnostics reveal diffuse impairments in skeletal muscle energetics in aging mice.
  21. DNA G-quadruplex profiling in skeletal muscle stem cells reveals functional and mechanistic insights.
  22. Satellite cells choreograph an immune cell-fibrogenic cell circuit during mechanical loading in geriatric skeletal muscle.
  23. FAP-CAR-T cells reduce dystrophic muscle fibrosis, improving adeno-associated virus gene transfer efficacy.
  24. Loss of COL20A1 in Schwann Cells Alters Regeneration of the Neuromuscular Junction and Locomotor Activity in Mice.
  25. All-in-one vectors for epigenetic CRISPR inhibition of DUX4-fl in facioscapulohumeral muscular dystrophy.
  26. Muscle Disuse Atrophy.
  27. Redox Control of Skeletal Muscle Function and Adaptations to Exercise.
  28. A combinatorial oligonucleotide therapy to improve dystrophin restoration and dystrophin-deficient muscle health.
  29. ZAG promotes exercise performance during endurance exercise by lipid utilization in skeletal muscle.
  30. The Structural Adaptations That Mediate Mechanical Load-Induced Changes in Muscle Mass.
  31. Skeletal Muscle and the Immune System.
  32. Skeletal Muscle as Endocrine Organ.
  33. Impaired xCT-mediated cystine uptake drives serine and proline metabolic reprogramming and mitochondrial fission in skeletal muscle cells.
  34. Slow- and fast-contracting skeletal muscle fibers have more similar cellular and molecular contractile function at 37°C than at 25°C in older adults.
  35. Intermittent ischemia-reperfusion as a potent insulin-sensitizing intervention via blood flow enhancement and muscle Decanoyl-L-carnitine suppression.
  36. Protein Acetylation and NAD+ Homeostasis in Aging Muscle.
  37. Glycocalyx-targeted therapy prevents age-related muscle loss and declines in maximal exercise capacity.
  38. Serum from patients with MuSK antibody-positive myasthenia gravis triggers transcriptomic changes leading to muscle atrophy and weakness in human myotube cells.
  39. Muscular Dystrophies.
  40. Mechanisms of Biological Aging with Special Reference to the Skeletal Muscle.
  41. RPS27L Enhances Myogenesis and Muscle Mass by Targeting IGF1 Through Liquid-Liquid Phase Separation.
  42. Cancer Cachexia.
  43. Angiotensin-converting enzyme and exercise adaptations: Genetic variability, pharmacological modulation and future directions.
  44. MyoAnalyst: an ImageJ plugin for accurate and automatic myofiber segmentation and analysis in skeletal muscle cross sections.
  45. Igf2 adult-specific skeletal muscle enhancer activity revealed in mice with intergenic CTCF boundary deletion.
  46. Galactose treatment rescues neuromuscular junction transmission in glutamine-fructose-6-phosphate transaminase 1 (Gfpt1) deficient mice.
  47. Muscle Plasticity, Adaptation and Epigenetics.
  48. Traumatic Skeletal Muscle Injury and Recovery.
  49. Metabolic and molecular regulation in skeletal muscle dysfunction and regeneration.
  50. Dual S100A1 and ARC gene therapy as a treatment for DMD cardiomyopathy.
  51. Skeletal Muscle Damage and Inflammation.
  52. Stage-specific requirement for METTL3-dependent m6A epitranscriptomic regulation during myogenesis.
  53. Muscle Proteome Dynamics.
  54. Human Mesenchymal Stem Cell-Derived Skeletal Muscle Cell Spheroids for Treating Dexamethasone-Induced Sarcopenia.
  55. Reevaluating the role of skeletal muscle in amyotrophic lateral sclerosis pathogenesis: Insights from muscle-derived factors.
  56. Farther and Faster: Enhancing Skeletal Muscle Performance.
  1. Redox Biol. 2025 Aug 28. pii: S2213-2317(25)00357-X. [Epub ahead of print]86 103844
    Skeletal muscle Rac1 mediates exercise training adaptations towards muscle glycogen resynthesis and protein synthesis.
    Steffen H Raun, Carlos Henriquez-Olguín, Emma Frank, Farina Schlabs, Nanna Just Hahn, Jonas Roland Knudsen, Mona S Ali, Nicoline R Andersen, Lisbeth L V Møller, Jonathan Davey, Hongwei Qian, Ana Coelho, Christian S Carl, Christian T Voldstedlund, Bente Kiens, Rikard Holmdahl, Paul Gregorevic, Thomas E Jensen, Atul S Deshmukh, Erik A Richter, Lykke Sylow.
      Long-term exercise training elicits tremendous health benefits; however, the molecular understanding is incomplete and identifying therapeutic targets has been challenging. Rho GTPases are among the most regulated groups of proteins after exercise in human skeletal muscle, yet, unexplored candidates for mediating the effects of exercise training. We found that the Rho GTPase Rac1 was activated acutely after multiple exercise modalities in human skeletal muscle. Loss of Rac1 specifically in muscle attenuated contraction-induced muscle protein synthesis, diminished improvements in running capacity, and prevented muscle hypertrophy after exercise training in mice. Additionally, Ncf1∗ mice revealed that Rac1 regulated glycogen resynthesis via a NOX2-dependent mechanism. Molecularly, Rac1 was required for contraction-induced p38MAPK signaling towards HSP27, MNK1, and CREB phosphorylation. In vivo muscle-targeted overexpression of a hyperactive Rac1-mutant elevated reactive oxidant species production during exercise but did not affect muscle mass. Using mass spectrometry-based proteomics, we found that loss or gain of Rac1 muscle protein affected pathways related to cytoskeleton organization, muscle adaptation, and large ribosomal subunits. Thus, skeletal muscle Rac1 mediates both molecular and functional adaptation to exercise training.
    Keywords:  Contraction; Exercise training; Glycogen; Metabolism; Muscle hypertrophy; Protein synthesis; Rac1; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.redox.2025.103844
  2. Adv Exp Med Biol. 2025 ;1478 19-50
    Mitochondrial Biogenesis in Skeletal Muscle.
    David A Hood, Jonathan M Memme, Ashley N Oliveira, Neushaw Moradi, Sabrina Champsi.
      Mitochondrial biogenesis refers to the synthesis of nuclear- and mitochondrially encoded proteins, along with phospholipids, that aid in the expansion of the mitochondrial network. In skeletal muscle, mitochondria are organized as a reticulum, as this ideal morphology complements the elongated shape of a myofibre. This allows for efficient substrate diffusion and supports the vigorously dynamic metabolic capabilities of this tissue type. Mitochondria are central responders to deviations in metabolic homeostasis and are thus required to support acute or chronic bouts of endurance exercise, cold exposure, starvation, or other externally imposed stimuli. This chapter marks the introduction to skeletal muscle mitochondrial adaptability as we discuss the subcellular events that contribute to mitochondrial biogenesis. Topics range from mitochondrial content and subpopulations in different muscle fibre types to signaling cascades and regulatory elements that support this mechanism. The characterization of mitochondrial biogenesis was made possible through clever models of both exercise and muscle disuse, at times with genetic modifications to important regulators, and is incorporated in this discussion. The chapter concludes with reviews on changes to signaling towards biogenesis with age. Altogether, our review attempts to highlight the vast revelations on the targeting, contribution, and significance of mitochondrial biogenesis in skeletal muscle.
    Keywords:  Aging; Calcium; Exercise signaling; Exercise training; Gene expression; Mitochondria; Mitochondrial dynamics; Muscle disuse; Protein import; ROS
    DOI:  https://doi.org/10.1007/978-3-031-88361-3_2
  3. Bio Protoc. 2025 Aug 20. 15(16): e5413
    Transplantation of Cultured Myoblasts Into Intact Skeletal Muscle and Analysis of Muscle Contraction Force in Mice Model.
    Kitora Dohi, Yasuro Furuichi.
      Cell transplantation is a promising strategy for treating age-related muscle atrophy, but its critical application remains limited. Cultured myoblasts, unlike freshly isolated muscle stem cells, show poor engraftment efficiency and fail to contribute effectively to muscle regeneration. Moreover, successful engraftment generally requires prior muscle injury, as skeletal muscle regeneration is typically triggered by a damaged microenvironment. These limitations present major obstacles for applying cell therapy to sarcopenia, where muscle degeneration occurs without injury. In this protocol, we describe a novel approach that enables the transplantation of cultured myoblasts into intact skeletal muscle without the need for preexisting injuries or genetic modification. By combining myoblasts with extracellular matrices (ECM), such as Matrigel, which mimic the native muscle niche and support cell survival, adhesion, proliferation, and differentiation, we achieve efficient engraftment and increased muscle mass without the need for preexisting injury. The ECM also provides a scaffold and retains bioactive factors that enhance the regenerative capacity of transplanted cells. This is the first protocol that enables robust myoblast engraftment in non-injury muscle conditions, offering a practical tool for studying and potentially treating sarcopenia. Key features • Cultured myoblasts mixed with extracellular matrix components are transplanted into intact skeletal muscle. • Contraction force measurement of the tibialis anterior muscle in vivo. • Cell transplantation without muscle injury would be applied for the treatment of sarcopenia.
    Keywords:  Cell transplantation; Extracellular matrix; Muscle contraction; Myoblast; Skeletal muscle
    DOI:  https://doi.org/10.21769/BioProtoc.5413
  4. FEBS J. 2025 Aug 28.
    Combating muscle atrophy: emerging therapeutic targets that are fiber-type-specific.
    Samrat Chakraborty, Raz Ben-David, Shenhav Shemer.
      Skeletal muscle is essential for life as it enables physical movement, maintains posture, is crucial for breathing, and serves as a major site for energy and carbohydrate metabolism. Pathological conditions that reduce skeletal muscle mass and function-such as muscular dystrophies, motor-neuron diseases, cancer, type-2 diabetes, or aging-have detrimental effects on human health, reducing quality of life and survival. Currently, exercise is the only validated treatment for increasing muscle mass and function, but it is impractical for bedridden patients or the frail elderly. Significant advances in understanding the molecular mechanisms underlying atrophy of slow- or fast-twitch muscle fibers have identified numerous previously unknown key players that may show promise as potential drug targets. Here, we review these recent advances and discuss the potential of these discovered mechanisms as therapeutic targets to combat muscle wasting.
    Keywords:  fiber type; muscle atrophy; myosin; skeletal muscle; therapeutic targets
    DOI:  https://doi.org/10.1111/febs.70241
  5. iScience. 2025 Sep 19. 28(9): 113301
    Combined endurance and resistance exercise training alters the spatial transcriptome of skeletal muscle in young adults.
    Michael J Stec, Zachary A Graham, Qi Su, Christina Adler, Min Ni, Valerie Le Rouzic, David R Golann, Patrick J Ferrara, Gabor Halasz, Mark W Sleeman, Kaleen M Lavin, Timothy J Broderick, Marcas M Bamman.
      Chronic exercise training substantially improves skeletal muscle function and performance. The repeated demands and stressors of each exercise bout drive coordinated molecular adaptations within multiple cell types, leading to enhanced neuromuscular recruitment and contractile function, stem cell activation, myofiber hypertrophy, mitochondrial biogenesis, and angiogenesis, among others. To comprehensively profile molecular changes induced by combined resistance and endurance exercise training, we employed spatial transcriptomics coupled with immunofluorescence and computational approaches to resolve effects on myofiber and mononuclear cell populations in human muscle. By computationally identifying fast and slow myofibers, we identified fiber type-specific, exercise-induced gene expression changes that correlated with muscle functional improvements. Additionally, integration of human muscle single cell RNAseq data identified an exercise-induced shift in interstitial cell populations coincident with angiogenesis. Overall, these data provide a unique spatial molecular profiling resource for exploring muscle adaptations to exercise, and provide a pipeline and rationale for future studies in human muscle.
    Keywords:  Exposure; Human; Integrative aspects of cell biology; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2025.113301
  6. Adv Exp Med Biol. 2025 ;1478 447-458
    Gene Manipulation of Muscle Phenotype.
