bims-moremu Biomed News
on Molecular regulators of muscle mass
Issue of 2026–06–28
48 papers selected by
Anna Vainshtein, Craft Science Inc.
  1. Estrogen-related receptor signaling counters sarcopenia and preserves exercise fitness in naturally aged mice.
  2. Potential Influence of Myokines on Skeletal Muscle Tissue Hypertrophy Signaling Pathways: A Narrative Review.
  3. miR-339-5p impairs myogenic proliferation and differentiation by repressing contractile gene programs in skeletal muscle.
  4. The Dual Role of Interleukin-6 in the Pathophysiology of Skeletal Muscle: Mechanisms, Challenges, and Therapeutic Prospects.
  5. CIRBP maintains skeletal muscle mitochondrial energy homeostasis via mt-ATP6 to ameliorate sarcopenia.
  6. Sarcopenia and satellite cell homeostasis disruption: the dual function of NAD+ metabolism.
  7. Exercise as a Bidirectional Regulator of Drp1: A Goldilocks Principle for Mitochondrial Adaptation in Skeletal Muscle.
  8. Resident mesenchymal progenitor cells require autocrine IGF-I in homeostatic and regenerating skeletal muscle.
  9. Elevated mitochondrial Ca2+ impairs satellite cell pool expansion in response to skeletal muscle injury.
  10. The two faces of mitochondrial Ca2+ dysregulation in skeletal muscle: overload and deficiency.
  11. Regulation of Myogenic Cell Apoptosis, UPS, and Autophagy During Mammalian Skeletal Myogenesis.
  12. Intrinsic exercise capacity is associated with skeletal muscle clock gene and IGF-1 signaling in aged low- and high-running capacity rats.
  13. VMA21 deficiency leads to autophagic dysregulation and altered vesicle trafficking in X-linked myopathy with excessive autophagy.
  14. Regular Aerobic Exercise Can Effectively Ameliorate the Skeletal Muscle and Mitochondrial Function Impairments Caused by bves Deficiency in Zebrafish.
  15. Efficient pharmacological modulation of autophagy in isolated muscle fibers: impact on excitation-contraction coupling.
  16. Calorie restriction and exercise differentially regulate AMP-activated protein kinase across subcellular compartments in skeletal muscle