    Chih-Hsuan Chou, Frank W Booth.
      How loss- or gain-of-function for a gene in skeletal muscle induces muscle phenotypes is an important topic. Two important underlying rationales are: (a) understanding the fundamentals of gene regulations in the skeletal muscle and (b) how they influence physiological and metabolic functions. The knowledge of gene functions in the skeletal muscle is crucial to target the selection of interventions that will promote muscle health, prevent muscle loss, and treat muscle diseases. This chapter briefly introduces current techniques, such as the Cre-LoxP system, and its application with muscle-specific gene promoters. These advances in studying skeletal muscle-specific gene manipulations in animal models consequently broadened our views of muscle phenotypes related to gene regulations. We then summarize some current findings in gene manipulations regarding muscle mass, fiber-type shifting, metabolism, muscle diseases, and exercise performance. Lastly, we discuss the precautions and future directions from the current knowledge. We anticipate that by using numerous examples in this chapter, readers could understand the concepts of genetic engineering contributing to altered skeletal muscle phenotype.
    Keywords:  Cre-LoxP; Gene manipulation; Gene regulation
    DOI:  https://doi.org/10.1007/978-3-031-88361-3_18
  7. J Physiol. 2025 Sep 05.
    Endurance training increases a ubiquitylated form of histone H3 in the skeletal muscle, supporting Notch1 upregulation in an MDM2-dependent manner.
    Brian Lam, Manpreet Gulri, Sokaina Akhtar, Pierre Lemieux, Monica Tawadrous, Mayoorey Murugathasan, Ali A Abdul-Sater, Emilie Roudier.
      At the onset of training, each exercise session transiently shifts the distribution of histone post-transcriptional modifications (HPTMs) to activate genes that drive muscle adaptations. The resulting cyclic changes in gene expression promote the acquisition of high oxidative capacities and gains in capillaries. If training stops or remains at the same intensity, adaptation ceases. Whether silencing HPTMs helps to halt adaptation remains understudied. The E3 ubiquitin ligase murine double minute (MDM2) and enhancer of zester homolog 2 (EZH2) interact and tri-methylate histone H3 on lysine 27 (H3K27me3), silencing genes. C57Bl6 mice ran for 9 weeks (5 days a week) maintaining a constant running speed for the last 5 weeks of training. Muscles were collected 72 h after the last run. Training increased MDM2 and EZH2 proteins and led to an H3K27me3 enrichment in Kdr and Notch1 regulatory sequences. Kdr mRNA levels decreased, following the canonical model that H3K27me3 silences genes. Notch1 mRNA increased. Trained muscles had greater levels of H3K27me3 detected at 25 kDa and no change at the expected molecular weight of 17 kDa. The 25 kDa band was identified as a ubiquitylated form of H3 (H3Ub). C2C12 myotubes exposed to four consecutive days of 90 min electrostimulation had higher levels of H3Ub. EZH2 inhibition counteracted the electrostimulation-driven accumulation of H3Ub and increased Notch1 mRNA. Serdemetan, an MDM2 ring domain inhibitor, reduced Notch1 mRNA and H3Ub level in myotubes. MDM2-dependent ubiquitylation of H3 might upregulate Notch1 when endurance training ceases. The role H3Ub plays in establishing a new muscle homeostasis remains unclear. KEY POINTS: Whether epigenetic silencing histone marks play a role once skeletal muscle adaptations have occurred following endurance training remains unclear. The E3 ubiquitin ligase MDM2 and the epigenetic writer EZH2 interact to establish H3K27me3 marks that silence genes, and endurance training increased the expression of both proteins. After weeks of training new capillaries were established, and lower levels of Kdr mRNA and increased H3K27me3 marking on Kdr regulatory sequences question whether silencing of this positive regulator of angiogenesis is required to halt microvascular remodelling. Training increases skeletal muscle abundance of a ubiquitylated form of H3 (H3Ub); in myotubes EZH2 inhibition limits H3Ub accumulation after contractile activity repeated over 4 days and MDM2 inhibition reduces H3Ub levels and upregulates Notch1 expression. MDM2-dependent ubiquitylation of H3 might explain why H3K27me3 enrichment fails to silence Notch1 after training; whether H3Ub is crucial to halt adaptation and establish a new muscle homeostasis requires further investigation.
    Keywords:  angiogenesis; epigenetics; exercise physiology; gene expression; histone modifications; murine double minute 2; muscle adaptation
    DOI:  https://doi.org/10.1113/JP288947
  8. Exp Gerontol. 2025 Sep 02. pii: S0531-5565(25)00209-8. [Epub ahead of print] 112880
    SLC38A1 protects against aging-related oxidative stress and lipid peroxidation in C2C12 myoblasts: Implication of a ferroptosis-related regulator for skeletal muscle aging.
    Chen Xi, Zhang Yingxiao, Zhao Yuxing, Zhou Min, Cheng Pan, Yang Hong, Shu Yue, Duan Liang, Wu Yongxin, Sun Yue, Gao Yuan, Zhao Kexiang, Xiao Qian, Yu Jing.
      Ferroptosis has been implicated in skeletal muscle aging. Nevertheless, specific ferroptosis-related genes (FRGs) governing skeletal muscle aging remain unclear. The aim of this study was to identify ferroptosis-related marker genes associated with skeletal muscle aging, uncovering potential therapeutic targets for skeletal muscle aging. Data from GSE38718 was utilized to identify differentially expressed FRGs (DE-FRGs) in aging versus normal human skeletal muscle by the least absolute shrinkage and selection operator (LASSO) and the support vector machine recursive feature elimination (SVM-RFE) algorithms. Validation was conducted using RT-qPCR and Western blot in aging mouse muscle and D-galactose (D-gal)-treated C2C12 cells. SLC38A1 was identified as a significantly downregulated marker for aging skeletal muscle. Overexpression of SLC38A1 mitigated cellular aging in D-gal treated C2C12 cells. In both D-gal treated and sh-SLC38A1 C2C12 cells, increased ROS levels, elevated mtROS, higher intracellular iron concentrations, and intensified lipid peroxidation were observed. In contrast, SLC38A1 overexpression markedly reduced the accumulation of ROS, mtROS, iron concentration, and lipid peroxidation associated with D-gal treatment in these cells. In conclusion, through screening analyses and validation experiments, we identified SLC38A1 as a ferroptosis-related regulator for skeletal muscle aging.
    Keywords:  Aging; Ferroptosis; Ferroptosis-related genes; SLC38A1; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.exger.2025.112880
  9. Life Sci Alliance. 2025 Nov;pii: e202503372. [Epub ahead of print]8(11):
    Elucidating the role of human skeletal muscles in the pathogenesis of enterovirus D68 infection.
    Brigitta M Laksono, Atze J Bergsma, Alessandro Iuliano, Dominique Y Veldhoen, Stefan van Nieuwkoop, Marjan Boter, Lonneke Leijten, Lisa Bauer, Bas B Oude Munnink, Wwm Pim Pijnappel, Debby van Riel.
      Enterovirus D68 (EV-D68) is an emerging respiratory virus associated with extra-respiratory complications, especially acute flaccid myelitis. However, the pathogenesis of acute flaccid myelitis is not fully understood. It is hypothesised that through infection of skeletal muscles, the virus further infects motor neurons via the neuromuscular junction. We hypothesise that EV-D68 infection of human skeletal muscles can impair muscle function directly, thereby contributing to the development of EV-D68-associated muscle weakness. Here, we inoculated human induced pluripotent stem cell-derived skeletal muscle myotubes grown in 2D and 3D with different EV-D68 isolates, which resulted in a productive infection and cell death. We showed through neuraminidase treatment that sialic acids facilitate infection of these cells. EV-D68 infection of the 3D model led to tissue damage, reduction of contractile force, and hampered muscle regeneration. Altogether, we showed that human skeletal muscle can act as an extra-respiratory replication site and infection of skeletal muscles may contribute to EV-D68-associated muscle weakness.
    DOI:  https://doi.org/10.26508/lsa.202503372
  10. Adv Exp Med Biol. 2025 ;1478 491-510
    Training-Induced Metabolic Adaptations in Skeletal Muscle.
    Esther Garcia-Dominguez, Maria Carmen Gomez-Cabrera, Gloria Olaso Gonzalez.
      Metabolism involves not only the conversion of nutrient fuel into usable energy but also includes the synthesis, modification, and exchange of cellular building blocks, acting as a regulator and sensor of cellular activities. Various components within metabolic pathways can affect cellular responses. A significant portion of daily energy intake is necessary for sustaining life, and physical activity demands are added to an intricately integrated machinery. Studying elite human performance offers valuable information about the molecular, cellular, tissue, and overall body adjustments to intense metabolic demands. Moreover, understanding the mechanisms and pathways activated during exercise could potentially uncover new therapeutic targets for prescription in patient populations.In this book chapter, we will review the structural and functional peculiarities of our skeletal muscle cells, the myofibers. After this brief introduction, we will also give an overview of skeletal muscle metabolism depending on the intensity of the exercise. The metabolic demands and regulation of very intense, intermittent, or "stop-and-go" sports and long-lasting exercise efforts will be reviewed. The main reasons to explain the importance of carbohydrates in supporting ATP production in high-intensity exercise and the downregulation of fat metabolism at high aerobic exercise intensities in athletes are also discussed. The last section of this book chapter is devoted to the main metabolic adaptations to cardiorespiratory and resistance exercise training. These include exercise-induced skeletal muscle fiber-type transitions, changes in capillaries and myoglobin, improvements in mitochondrial content and function, changes in glycogen and intramuscular triglyceride skeletal muscle stores, and improvements in tolerance for acid-base imbalances.
    Keywords:  Energy expenditure; Energy intake; Exercise; Nutrients; Skeletal muscle
    DOI:  https://doi.org/10.1007/978-3-031-88361-3_21
  11. Adv Exp Med Biol. 2025 ;1478 85-100
    Hormesis and Muscle Plasticity.
    Zsolt Radak.
      The skeletal muscle is one of the most plastic organs in our body. It readily responds to increased physical activity, and inactivity, and as the largest organ in the body, it plays a crucial role in the regulation of all major metabolic events in the body. Due to the great adaptability, skeletal muscles process well-described dose response, and this chapter deals with the unique and universal nature of this response. The activation of satellite cells via different exercise-associated agents, like lactate, nitric oxide, or 8-oxoG-OGG1 complex, has a great impact of the adaptability of skeletal muscle. The trainability of skeletal muscle is also discussed in this chapter.
    Keywords:  Adaptation; Antioxidants; DNA methylation; Epigenetics; Free Radicals; Hormesis; Trainability
    DOI:  https://doi.org/10.1007/978-3-031-88361-3_5
  12. J Gerontol A Biol Sci Med Sci. 2025 Aug 28. pii: glaf189. [Epub ahead of print]
    Rimonabant treatment partly attenuates skeletal muscle loss following immobilization in young and in old, sarcopenic male mice.
    Sebastiaan Dalle, Kaat Vanderbeke, Moniek Schouten, Monique Ramaekers, Michel Abou-Samra, Domiziana Costamagna, Katrien Koppo.
      Muscle tissue is important for locomotion and metabolic health. Muscle disuse (e.g. post-operative) occurs more often in older adults, and results in rapid muscle wasting. Currently, there is no effective treatment to combat immobilization-induced atrophy, which is why novel therapeutic strategies are needed. Antagonism of cannabinoid receptor 1 (CB1) can stimulate muscle protein synthesis, thereby protecting against glucocorticosteroid-induced atrophy. However, its therapeutic potential against (age-related) immobilization-induced atrophy remains unknown. Therefore, we investigated the effect of CB1 antagonism on muscle responses following immobilization in young and old, sarcopenic male mice. One hind limb of young and old male C57BL/6 mice was immobilized for five days, during which they were treated with the CB1 antagonist Rimonabant (10 mg/kg/d) or vehicle. Hereafter, mice were euthanized and muscles were collected. Endocannabinoid, anabolic and catabolic markers were analyzed in the gastrocnemius muscle via western blotting. Rimonabant attenuated immobilization-induced gastrocnemius muscle mass loss in both ages (-7.9% vs. vehicle: -11.2%; p = 0.0027). Immobilization increased expression of the anabolic regulators (p-S6rp, p-4E-BP1), and of the catabolic markers (LC3b-II/I, MAFbx), which remained unaffected by Rimonabant treatment. Surprisingly, Rimonabant amplified the immobilization-induced decrease in muscle protein synthesis (-45.8% vs. vehicle: -27%; p = 0.0180), to a larger extent in young vs. old mice (p = 0.0005). Immobilization decreased the expression of the enzyme NAPE-PLD, responsible for synthesis of the endocannabinoid anandamide, whereas its degrading enzyme FAAH was higher expressed. More research is needed to unravel the mechanisms underlying the muscle sparing effect of Rimonabant, and anandamide's role in muscle degeneration.
    Keywords:  cannabinoid receptor; muscle disuse; sarcopenia; skeletal muscle anabolism; skeletal muscle catabolism
    DOI:  https://doi.org/10.1093/gerona/glaf189
  13. Adv Exp Med Biol. 2025 ;1478 51-60
    Mitochondrial Quality Control.
    Yuntian Guan, Zhen Yan.
      Mitochondria, the power plants of cells, are essential for various cellular functions. In skeletal muscle, mitochondria form a network, called mitochondrial reticulum, which fuels muscle contractile and metabolic functions. The high degree of structure-to-function specialization of mitochondria in skeletal muscle implies that it is closely gauged and regulated to maintain energy production capacity to match the functional demands. The processes that regulate the overall structure and function of mitochondrial reticulum are collectively referred to as mitochondrial quality control. Mitochondrial quality control consists of mitochondrial biogenesis, dynamics (i.e., fission and fusion), and selective degradation via proteolysis and mitophagy. In this chapter, we will discuss different aspects of contemporary understanding of mitochondrial quality control, their respective mechanisms, and their adaptability to exercise training.
    Keywords:  Adaptation; Exercise; Mitochondrial biogenesis; Mitochondrial fission; Mitochondrial fusion; Mitochondrial reticulum; Mitophagy; Skeletal muscle
    DOI:  https://doi.org/10.1007/978-3-031-88361-3_3
  14. Adv Exp Med Biol. 2025 ;1478 101-112
    Circadian Rhythm and Muscle Function.
    Hyeon-Ki Kim, Shigenobu Shibata.
      Since the discovery of clock gene in mammals, the physiological role of the internal clock, which produces a rhythm of approximately 24 h per day, has been revealed, and it has become clear that a regular life rhythm is important for maintaining good health. Skeletal muscle function is no exception, and has been reported to be regulated by the internal clock. In the skeletal muscle, more than 2300 genes exhibit circadian rhythms and are involved in a wide range of functions, including myogenesis, transcription, and metabolism. In this chapter, we discuss the effects of exercise on the regulation of the skeletal muscle internal clock and its potential timing effects, starting from the regulation of skeletal muscle function by the internal clock.
    Keywords:  Chrono-exercise; Circadian rhythm; Muscle clock; Muscle function
    DOI:  https://doi.org/10.1007/978-3-031-88361-3_6
  15. PLoS One. 2025 ;20(9): e0321839
    Distribution of myogenic stem cell activator, hepatocyte growth factor, in skeletal muscle extracellular matrix and effect of short-term disuse and reloading.
    So Kuwakado, Alaa Elgaabari, Kahona Zushi, Sakiho Tanaka, Miyumi Seki, Ryuki Kaneko, Yuji Matsuyoshi, Takahiro Suzuki, Kenichi Kawaguchi, Yasuharu Nakashima, Ryuichi Tatsumi.
      Hepatocyte growth factor (HGF) is a key myogenic stem cell (satellite cells) activator, that resides in the extracellular matrix (ECM). However, HGF distribution in the ECM varies depending on the muscle fiber type. Furthermore, aging impedes the binding of HGF to its receptors owing to nitration by peroxynitrite (ONOO-). Though oxidative stress increases rapidly during muscle disuse atrophy, satellite cells are rapidly activated upon reloading. In this study, we investigated the distribution of HGF in the ECM in various muscle fiber types, and examined nitration of HGF in disuse and reloading models. Immunofluorescence staining was performed on the soleus (Sol), plantaris (Pla), and gastrocnemius (Gas) muscles of 10-week-old mice. Six mice were used to assess HGF distribution, while 12 mice, divided into control, disuse, and reloading groups were used for qualitative evaluation of nitrated HGF (nitroHGF). Student's t-tests and the Bonferroni correction were employed for statistical analysis (p < 0.05/3 = 0.0167). In Sol muscle, type IIa and IIx muscle fibers exhibited higher HGF distribution in the ECM (61.5 ± 1.0% and 56.7 ± 1.1%, respectively) than type I fibers (32.3 ± 1.0%; p < 0.001). In Pla and Gas muscle, type IIa 55.8 ± 0.9% and 58.8 ± 1.5%, respectively) and type IIx fibers (49.6 ± 0.9% and 48.9 ± 1.1%, respectively) had significantly higher HGF distribution in the ECM than type IIb fibers (18.6 ± 0.9% and 13.0 ± 1.0%; p < 0.001, respectively). The amount of nitroHGF increased in the disuse group compared to that in the control group but decreased in the reloading group compared to that in the disuse group. This preferential HGF distribution around type IIa and IIx muscle fibers indicates a distinct mechanism for satellite cell activation, differing from the satellite cell-rich environment associated with type I fibers and the lower HGF association with type IIb fibers. Disuse-induced HGF nitration may inhibit satellite cell activation. Reloading likely triggers mechanisms that counteract nitration, enabling satellite cell reactivation in young muscle.
    DOI:  https://doi.org/10.1371/journal.pone.0321839
  16. Adv Exp Med Biol. 2025 ;1478 343-363
    Mitochondrial DNA Deletion Mutations: A Molecular Cause of Age-Induced Skeletal Muscle Fiber Dysfunction and Fiber Death Contributing to Sarcopenia.
    Jonathan Wanagat, Robert Musci, Allen Herbst, Judd M Aiken.
      This chapter describes a molecular basis for age-induced muscle fiber loss involving the mammalian mitochondrial genome (mtDNA). Early studies of human mitochondrial myopathies, which display many phenotypes associated with muscle aging, led to the search for and subsequent discovery of similar genetic and histopathological changes in aging skeletal muscle. A diverse spectrum of mtDNA deletion mutations increase in abundance with age and clonally accumulate to high abundance within individual cells. Deletion accumulation results in a focal loss of electron transport and oxidative phosphorylation. These metabolic derangements activate apoptosis, leading to necrosis, fiber splitting, and eventual fiber loss. We have identified a number of interventions that are capable of modulating mtDNA deletion mutation frequency and the abundance of electron transport chain deficient fibers. Interestingly, in each case, the genetic and histological measures of mtDNA quality predict the lifespan effects of these interventions. We highlight the value of incorporating a geroscience view into the study of sarcopenia. The sequence of events from the deletion mutation of a single mtDNA molecule to muscle fiber death is not limited to skeletal muscle and has been observed in most other aging tissues, where these events likely contribute to cell loss.
    Keywords:  Mitochondria; Mitochondrial DNA; Mutations; Sarcopenia
    DOI:  https://doi.org/10.1007/978-3-031-88361-3_14
  17. Adv Exp Med Biol. 2025 ;1485 437-448
    CircularRNA and Musculoskeletal Diseases.
    Pujiao Yu, Yuan Qi, Hui Huang, Hairong Wang, Jiahong Xu.
      The skeletal muscle is the largest organ in the human body and plays a crucial role in the locomotion, metabolism, and homeostasis. Myogenesis is regulated by a complex molecular network and is kept finely balanced under physiological conditions. The disorder of muscular homeostasis results in musculoskeletal diseases, including myositis, dystrophy, sarcopenia, atrophy, and cachexia. These diseases severely affect the life quality of humans. In recent years, with the progress of high-throughput sequencing technology and the development of bioinformatics, a large number of noncoding RNAs (ncRNAs) have been identified in the skeletal muscle, and numerous experiments to date have shown that those ncRNAs are widely involved in multiple pathophysiological process of skeletal muscle. Circular RNAs (circRNA) are a class of noncoding RNAs formed by covalently closed loops through back-splicing and exon skipping. circRNAs have been confirmed to play a vital role in various biological functions, acting as microRNA sponges and reservoirs, as well as combining with RNA-binding proteins during the progression of myogenesis. In this chapter, we will summarize the progress of circRNA in regulating skeletal muscle and provide new information to better understand muscle diseases development and therapeutic strategy.
    Keywords:  Cachexia; Circular RNA; Duchenne muscular dystrophy; Muscle atrophy; Muscular disease; Myasthenia gravis; Myogenesis; Myotonic Dystrophy; Skeletal muscle
    DOI:  https://doi.org/10.1007/978-981-96-9428-0_25
  18. Am J Physiol Endocrinol Metab. 2025 Sep 02.
    Respiratory Resilience as Form Fades: Skeletal Muscle Mitochondrial Adaptation in Aging.
    John Noone.
      
    Keywords:  Mitochondria; aging; flux control ratios; morphology; skeletal muscle
    DOI:  https://doi.org/10.1152/ajpendo.00369.2025
  19. Physiol Genomics. 2025 Aug 29.
    The skeletal muscle of aged male mice exhibits sustained growth regulatory transcriptional profile following glucocorticoid exposure compared to young males.
    Grant R Laskin, Cynthia Vied, David S Waddell, Bradley S Gordon.
      Excess glucocorticoids induce skeletal muscle myopathy by changing gene expression. Advanced age augments glucocorticoid-mediated muscle phenotypes, yet the transcriptional responses underlying those augmented phenotypes are unclear. The purpose of this study was to define the glucocorticoid-responsive transcriptome in young and aged muscle following both acute and more prolonged glucocorticoid treatment. Young (4-month-old) or aged (24-month-old) male mice were administered either an acute injection of dexamethasone (DEX) or vehicle, or daily DEX or vehicle injections for 7 days. Muscles were harvested 6.5 h after the final or only injection. The tibialis anterior (TA) was selected for RNA sequencing analysis as DEX treatment lowered TA mass specifically in aged males. In silico analyses identified enriched pathways and transcription factors predicted to regulate DEX-sensitive genes. Acute DEX altered similar numbers of genes in young (950) vs. aged males (913), although aged males had greater magnitudes of fold change. After 7 days of DEX treatment, aged muscle exhibited more DEGs compared to acute exposure (1,196 vs. 913), while young muscle exhibited fewer DEGs than after acute exposure (599 vs. 950). In aged males, glucocorticoid-sensitive genes were consistently enriched for growth regulatory processes across both time points, a pattern that was not evident in young males. Despite those age-associated transcriptional differences, the transcription factors predicted to regulate the glucocorticoid-sensitive genes were similar in young and aged males. These data expand our understanding into how aging modifies the transcriptional response to excess glucocorticoids in skeletal muscle.
    Keywords:  Atrophy; Dexamethasone; Gene Expression; Myopathy
    DOI:  https://doi.org/10.1152/physiolgenomics.00083.2025
  20. J Appl Physiol (1985). 2025 Sep 04.
    Mitochondrial diagnostics reveal diffuse impairments in skeletal muscle energetics in aging mice.
    Keon D Wimberly, Mia Y Kawaida, Abigail L Tice, Xiaoping Luo, Jacob A Lackey, Samuel Alvarez, Lan Wei-LaPierre, Russell T Hepple, Terence E Ryan.
      Aging is associated with progressive declines in skeletal muscle mass, strength, and endurance, often linked to mitochondrial dysfunction. However, a complete understanding of mitochondrial impairments during aging is lacking. Herein, we examined how biological sex and aging affect muscle function and mitochondrial energy transduction. Methods: Male and female C57BL/6 mice at 16 and 26 months of age (N=48) were assessed for physical function, muscle contractility, histology, and mitochondrial bioenergetics. Using isolated limb muscle mitochondria, we employed a diagnostic approach to evaluate respiration, redox potential, and membrane polarization under physiologically relevant energy demands. Results: Aged mice had significantly lower grip strength (P = 2.7E-09), walking speed (P = 0.024), and endurance capacity (P = 1.24E-08). Muscle mass and contractile function were also significantly lower in 26-mo. old mice regardless of sex. Mitochondrial diagnostics revealed a significant reduction (30-50%) in oxygen consumption rates across a range of energy demands and substrate conditions in both male and female 26-mo. old mice. Redox and membrane potentials were also reduced (P < 0.05) in aged mice resulting in a lower respiratory efficiency when compared to 16-mo. old mice. Notably, aged males exhibited greater mitochondrial deficits with carbohydrate substrates, while aged females showed larger declines with fatty acid substrates. Conclusion: Aging induces diffuse impairments in mitochondrial energy transduction in skeletal muscle of mice of both sexes. The application of mitochondrial diagnostics platform offers new insights into the changes in muscle mitochondria with aging and could enhance the identification of interventions for preserving mitochondrial health in aging.
    Keywords:  aging; metabolism; mitochondria; muscle
    DOI:  https://doi.org/10.1152/japplphysiol.00601.2025
  21. Genome Biol. 2025 Sep 05. 26(1): 269
    DNA G-quadruplex profiling in skeletal muscle stem cells reveals functional and mechanistic insights.
    Xiaona Chen, Feng Yang, Suyang Zhang, Xiaofan Guo, Jieyu Zhao, Yulong Qiao, Liangqiang He, Yang Li, Qin Zhou, Michael Tim-Yun Ong, Chun Kit Kwok, Hao Sun, Huating Wang.
       BACKGROUND: DNA G-quadruplexes (G4s) are non-canonical secondary structures formed in guanine-rich DNA sequences and play important roles in modulating biological processes through a variety of gene regulatory mechanisms. Emerging G4 profiling allows global mapping of endogenous G4 formation.
    RESULTS: Here in this study, we map the G4 landscapes in adult skeletal muscle stem cells (MuSCs), which are essential for injury-induced muscle regeneration. Throughout the myogenic lineage progression of MuSCs, we uncover dynamic endogenous G4 formation with a pronounced G4 induction when MuSCs become activated and proliferating. We further demonstrate that the G4 induction promotes MuSC activation thus the regeneration process. Mechanistically, we found that promoter-associated G4s regulate gene transcription through facilitating chromatin looping. Furthermore, we found that G4 sites are enriched for transcription factor (TF) binding events in activated MuSCs; MAX binds to G4 structures to synergistically facilitate chromatin looping and gene transcription, thus promoting MuSC activation and regeneration. The above uncovered global regulatory functions/mechanisms are further dissected on the paradigm of Ccne1 promoter, demonstrating that Ccne1 is a bona fide G4/MAX regulatory target in activated MuSCs.
    CONCLUSIONS: Altogether, our findings for the first time demonstrate the prevalent and dynamic formation of G4s in adult MuSCs and the mechanistic role of G4s in modulating gene expression and MuSC activation/proliferation.
    Keywords:  Chromatin looping; DNA G-quadruplex; MAX; Muscle regeneration; Skeletal muscle stem cells
    DOI:  https://doi.org/10.1186/s13059-025-03753-w
  22. PNAS Nexus. 2025 Sep;4(9): pgaf236
    Satellite cells choreograph an immune cell-fibrogenic cell circuit during mechanical loading in geriatric skeletal muscle.
    Nicholas T Thomas, Camille R Brightwell, Allison M Owen, Alexander R Keeble, Sabin Khadgi, Yuan Wen, Christopher S Fry, Kevin A Murach.
      Muscle stem cells, or satellite cells (SCs), decline in number throughout the lifespan and may become senescent in very old age. Whether and how remaining SCs contribute to muscle adaptation in the oldest-old is unclear. Using acute mechanical overload in geriatric SC replete and depleted mice (28-month-old) combined with single-cell RNA-sequencing, we show: (i) subsets of geriatric SCs display signs of senescence as well as normal fate progression during overload, (ii) SCs express markers that may contribute to the regulation of innervation, (iii) the presence of SCs during overload enhances global intercellular communication and increases mRNA levels of the cell surface receptor Cd74 in immune cells, (iv) macrophage migration inhibitory factor (Mif), the primary ligand for CD74, is enriched in fibrogenic cells and is more pronounced in the absence of SCs-perhaps to normalize dysregulated fibrotic signaling and migration in macrophages, and (v) SCs influence cell fate dynamics to promote the canonical macrophage response to hypertrophic loading. Our findings expose the behavior of SCs in response to mechanical loading in the oldest-old in vivo and reveal a SC-macrophage-fibrogenic cell circuit in geriatric muscle that could support an early proadaptive inflammatory environment.
    Keywords:  Cd74; Mif; muscle hypertrophy; muscle stem cells; single-cell RNA-sequencing
    DOI:  https://doi.org/10.1093/pnasnexus/pgaf236
  23. Mol Ther Methods Clin Dev. 2025 Sep 11. 33(3): 101545
    FAP-CAR-T cells reduce dystrophic muscle fibrosis, improving adeno-associated virus gene transfer efficacy.
    Maxime Ferrand, Céline J Rocca, Guillaume Corre, Valentina Buffa, Sophie Frin, Francine Garnache-Ottou, Elodie Bôle-Richard, Sonia Albini, Isabelle Richard, Anne Galy.
      Tissue fibrosis is a pathological feature of many diseases including muscular dystrophies such as Duchenne muscular dystrophy (DMD). Fibrosis may limit the effectiveness of gene therapy in muscle impacting on viral dosing but direct evidence is lacking. Strategies to reduce skeletal muscle fibrosis are limited. The fibrosis Fap gene is over-expressed in the skeletal muscles of a severe mouse model of DMD, suggesting that cells expressing membrane fibroblast activation protein (FAP) could be targeted by chimeric antigen receptor (CAR)-T cells. Two consecutive administrations of FAP-specific CAR-T cells in the severe DMD model reduced collagen deposits and fibrotic biomarkers and also reduced the number of FAP-positive cells in muscle. Single cell transcriptomics revealed that FAP-CAR-T cells triggered cellular interactions with otherwise inactive muscle resident macrophages and depleted specific subsets of FAP-highly-expressing fibro-adipogenic progenitor cells, pointing to their importance in the fibrosis process. Reducing fibrosis with FAP-CAR-T cells enhanced adeno-associated virus (AAV) microdystrophin gene transfer in the model by increasing vector copies, demonstrating that fibrosis is a restriction factor for AAV gene delivery in skeletal muscle. These results provide novel insights into therapeutic strategies for DMD or other fibrotic diseases.
    Keywords:  AAV; CAR-T cells; FAP protein; fibro-adipogenic progenitor cells; fibrosis; immunotherapy; muscular dystrophy; scRNA-seq
    DOI:  https://doi.org/10.1016/j.omtm.2025.101545
  24. J Mol Neurosci. 2025 Sep 04. 75(3): 113
    Loss of COL20A1 in Schwann Cells Alters Regeneration of the Neuromuscular Junction and Locomotor Activity in Mice.
    Robert Louis Hastings, William Boyce, Devin Juros, Jinho Kim, Zaid Khan, Aatish Sethi, Gregorio Valdez.
      Collagen type XX alpha 1 (COL20A1) was recently found to be highly concentrated in perisynaptic Schwann cells (PSCs), the synaptic glia of the neuromuscular junction (NMJ), suggesting that COL20A1 plays important roles in PSCs and at the NMJ. To investigate this possibility, we generated mice lacking Col20a1 only in Schwann cells (Col20a1-SCKO) and globally (Col20a1-gKO). PSCs and NMJs were morphologically unchanged in adult Col20a1-SCKO mice despite these conditional mice exhibiting gait abnormalities. Additional analysis revealed roles of COL20A1 at regenerating NMJs. We found that loss of COL20A1 altered the time course of migrating Schwann cells associated with NMJs. It also inhibited the remodeling of the post-synaptic region that naturally occurs following reinnervation. However, the timing of NMJ reinnervation was unchanged in Col20a1-SCKO compared to control mice. We next examined adult Col20a1-gKO mice. These mice did not exhibit overt morphological differences compared to control mice. Col20a1-gKO mice also did not exhibit NMJ alterations despite presenting with increased mass of the extensor digitorum longus and soleus muscles. Together, these data provide important leads about potential roles of COL20A1 in healthy and injured adult PSCs, NMJs, and muscles.
    Keywords:  Motor neuron; Peripheral nervous system; Regeneration; Skeletal muscle
    DOI:  https://doi.org/10.1007/s12031-025-02406-8
  25. Mol Ther Methods Clin Dev. 2025 Sep 11. 33(3): 101546
    All-in-one vectors for epigenetic CRISPR inhibition of DUX4-fl in facioscapulohumeral muscular dystrophy.
    Charis L Himeda, Takako I Jones, Peter L Jones.
      Facioscapulohumeral muscular dystrophy (FSHD) is caused by incomplete epigenetic silencing of the disease locus, leading to pathogenic misexpression of DUX4 in skeletal muscle. Previously, we showed that CRISPR inhibition (CRISPRi) using several epigenetic regulators successfully targets and represses DUX4 in FSHD myocytes with no adverse effects on the muscle transcriptome. However, for translatability, adeno-associated virus (AAV)-mediated gene therapies must include all components within a single vector that expresses at therapeutic levels in all target tissues. Thus, we have re-engineered our CRISPRi platform to an all-in-one (AIO) single-vector system. Key modifications were as follows: (1) optimizing our regulatory cassette for high activity in all skeletal muscles while maintaining low or no activity in FSHD-unaffected tissues and (2) minimizing epigenetic regulators to their essential functional repressor domains, together creating enough space to include a single guide RNA (sgRNA) expression cassette within the AAV packaging limit. Targeting these AIO cargos to DUX4 suppressed pathogenic gene expression in FSHD1 and FSHD2 myocytes. Importantly, AAV-mediated delivery of our best AIO cargo also repressed DUX4 in an FSHD xenograft mouse model. These therapeutic cassettes represent a clinically relevant CRISPRi platform for gene therapy of FSHD and a useful proof-of-concept platform for other skeletal muscle gene therapies.
    Keywords:  AAV; CRISPR inhibition; DUX4; FSHD; Facioscapulohumeral muscular dystrophy; dCas9; epigenetic repression; gene therapy; muscular dystrophy
    DOI:  https://doi.org/10.1016/j.omtm.2025.101546
  26. Adv Exp Med Biol. 2025 ;1478 157-183
    Muscle Disuse Atrophy.
    Dongwook Yeo.
      Muscle disuse atrophy is characterized by a significant reduction in skeletal muscle mass and strength, primarily induced by prolonged periods of inactivity and inadequate mechanical stimulus. This condition is frequently encountered in clinical scenarios, especially in cases where patients undergo limb immobilization due to injuries or suffer from spinal cord impairments. The severity of muscle atrophy is often exacerbated by additional factors, such as advancing age and nutritional deficiencies, underscoring the multifaceted nature of this condition. Over the last two decades, significant advancements have been made in understanding the processes that lead to muscle degradation. Insights into the molecular and cellular mechanisms driving muscle catabolism in the absence of regular physical activity have been gained through research utilizing rodent models such as hindlimb unloading and immobilization, denervation, and spinal cord isolation. These experimental models have provided information on the morphological and functional deterioration as well as the extent of understanding of the molecular and cellular processes in response to disuse-induced muscle wasting. Despite these efforts, the therapeutic options for ameliorating muscle disuse atrophy are limited. Resistance training has been identified as the most effective intervention for reversing muscle mass and strength loss, yet it may only be feasible for some patients due to physical limitations or a lack of motivation to engage in intensive exercise routines. In response to these challenges, ongoing research is focused on identifying alternative therapeutic strategies, encompassing both pharmacological and non-pharmacological approaches, aimed at either preventing the onset of muscle atrophy or facilitating recovery following atrophic events. The implications of muscle disuse atrophy extend beyond clinical manifestations, impacting individuals' quality of life by impairing physical endurance and the capacity to perform daily activities. This chapter aims to offer an exhaustive summary of the various signals, pathways, and breakdown mechanisms implicated in muscle atrophy. Additionally, it will present the latest developments in therapeutic strategies addressing this condition.
    Keywords:  Autophagy; Mitochondria; Muscle atrophy; Pgc-1alpha; Ubiquitin proteasome
    DOI:  https://doi.org/10.1007/978-3-031-88361-3_8
  27. Adv Exp Med Biol. 2025 ;1478 459-473
    Redox Control of Skeletal Muscle Function and Adaptations to Exercise.
    Malcolm J Jackson, Robert Heaton, Caroline Staunton, Samrajni Banerjee, Anne McArdle.
      Since the first clear observation that skeletal muscle contained increased amounts of free radical species in the early 1980s, there has been increasing interest in how such species are formed and what functions they might have in skeletal muscle. Superoxide and nitric oxide are formed in increased amounts in skeletal muscle during contractile activity and these species together with the important derivative, hydrogen peroxide, are now recognised to play an important role in the physiological responses of muscle to contractile activity or exercise. In this chapter the potential sites for generation of superoxide and hydrogen peroxide during contractile activity will be examined together with the mechanisms for their formation. A major role for these species appears to be to signal the initiation of responses by which the muscle adapts to contractile activity and the potential mechanisms by which they exert such effects will be discussed. This appears to be a still poorly understood area of skeletal muscle biology which however has the potential for exploitation to optimise the beneficial effects of exercise and may well point to pharmacological approaches that can provide the benefits of exercise in immobile, ill or infirm subjects that are unable to take part in traditional exercise regimens.
    Keywords:  Adaptation; Exercise; Reactive oxygen species; Redox control; Skeletal muscle
    DOI:  https://doi.org/10.1007/978-3-031-88361-3_19
  28. Mol Ther Nucleic Acids. 2025 Sep 09. 36(3): 102665
    A combinatorial oligonucleotide therapy to improve dystrophin restoration and dystrophin-deficient muscle health.
    Young Jae Moon, Ravi Hindupur, Iteoluwakishi H Gamu, Nikki M McCormack, Fatima Shaikh, James S Novak, Jyoti K Jaiswal.
      Despite the proven safety of dystrophin-targeting phosphorodiamidate morpholino oligomer (PMO) therapy, poor delivery of the PMOs limit the efficacy of this dystrophin restoring gene therapy for Duchenne muscular dystrophy (DMD). Limited myogenesis and excessive fibrosis in DMD are pathological features that contribute to the poor efficacy of PMOs. We show that the severe DMD mouse model (D2-mdx) not only replicates these pathological features of DMD but also mirrors the resulting PMO-mediated dystrophin restoration deficit. High transforming growth factor β (TGF-β) activity, which is a common feature of DMD patient and D2-mdx muscles, limits myogenesis and causes fibrosis. We developed a TGF-β-targeting PO (TPMO), which when used acutely, lowered macrophage TGF-β activity and signaling in the dystrophic muscle, enhanced muscle regeneration, and enhanced dystrophin restoration when used in combination with dystrophin exon skipping PMO (DPMO). Chronic use of this combination PMO therapy in D2-mdx mice reduced muscle fibrosis and muscle loss, allowed dystrophin restoration in skeletal muscle and heart, and led to an overall enhancement of skeletal muscle function. This approach leverages the safety of PMO-based therapy and represents the first combination PMO treatment for DMD that simultaneously enhances dystrophin restoration, reduces fibrosis, and alleviates myogenic deficits to ultimately improve health and function of dystrophic muscles.
    Keywords:  Duchenne muscular dystrophy, DMD; MT: Oligonucleotides: Therapies and Applications; PMO; TGF-β; exon skipping; fibroadipogenic; fibrosis; inflammation; muscle regeneration; myogenesis; phosphoro-diamidate morpholino oligomer; transforming growth factor β
    DOI:  https://doi.org/10.1016/j.omtn.2025.102665
  29. Appl Physiol Nutr Metab. 2025 Sep 02.
    ZAG promotes exercise performance during endurance exercise by lipid utilization in skeletal muscle.
    Yanfei Li, Huangbin Sun, Xiaofang He, Xiaoyi Suo, Guoqiang Fan, Xiaojing Yang.
      Endurance exercise significantly enhances energy expenditure with lipids serving as a crucial energy source for skeletal muscle during exercise. The adipocytokine Zinc-α2-glycoprotein (ZAG) in endurance exercise remains largely uncertain. This study utilized ZAG knockout and overexpression mice to investigate ZAG's role in regulating lipid metabolism in skeletal muscle during endurance exercise. Results showed the serum ZAG level of mice was significantly increased after exercised, and ZAG knockout mice decreased the exercise performance. Subsequent research revealed that ZAG knockout notably elevated triglyceride (TG) level in skeletal muscle, reduced the expression of lipolysis-related factors such as adipose triglyceride lipase (ATGL), carnitine palmitoyl transferase-1b (CPT1b) and acyl-CoA synthetase long chain family member 1 (ACSL1), while enhancing the expression of lipid synthesis factor fatty acid synthase (FASN) during exercise. The expressions of mitochondrial energy metabolism related factors uncoupling protein 2 (UCP2) and cytochrome c oxidase subunit I (COX1) were reduced in ZAG knockout mice during endurance exercise. To assess ZAG's impact on lipid metabolism in skeletal muscle, we used ZAG overexpression plasmid in mice and C2C12 cells. ZAG overexpression decreased TG levels, enhanced ATGL expression, and increased CPT1b expression. In conclusion, ZAG can improve the level of skeletal muscle lipid metabolism and mitochondrial function during exercise, and improve the endurance exercise performance of mice.
    DOI:  https://doi.org/10.1139/apnm-2025-0137
  30. Adv Exp Med Biol. 2025 ;1478 61-84
    The Structural Adaptations That Mediate Mechanical Load-Induced Changes in Muscle Mass.
    Troy A Hornberger.
      During the last century, it has become clear that mechanical signals play a pivotal role in the regulation of skeletal muscle mass. For instance, numerous studies have shown that an increase in mechanical loading will lead to an increase in muscle mass, and a decrease in mechanical loading will lead to a decrease in muscle mass. These same studies have not only led to the widely adopted terms of "mechanical load-induced growth" and "disuse atrophy," but they have also shaped our understanding of the macroscopic, microscopic, and ultrastructural adaptations that contribute to the changes in muscle mass. These structural adaptations serve as the foundational events via which mechanical signals regulate skeletal muscle mass and, in this chapter, we will explore what is known about these adaptations and pinpoint the critical gaps in knowledge that remain to be filled.
    Keywords:  Fascicle; Hypertrophy; Muscle fiber; Myofibril; Myofibrillogenesis; Sarcomere
    DOI:  https://doi.org/10.1007/978-3-031-88361-3_4
  31. Adv Exp Med Biol. 2025 ;1478 545-571
    Skeletal Muscle and the Immune System.
    Brandt D Pence.
      The mammalian immune system consists of anatomical barriers, nonspecific innate immune responses, and highly specific adaptive immune responses that work in concert to protect the host from pathogens and to repair cellular damage. This chapter focuses on the basics of immunology, before turning to aspects of the immune system specifically relevant to skeletal muscle. In skeletal muscle, immune cells are important regulators of damage clearance, satellite cell proliferation and differentiation, and hypertrophy and are therefore integral to muscle adaptation to both pathology and exercise. Skeletal muscle is also a routine route of vaccination, due to its high degree of vascularization, relative lack of adipose tissue, and proximity to draining lymph nodes. Finally, skeletal muscle is an important producer of proteins and metabolites which are released into the extracellular space to modulate immune and other physiological functions both in the local muscle and in distant tissues. Importantly, this is thought to be a mechanism underlying the immune modulatory properties of physical exercise. However, despite our vast knowledge both of immunity and skeletal muscle physiology, comparatively little is known about the relationship between these two important systems.
    Keywords:  Immune system; Inflammation; Leukocytes; Myokines; Vaccination
    DOI:  https://doi.org/10.1007/978-3-031-88361-3_23
  32. Adv Exp Med Biol. 2025 ;1478 513-543
    Skeletal Muscle as Endocrine Organ.
    Mei Ma, Ziyi Zhang, Hai Bo, Yong Zhang.
      Skeletal muscle is widely recognized as an endocrine organ capable of synthesizing and secreting various cytokines and peptides collectively known as myokines. These myokines play a crucial role in the communication between muscle and other organs, including adipose tissue, liver, pancreas, bone, and brain. Research indicates that physical activity can stimulate the production of myokines in skeletal muscle, which then impact various organ functions through autocrine, paracrine, and endocrine pathways. Myokines contribute to the health benefits associated with exercise, including improved cognitive function, regulation of lipid and glucose metabolism, and promotion of muscle and bone development. Although our understanding of the specific functions of myokines in humans is still limited, their potentials as biomarkers for monitoring exercise programs and managing chronic diseases are significant. In summary, this study reviews the types and functions of myokines, as well as the effects of exercise on their expression, emphasizing the potential importance of skeletal muscle as an endocrine organ in promoting health and preventing chronic diseases. Additionally, it highlights the clinical significance of recognizing skeletal muscle as an endocrine organ and provides new insights for future research directions.
    Keywords:  Diseases; Exercise; Muscle-organ crosstalk; Myokines
    DOI:  https://doi.org/10.1007/978-3-031-88361-3_22
  33. Redox Biol. 2025 Aug 21. pii: S2213-2317(25)00352-0. [Epub ahead of print]86 103839
    Impaired xCT-mediated cystine uptake drives serine and proline metabolic reprogramming and mitochondrial fission in skeletal muscle cells.
    Michel N Kanaan, Charbel Y Karam, Luke S Kennedy, Chantal A Pileggi, Lauren Hamilton, Miroslava Cuperlovic-Culf, Mary-Ellen Harper.
      Muscle satellite cell (MuSC) proliferation is tightly regulated by redox homeostasis and nutrient availability, which are often disrupted in muscular pathologies. Beyond its role in maintaining cellular redox homeostasis, this study identified a key metabolic role for cystine/glutamate antiporter xCT in proliferating MuSCs. We investigated the impact of impaired xCT-mediated cystine import in Slc7a11sut/sut MuSCs isolated from mice that harbor a mutation in the SLC7A11 gene, which encodes xCT. We used complementary approaches to study how disrupted cystine import affects glutathione (GSH) redox, cellular bioenergetics, mitochondrial dynamics, and metabolism. Oxygen consumption rates of Slc7a11sut/sut MuSCs were lower, indicative of compromised mitochondrial oxidative capacity. This was accompanied by a fragmented mitochondrial network associated with OPA1 cleavage and redox-sensitive DRP1 oligomerization. Metabolomic profiling revealed a distinct metabolic signature in Slc7a11sut/sut MuSCs, manifested by major differences in BCAAs, pyrimidines, cysteine, methionine, and GSH. Despite lower overall bioenergetic flux, stable-isotope tracing analyses (SITA) showed that xCT deficiency increased glucose uptake, channeling glucose-derived carbons into de novo serine biosynthesis to fuel cysteine production via the transsulfuration pathway, partially compensating for disrupted GSH redox. Furthermore, xCT deficiency triggered upregulated pyrroline-5-carboxylate synthase (P5CS)-mediated proline reductive biosynthesis. By directing glutamate into proline synthesis, MuSCs apparently downregulate oxidative phosphorylation (OXPHOS) and regulate intracellular glutamate levels in response to impaired cystine/glutamate antiporter function. Our findings highlight the roles of xCT in regulating redox balance and metabolic reprogramming in proliferating MuSCs, providing insights that may inform therapeutic strategies for muscular and redox-related pathologies.
    Keywords:  Cysteine; Cystine/glutamate antiporter; Glycolysis; Metabolic reprogramming; Mitochondria; Myopathy; Oxidative phosphorylation; Proline; Skeletal muscle; Slc7a11; System Xc−; Transsulfuration pathway
    DOI:  https://doi.org/10.1016/j.redox.2025.103839
  34. bioRxiv. 2025 Aug 27. pii: 2025.08.27.670366. [Epub ahead of print]
    Slow- and fast-contracting skeletal muscle fibers have more similar cellular and molecular contractile function at 37°C than at 25°C in older adults.
    Brent A Momb, Stuart R Chipkin, Jane A Kent, Mark S Miller.
      As human skeletal muscle cellular and molecular contractile properties are temperature-sensitive, the ability to perform experiments at body temperature (∼37°C) may lead to a better understanding of their in vivo responses and potentially their effects upon whole-muscle and whole-body performance. We quantified molecular (myosin-actin cross-bridge mechanics and kinetics) and cellular (specific tension; force divided by cross-sectional area) function in slow-contracting myosin heavy chain (MHC) I and fast-contracting MHC IIA fibers from older adults (n=13, 8 female) at 37°C and compared these to results at 25°C. MHC I fibers were more temperature-sensitive than MHC IIA fibers, showing greater increases in cross-bridge kinetics (MHC I: 4.9-8.7x; IIA: 4x) and number or stiffness of strongly-bound cross-bridges (MHC I: 86%; IIA: 34%), leading to increased specific tension in MHC I (19%), with no change in MHC IIA fibers. The expected relationship between fiber force and size (cross-sectional area, CSA) was stronger at 37°C in both fiber types, explaining 80-82% of the variance compared to 51-52% at 25°C. Specific tension was unchanged with size at 37°C in both fiber types, showing that force increases proportionally with CSA, which may be due to the increased number or stiffness of strongly-bound cross-bridges at this temperature. At 25°C, specific tension decreased with size in agreement with previous experiments. Overall, MHC I and IIA fibers at body temperature (37°C) became more analogous, including similar specific tension and closer cross-bridge kinetics, and force production was more strongly correlated with fiber size compared to a non-physiological temperature.
    Abstract Figure:
    KEY POINTS SUMMARY: Although skeletal muscle function is highly sensitive to temperature, human single fiber studies have only been conducted at ≤30°C.Small-amplitude sinusoidal perturbations were utilized to elucidate mechanisms of single fiber force production at human physiological temperature (37°C).We found that functional differences in slow-contracting myosin heavy chain (MHC I) and fast-contracting MHC IIA fibers observed at 25°C were less apparent at 37°C, as force, crossbridge kinetics, and strongly-bound crossbridges increased more in MHC I fibers than MHC IIA fibers at 37 vs. 25°C. These results indicate that, given the different sensitivity of each fiber type to changes in temperature, functional assessments of muscle should be conducted at 37°C to better translate to vivo conditions.
    DOI:  https://doi.org/10.1101/2025.08.27.670366
  35. J Clin Invest. 2025 09 02. pii: e183567. [Epub ahead of print]
    Intermittent ischemia-reperfusion as a potent insulin-sensitizing intervention via blood flow enhancement and muscle Decanoyl-L-carnitine suppression.
    Kohei Kido, Janne R Hingst, Johan Onslev, Kim A Sjøberg, Jesper B Birk, Nicolas O Eskesen, Tongzhu Zhou, Kentaro Kawanaka, Jesper F Havelund, Nils J Færgeman, Ylva Hellsten, Jørgen F P Wojtaszewski, Rasmus Kjøbsted.
      A single bout of exercise improves muscle insulin sensitivity for up to 48 hours via the AMP-activated protein kinase (AMPK). Limb ischemia activates AMPK in muscle, and subsequent reperfusion enhances insulin-stimulated vasodilation, potentially eliciting a more pronounced exercise effect with reduced workload. Here, we investigated the combined effect of upper leg intermittent ischemia-reperfusion (IIR) and continuous knee-extension exercise on muscle insulin sensitivity regulation. We found that IIR-exercise potentiated AMPK activation and muscle insulin sensitivity. The potentiating effect of IIR-exercise on muscle insulin sensitivity was associated with increased insulin-stimulated blood flow in parallel with enhanced phosphorylation of endothelial nitric oxide synthase. Metabolomics analyses demonstrated a suppression of muscle medium-chain acylcarnitines during IIR-exercise, which correlated with insulin sensitivity and was consistent with findings in isolated rat muscle treated with Decanoyl-L-carnitine. Collectively, combining IIR with low-to-moderate intensity exercise may represent a promising intervention to effectively enhance muscle insulin sensitivity. This approach could offer potential for mitigating muscle insulin resistance in clinical settings and among individuals with lower physical activity levels.
    Keywords:  Glucose metabolism; Insulin; Metabolism; Muscle biology; Skeletal muscle
    DOI:  https://doi.org/10.1172/JCI183567
  36. Adv Exp Med Biol. 2025 ;1478 421-443
    Protein Acetylation and NAD+ Homeostasis in Aging Muscle.
    Li Li Ji.
      Hyperacetylation of proteins represents a stress to aged organisms. Increased consumption and loss of NAD+ homeostasis underlie a major mechanism for the disturbed acetylation/deacetylation balance during aging. Nicotinamide adenine dinucleotide (NAD) is a versatile chemical compound serving as a coenzyme in metabolic pathways and as a substrate to support the enzymatic functions of sirtuins (SIRTs), poly (ADP-ribose) polymerase-1 (PARP-1), and cyclic ADP ribose hydrolase (CD38). Under normal physiological conditions, NAD+ consumption is matched by its synthesis primarily via the salvage pathway catalyzed by nicotinamide phosphoribosyltransferase (NAMPT). However, aging and muscular contraction enhance NAD+ utilization, whereas NAD+ replenishment is limited by cellular sources of NAD+ precursors and/or enzyme expression. This chapter will briefly review NAD+ metabolic functions, its roles in regulating cell signaling, mechanisms of its degradation and biosynthesis, and major challenges to maintain its cellular level in skeletal muscle. The effects of aging, physical exercise, and dietary supplementation on NAD+ homeostasis will be highlighted based on recent literature.
    Keywords:  Acetylation; Aging; Exercise; NAD+; Sirtuin; Skeletal muscle
    DOI:  https://doi.org/10.1007/978-3-031-88361-3_17
  37. Aging (Albany NY). 2025 Aug 30. 17
    Glycocalyx-targeted therapy prevents age-related muscle loss and declines in maximal exercise capacity.
    Daniel R Machin, Md Torikul Islam, Alec Malouf, Daniel Nguyen, Mostafa Sabouri, Maryana Boulos, Andrew G Horn, Kiana M Schulze, Gwenael Layec, Lisa A Lesniewski, Anthony J Donato.
      Age-related declines in cardiovascular function contribute to reduced physical capacity, both of which are independent predictors of mortality. We have previously demonstrated that glycocalyx-targeted therapy with Endocalyx™ that contains high-molecular-weight hyaluronan (HMW-HA) improves cardiovascular health in old age, raising the possibility that HMW-HA also plays a role in age-related physical dysfunction. Here, we first demonstrate that tamoxifen-inducible deletion of Has2, which produces HMW-HA, leads to glycocalyx depletion, decreases exercise capacity, and impairs skeletal muscle respiratory capacity. We then sought to determine the effects of Endocalyx™ on physical function in old mice. Young (7 months) and old (29 months) mice underwent standard diet or Endocalyx™-supplemented diet for 10 weeks. Glycocalyx thickness was higher in young and Endocalyx™-treated old mice compared to standard diet-fed old mice. While standard diet-fed old mice demonstrated a reduction in running exercise capacity over the intervention, Endocalyx™-supplemented diet prevented this age-related decline. Gastrocnemius citrate synthase activity, a marker of mitochondrial content in skeletal muscle, was lower in standard diet-fed old mice compared to young and Endocalyx™-treated old mice. Collectively, these findings suggest that glycocalyx integrity is a critical determinant of physical function and that glycocalyx-targeted interventions may be a viable therapeutic strategy to treat age-related physical dysfunction.
    Keywords:  aging; glycocalyx; hyaluronan
    DOI:  https://doi.org/10.18632/aging.206313
  38. J Neuroimmunol. 2025 Aug 25. pii: S0165-5728(25)00216-4. [Epub ahead of print]408 578735
    Serum from patients with MuSK antibody-positive myasthenia gravis triggers transcriptomic changes leading to muscle atrophy and weakness in human myotube cells.
    Keisuke Tanaka, Akiyuki Uzawa, Manato Yasuda, Yosuke Onishi, Hiroyuki Akamine, Hideo Handa, Etsuko Ogaya, Shota Miyake, Masayuki Baba, Hiroto Abe, Koki Nagaoka, Yuko Nakatake-Furuie, Yoshichika Katsura, Kenichi Serizawa, Satoshi Kuwabara.
      Myasthenia gravis (MG) is an autoimmune disease characterized by autoantibodies targeting the acetylcholine receptor (AChR) or muscle-specific tyrosine kinase (MuSK). These autoantibodies inhibit ACh signal transmission at the neuromuscular junction, leading to muscle weakness and fatigue. Anti-MuSK antibody-positive MG (MuSK+MG) appears more rarely than anti-AChR antibody-positive MG but more frequently results in muscle atrophy. However, the underlying mechanism is unknown. In this study, we analyzed whether serum from MuSK+MG patients has any pathogenic effect on cultured myotube cells. Primary human skeletal muscle myoblasts were differentiated into myotubes, which were then treated with serum from healthy control individuals or MuSK+MG patients. After one day, RNA-seq analysis and Western blotting were performed and myotube diameters were measured. Calcium dynamics following caffeine stimulation was also assessed. Comparing myotube cells treated with healthy control serum with those treated with serum from MuSK+MG patients, RNA-seq analysis showed suppression of pathways associated with muscle function and Western blotting analysis revealed reduced expression of Type II myosin heavy chain. These changes are consistent with muscle atrophy and weakness, although myotube diameter remained unchanged. Caffeine stimulation induced higher cytoplasmic calcium levels. Expression of sarcomere components was significantly reduced. Serum from MuSK+MG patients directly affected gene and protein expression in cultured human myotube cells, leading to changes associated with muscle atrophy and weakness. These findings suggest that there are mechanisms in addition to impaired ACh signal transmission at the neuromuscular junction that can cause muscle weakness and fatigue in MG patients.
    Keywords:  Human myotube cells; MuSK antibody-positive serum; Muscle atrophy; Myasthenia gravis
    DOI:  https://doi.org/10.1016/j.jneuroim.2025.578735
  39. Adv Exp Med Biol. 2025 ;1478 245-284
    Muscular Dystrophies.
    Yi-Wen Chen, Adam J Bittel, Daniel C Bittel, Young Jae Moon, Nikki M McCormack, Jyoti K Jaiswal.
      Skeletal muscles remodel and regenerate in response to physiological and pathological conditions. Muscle disorders can be caused by disturbance of molecular and cellular pathways that are important in maintaining muscle homeostasis in response to physiological stimuli and environmental challenges. Muscular dystrophies are a heterogeneous group of rare, progressive diseases involving muscle degeneration and regeneration, with defects and failure in regeneration contributing to muscle loss and functional decline. Currently, there is no cure for these diseases, although many therapeutic approaches are in development. In this chapter, we discuss genetic causes, disease mechanisms, and therapeutic development for the most common muscular dystrophies, including Duchenne muscular dystrophy (DMD), myotonic dystrophy (MD) facioscapulohumeral muscular dystrophy (FSHD), and limb-girdle muscular dystrophies (LGMD).
    Keywords:  Atrophy; Degeneration; Dystrophy; Myopathy; Regeneration
    DOI:  https://doi.org/10.1007/978-3-031-88361-3_11
  40. Adv Exp Med Biol. 2025 ;1478 317-342
    Mechanisms of Biological Aging with Special Reference to the Skeletal Muscle.
    Sataro Goto, Zsolt Radak.
      Model animals for aging research are described referring to the definition of biological aging, emphasizing importance of post-mitotic or slowly dividing cells in multicellular organisms. Selected theories of the molecular mechanisms of biological aging are examined in general including historical backgrounds on the genome instability theory of aging, free radical or oxidative stress theory of aging, mitochondrial theory of aging, error catastrophe theory of aging or translational error theory of aging, altered protein theory of aging or proteostasis theory of aging, and epigenetic theory of aging. The special relevance of these theories to the skeletal muscle aging are referred in each section.
    Keywords:  Aging theories; Definition of aging; Mechanisms of aging
    DOI:  https://doi.org/10.1007/978-3-031-88361-3_13
  41. Adv Sci (Weinh). 2025 Aug 31. e12354
    RPS27L Enhances Myogenesis and Muscle Mass by Targeting IGF1 Through Liquid-Liquid Phase Separation.
    Xiaoqin Liu, Yilong Yao, Junyu Yan, Mu Zeng, Xinhao Fan, Yijie Tang, Jiju Li, Yanwen Liu, Shanying Yan, Wei Wang, Lijuan Chen, Ruipu Chen, Yuxin Huang, Honor Calnan, Heng Wang, Graham Gardner, Yalan Yang, Zhonglin Tang.
      RNA-binding proteins (RBPs) play a pivotal role in post-transcriptional regulation of gene expression, critically influencing skeletal myogenesis, muscle growth, and regeneration. Despite the recent identification of RBP Rps27l (ribosomal protein S27-like) as a regulator affecting myogenic proliferation and differentiation, its functions and regulatory mechanisms in skeletal muscle development remain largely unknown. In this study, it is observed that muscle-specific Rps27l knock-in (M─KI) mice exhibit significantly increased muscle mass, enlarged myofiber size, a higher proportion of fast-twitch myofibers, and enhanced muscle regeneration capabilities compared to wild-type controls. Overexpression of Rps27l promotes myoblast proliferation while inhibiting differentiation in skeletal muscle cells. Mechanistically, it is revealed that the expression of Rps27l is negatively regulated by SIX4, a myogenic transcription factor. The N-terminal intrinsically disordered region of RPS27L facilitates liquid-liquid phase separation (LLPS) and interacts with IGF1 to collaboratively regulate myogenesis. The findings uncover the novel regulatory roles of RPS27L in skeletal muscle and highlight the significance of RPS27L-driven LLPS in myogenesis.
    Keywords:  IGF1; RPS27L; liquid‐liquid phase separation; muscle mass; myofiber sizes; skeletal muscle
    DOI:  https://doi.org/10.1002/advs.202512354
  42. Adv Exp Med Biol. 2025 ;1478 285-314
    Cancer Cachexia.
    Melissa J Puppa, James A Carson.
      Skeletal muscle's metabolic and mechanical functions make it critical for maintaining human health, physical function, and quality of life in adults. The impact of skeletal muscle mass and the metabolic quality of muscle tissue becomes even more critical with advancing age and in patients with chronic diseases. To this end, cachexia is the involuntary loss of body weight, including muscle and fat loss, accompanying an underlying disease or condition. Cancer-induced cachexia occurs across many types of cancer and contributes to increased patient mortality, morbidity, and treatment toxicities, negatively impacting survival. Furthermore, there are currently no approved pharmacological treatments and limited evidence-based therapeutic options to prevent muscle loss or promote muscle recovery in cancer patients. While the systemic effects of cancer and subsequent treatment continue to be examined as drivers of overall wasting, the impact of skeletal muscle mass and metabolic quality in the cancer patient remains a critical area of investigation. A vital knowledge gap exists in understanding how maintaining muscle function and metabolic properties improves cancer patients' survival. The chapter explores the current understanding of how cancer and subsequent treatment impact skeletal muscle mass, function, and metabolic quality. To this end, the current understanding of systemic mediators and metabolic crosstalk between tissues that promote cancer-induced wasting is explored. Additional factors related to sex, physical activity level, chemotherapy-specific effects, and cancer heterogeneity are discussed concerning their impact on cancer-induced muscle wasting.
    Keywords:  Cancer; Muscle atrophy; Wasting; Weight loss
    DOI:  https://doi.org/10.1007/978-3-031-88361-3_12
  43. J Physiol. 2025 Sep 02.
    Angiotensin-converting enzyme and exercise adaptations: Genetic variability, pharmacological modulation and future directions.
    Tórur Sjúrðarson, Nikolai B Nordsborg.
      Individual responses to exercise training vary widely, shaping athletic performance, rehabilitation outcomes and long‑term health trajectories. This review synthesizes evidence on how angiotensin-converting enzyme (ACE) activity, influenced by genetic variation, epigenetic regulation and pharmacological modulation, shapes adaptations in skeletal muscle hypertrophy, cardiac remodelling, erythropoiesis, endurance capacity and injury susceptibility. We highlight ACE's nuanced role, showing that pharmacological inhibition selectively attenuates cardiac and haematological adaptations, such as haemoglobin mass and lean body mass, without affecting peripheral muscle adaptations and aerobic performance. Additionally, exercise itself modulates ACE expression and the broader renin-angiotensin system signalling network in a context-dependent manner, complicating genotype-phenotype interactions. Future research should move decisively beyond genotype-based stratification and prioritize direct phenotyping of ACE activity, together with comprehensive profiling of the entire renin-angiotensin system axis, as genotype alone poorly predicts enzyme levels or downstream signalling. More broadly, ACE inhibition serves as a mechanistic model for systematically investigating biological pathways underlying individual variability in training responses, advancing precision exercise medicine.
    Keywords:  ACE I/D polymorphism; ACE inhibition; body composition; cardiovascular adaptations; exercise physiology; human adaptation; injury rehabilitation; precision exercise medicine; skeletal muscle adaptation
    DOI:  https://doi.org/10.1113/JP288202
  44. Histochem Cell Biol. 2025 Sep 05. 163(1): 89
    MyoAnalyst: an ImageJ plugin for accurate and automatic myofiber segmentation and analysis in skeletal muscle cross sections.
    Bao Zhang, Shuaiyu Wang, Yaning Wang, Chen Liang, Hongbo Zhang.
      Quantifying myofiber size is essential for assessing the health and function of skeletal muscle. Although several ImageJ plugins are currently available for myofiber segmentation and size quantification, significant challenges remain-most notably limited accuracy and poor compatibility with hematoxylin and eosin (H&E)-stained skeletal muscle cross sections. In this study, we introduce MyoAnalyst, an ImageJ plugin designed to enable automated analysis of both immunofluorescence (IF)- and H&E-stained skeletal muscle cross sections. Compared to existing ImageJ plugins, MyoAnalyst delivers enhanced segmentation sensitivity and superior boundary delineation accuracy across both healthy and injured muscle tissue stained with IF. Importantly, it also supports fully automated analysis of H&E-stained sections. With its intuitive graphical interface and batch processing capabilities, MyoAnalyst provides a potentially efficient tool for myofiber size quantification in both research and clinical settings.
    Keywords:  Automated analysis; MyoAnalyst; Myofiber segmentation; Skeletal muscle cross section
    DOI:  https://doi.org/10.1007/s00418-025-02414-0
  45. PLoS Genet. 2025 Aug 29. 21(8): e1011834
    Igf2 adult-specific skeletal muscle enhancer activity revealed in mice with intergenic CTCF boundary deletion.
    Joanne L Thorvaldsen, Aimee M Juan, Yemin Lan, Christopher Krapp, Marisa S Bartolomei.
      Precise, monoallelic expression of imprinted genes is governed by cis regulatory elements called imprinting control regions (ICRs) and enhancer-promoter (E-P) interactions shaped by local chromatin architecture. The Igf2/H19 locus employs allele-specific CTCF binding at the ICR to instruct enhancer accessibility to maternal H19 and paternal Igf2 promoters. Here, we investigate the CTCF-bound centrally conserved domain (CCD), intergenic to H19 and Igf2, and an adjacent widely expressed lncRNA. Using transgenic mice, deletion alleles reinforced CCD as a neonatal muscle-specific repressor of maternal Igf2. However, deletion of the abutting lncRNA did not affect Igf2 levels. Unexpectedly, in adult skeletal muscle where Igf2 is normally repressed, absence of CCD resulted in remarkable, high-level activation of Igf2 from both parental alleles. Through multimodal chromatin analyses, we identified a conserved putative adult skeletal muscle enhancer (PaSME) insulated between chromatin domains at ICR and CCD. We propose that removal of CCD allows PaSME to drive robust abnormal Igf2 activation on both alleles in adult skeletal muscle. Thus, we uncover CCD as a developmental biallelic muscle-specific repressor, adding a new layer of architectural regulation to the extensively studied Igf2/H19 locus.
    DOI:  https://doi.org/10.1371/journal.pgen.1011834
  46. Hum Mol Genet. 2025 Aug 29. pii: ddaf140. [Epub ahead of print]
    Galactose treatment rescues neuromuscular junction transmission in glutamine-fructose-6-phosphate transaminase 1 (Gfpt1) deficient mice.
    Stephen Henry Holland, Ricardo Carmona-Martinez, Daniel O'Neil, Kelly Ho, Kaela O'Connor, Yoshiteru Azuma, Andreas Roos, Sally Spendiff, Hanns Lochmüller.
      Congenital myasthenic syndromes (CMS) arise from mutations to proteins involved in neuromuscular junction (NMJ) development, maintenance, and neurotransmission. To date, mutations in more than 35 genes have been linked to CMS development. Glutamine fructose-6-phosphate transaminase 1 (GFPT1/Gfpt1) serves as the rate-limiting enzyme of the hexosamine biosynthetic pathway (HBP), producing the byproduct (UDP-GlcNAc) necessary for protein glycosylation. Gfpt1-deficient models have impaired protein glycosylation, impacting key proteins at the NMJ. The Leloir pathway is a galactose metabolizing pathway which produces UDP-GalNAc as its final product. The enzyme UDP-GalNAc Epimerase (GALE) can also convert excess UDP-GalNAc into UDP-GlcNAc, the byproduct of the HBP. We hypothesized that treatment with galactose both in vitro and in vivo in Gfpt1-deficient models would rescue impaired protein O-GlcNAcylation and reverse the glycosylation status of key NMJ-associated proteins. We show that galactose treatment in vitro activated the Leloir pathway and rescued protein O-GlcNAcylation in Gfpt1-deficient C2C12 myoblasts. In addition, we demonstrated that galactose therapy rescued neuromuscular deficits, improved muscle fatigue and restored NMJ morphology in a skeletal muscle-specific Gfpt1 knockout mouse model. Lastly, we showed that galactose treatment rescued protein O-GlcNAcylation in skeletal muscle, preserving the glycosylation status of the delta (δ) subunit of the acetylcholine receptor (AChRδ). Taken together, we suggest that galactose supplementation can be further explored as a therapy for GFPT1-CMS patients.
    Keywords:  Congenital Myasthenic Syndrome; Galactose; Glutamine-Fructose-6-Phosphate Transaminase 1; Glycosylation; Neuromuscular Junction
    DOI:  https://doi.org/10.1093/hmg/ddaf140
  47. Adv Exp Med Biol. 2025 ;1478 475-489
    Muscle Plasticity, Adaptation and Epigenetics.
    Jonathan Charles Jarvis.
      Muscle was one of the first tissues in which substantial phenotypic adaptation of fully differentiated adult cells was demonstrated. The control of gene expression, and therefore the nature of the proteome, is under the control of external influences, including hormonal signals, but most remarkably, allows the muscle fibre to adapt to the accustomed pattern of activity. When that pattern of activity changes in terms of daily amount or pattern, the muscle fibres change to accommodate the required activity. If daily activity increases, then the mechanisms of sustained energy supply are enhanced, and one can identify an 'endurance' phenotype. If only short bursts of activity are required relatively infrequently, the fibres tend to become fast and powerful, taking on a 'sprint' phenotype.The intracellular mechanisms that tend to match the phenotype with the required activity are multifaceted. A period of painstaking mechanistic analyses during the past decades can now be re-evaluated with much more comprehensive analyses based on the dynamic changes in the transcriptome, epigenome and proteome.Such adaptation is an important component of athletic training for power or endurance events, the problematic loss of muscle with ageing, forced bedrest, or cachexia, and the healthy control of blood glucose in feeding, fasting and exercise.This chapter reviews the historical evidence, focusing on the progressive improvement in the experimental models available to probe this remarkable aspect of neuromuscular physiology.
    Keywords:  Exercise response; Muscle adaptation; Muscle fibre type; Muscle training; Plasticity
    DOI:  https://doi.org/10.1007/978-3-031-88361-3_20
  48. Adv Exp Med Biol. 2025 ;1478 213-242
    Traumatic Skeletal Muscle Injury and Recovery.
    Sarah M Greising, Jarrod A Call, Cory W Baumann.
      Skeletal muscle is integral to life and functions to produce movement and locomotion, postural control, respiratory activity, and heat production. Yet, injuries to skeletal muscles occur across the lifespan, and depending on the injury mechanism, nuances in physiology and severity, how and if recovery of muscle function is possible is varied. This chapter presents the current physiologic understanding of various traumatic skeletal muscle injuries with attention to landmark work that has built the foundation for our current understanding. Injuries ranging from those that leave the extracellular matrix (ECM) intact or completely lost will be discussed as well as the common eccentric contraction-induced and ischemia-reperfusion injuries.
    Keywords:  Eccentric contraction; Extracellular matrix; Freeze injury; Muscle function; Regeneration; Repair; Toxin injury; Volumetric muscle loss
    DOI:  https://doi.org/10.1007/978-3-031-88361-3_10
  49. Front Cell Dev Biol. 2025 ;13 1651553
    Metabolic and molecular regulation in skeletal muscle dysfunction and regeneration.
    Jong Beom Jin, Angelique Robinson, Tori Soukup, Ember Black, André Abit, Shane M Hammer, Anna Han, Edralin Lucas, Yoo Kim, Jiyoung Bae.
      Skeletal muscle is an important organ in the human body for maintaining overall strength and mobility. Skeletal muscle has the capability of self-regeneration, which can be achieved by utilizing specific energy pathways. Therefore, understanding the energy metabolism of skeletal muscle is essential to exploring its regenerative mechanisms. This review addresses the current progress in understanding the essential role of metabolic pathways in skeletal muscle function, regeneration, and muscle dysfunction as it relates to diseases such as type 2 diabetes mellitus (T2DM), obesity, and aging (sarcopenia). Furthermore, we explore the fundamental metabolisms of skeletal muscle while considering not only disease progression but also therapeutic strategies. Experimental models (in vivo and in vitro) and other signaling pathways are additionally discussed while proposing that the association between energy metabolism markers and metabolic diseases in skeletal muscle could provide innovative implications. Finally, the need for developing human-relevant models to study muscle regeneration is emphasized as most current findings are derived from in vivo and in vitro models.
    Keywords:  mechanism; metabolic diseases; metabolism; regeneration; skeletal muscle
    DOI:  https://doi.org/10.3389/fcell.2025.1651553
  50. bioRxiv. 2025 Aug 23. pii: 2025.08.23.671924. [Epub ahead of print]
    Dual S100A1 and ARC gene therapy as a treatment for DMD cardiomyopathy.
    David W Hammers, Cora C Hart, Young Il Lee, Margaret M Sleeper, H Lee Sweeney.
      Duchenne muscular dystrophy (DMD) is a lethal pediatric striated muscle disease caused by loss of dystrophin for which there is no cure. Cardiomyopathy is the leading cause of death amongst individuals with DMD, and effective therapeutics to treat DMD cardiomyopathy are a major unmet clinical need. This work investigated adeno-associated viral (AAV) gene therapy approaches to treat DMD cardiomyopathy by overexpression of the calcium binding proteins S100A1 and apoptosis repressor with caspase recruitment domains (ARC). Using the severe D2.mdx mouse model of DMD, we identified that S100A1 gene therapy improves the diastolic dysfunction associated with DMD cardiomyopathy, whereas ARC gene therapy prolongs survival. The combination of both S100A1 and ARC in a single bicistronic vector improves the long-term cardiac outcome of D2.mdx mice, development of heart failure caused by micro-dystrophin expression, and exhibits safety via intracoronary delivery in a canine model of DMD. Furthermore, S100A1-ARC gene therapy provides functional benefits when expressed in D2.mdx skeletal muscle. Together, these findings indicate that S100A1-ARC gene therapy represents an effective treatment for DMD cardiomyopathy and may be effective in treating other forms of cardiomyopathy and muscle pathologies.
    Keywords:  Biological Sciences- Medical Sciences; Calcium handling; Cardiomyopathy; Duchenne muscular dystrophy; Gene therapy; S100A1
    DOI:  https://doi.org/10.1101/2025.08.23.671924
  51. Adv Exp Med Biol. 2025 ;1478 185-212
    Skeletal Muscle Damage and Inflammation.
    Tyrone A Washington, Eleanor R Schrems.
      Skeletal muscle is an extremely plastic tissue that can respond to a variety of insults. If the insult is sufficient, it may reduce damage to the skeletal muscle. Damage to skeletal muscle is associated with an inflammatory response. This inflammatory response is required for optimal regeneration. There are several models used to induce damage to skeletal muscle from eccentric muscle actions to myotoxin injections. While the method of inducing damage may vary the inflammatory response is similar. Upon damage, circulating immune cells are activated and infiltrate the tissue. The first to arrive is the neutrophil followed by the macrophage. The neutrophil clears debris and releases pro-inflammatory signals which facilitate the recruitment of macrophages. Macrophages are recruited and begin as pro-inflammatory macrophages (M1) continuing to facilitate the clearance of debris before macrophage polarization occurs in which they become anti-inflammatory macrophage (M2). The anti-inflammatory macrophages facilitate the myogenic response critical for optimal regeneration. Disruptions to the inflammatory response will directly affect the ability of the skeletal muscle to recover from injury.
    Keywords:  Injury; Macrophage; Natural killer cells; Neutrophils
    DOI:  https://doi.org/10.1007/978-3-031-88361-3_9
  52. Commun Biol. 2025 Aug 30. 8(1): 1317
    Stage-specific requirement for METTL3-dependent m6A epitranscriptomic regulation during myogenesis.
    Ye-Ya Tan, Yang-Wen Ou, Qin Zuo, Yi Luo, Wei-Cai Chen, Wan-Xin Chen, Xin-Wang Zhi, Pei-Wen Lin, Jia-Xing Lu, Peng Liu, Si-Min Liang, Qing-Hai Lian, Lian-Dong Zuo, Hong-Wen Xu, Shu-Juan Xie.
      The regulatory role of N6-methyladenosine (m6A) modification in skeletal muscle myogenesis and muscle homeostasis remains poorly characterized, particularly regarding the functional significance of methyltransferase-like 3 (METTL3), the catalytic subunit of the m6A methyltransferase complex (MTC), in myogenic regulation. Through systematic investigation of m6A epitranscriptomic remodeling during myogenesis, we demonstrate that METTL3-mediated m6As orchestrates myoblast fusion processes in both differentiation and regeneration contexts. Notably, we observed marked induction of Mettl3 expression post-injury, accompanied by substantial transcriptomic alterations in myogenesis-related pathways. High-resolution m6A mapping revealed distinct dynamic patterns of METTL3-regulated m6As during differentiation, exhibiting dichotomous regulation across target transcripts. Mechanistically, we identified myogenic fusion factors Mymx and Mymk as direct targets of METTL3, showing concomitant upregulation of both transcript abundance and m6A deposition during myogenesis. This study provides comprehensive multi-omics resources delineating the mechanistic landscape of METTL3-regulated m6As in myogenic programming, establishing METTL3 as a critical regulatory node governing myoblast fusion dynamic.
    DOI:  https://doi.org/10.1038/s42003-025-08759-5
  53. Adv Exp Med Biol. 2025 ;1478 113-153
    Muscle Proteome Dynamics.
    Connor A Stead, Aaron Thomas, Yusuke Nishimura, Marjan Abbasi, Jennifer Barrett, Jatin G Burniston.
      Skeletal muscle demonstrates remarkable malleability and can alter in metabolic and contractile properties in response to changes in environmental stimuli, in particular contractile work. The muscle proteome defines muscle by dictating its functional characteristics and coordinating its adaptive responses to external stimuli. The dynamic aspects of the proteome have not yet been widely studied and most current proteomic data chart changes to the abundance profile or post-translational state of proteins during the process of adaptation. Nevertheless, the proteome is a dynamic entity. Proteins exist in a constant cycle of renewal, known as protein turnover, which is essential to maintain the quality of the proteome and to facilitate adaptation. Adaptation is only possible because proteins exist in a flux of synthesis and degradation. Furthermore, synthesis and degradation are each highly regulated processes and, in themselves, change in response to stimuli. Isotope tracers are required to study proteome dynamics, and stable isotopes, such as deuterium that impart a mass tag to newly synthesised proteins, are ideally suited to mass spectrometry-based proteomic analyses. New proteomic methods are now emerging that simultaneously measure the abundance and synthesis rate of large numbers of individual proteins. This chapter provides an overview of developments in this field.
    Keywords:  Deuterium oxide; Mass spectrometry; Muscle protein synthesis; Proteomics; Proteostasis; Stable isotopes
    DOI:  https://doi.org/10.1007/978-3-031-88361-3_7
  54. Tissue Eng Regen Med. 2025 Sep 03.
    Human Mesenchymal Stem Cell-Derived Skeletal Muscle Cell Spheroids for Treating Dexamethasone-Induced Sarcopenia.
    Yoonji Yum, Juhee Yoon, Yu Hwa Nam, Duk-Hee Kang, Sung-Chul Jung, Saeyoung Park.
       BACKGROUND: Sarcopenia, a musculoskeletal disease associated with aging or certain factors, is characterized by a reduction in muscle mass, strength, and performance. Dexamethasone (DEX)-induced muscular atrophy in animals, which shows a significant decrease in muscle mass, strength, and function, serves as a model for sarcopenia. Mesenchymal stem cell-based therapies, particularly those using 3D cultured spheroids, have emerged as a prominent area in muscle regeneration. Previous research has demonstrated that tonsil-derived mesenchymal stem cells (TMSCs) can differentiate into skeletal muscle cells (SKMCs) that exhibit attributes of skeletal muscles.
    METHODS: Spheroids formed from TMSC-derived skeletal muscle cells (TMSC-SKMC-spheroids) were produced using microwells and subsequently transplanted into a sarcopenia model. This model utilized a dexamethasone (DEX)-induced muscular atrophy rat to mimic sarcopenia. The effectiveness of TMSC-SKMC-spheroid transplantation was assessed through grip strength tests, running fatigue tests, measurements of gastrocnemius muscle thickness and weight, and histopathological evaluations.
    RESULTS: Post-transplantation, the rat models exhibited improvement in hind limb motor functions and gastrocnemius muscle regeneration. Additionally, the neuromuscular junctions in the gastrocnemius muscle of the transplantation group were restored.
    CONCLUSION: These findings demonstrate the therapeutic potential of TMSC-SKMC-spheroids in the DEX-induced atrophy rat model and suggest their promise as a valuable therapeutic resource for sarcopenia caused by various factors.
    Keywords:  Dexamethasone-induced Sarcopenia; Spheroid; Tonsil-derived mesenchymal stem cells
    DOI:  https://doi.org/10.1007/s13770-025-00753-6
  55. Neural Regen Res. 2025 Sep 03.
    Reevaluating the role of skeletal muscle in amyotrophic lateral sclerosis pathogenesis: Insights from muscle-derived factors.
    Pablo Martinez, Brigitte van Zundert, Fernando J Bustos.
      
    DOI:  https://doi.org/10.4103/NRR.NRR-D-25-00567
  56. Am J Physiol Heart Circ Physiol. 2025 Sep 05.
    Farther and Faster: Enhancing Skeletal Muscle Performance.
    Ali Boolani, Matthew Lee Smith, Joshua T Butcher.
      
    DOI:  https://doi.org/10.1152/ajpheart.00657.2025
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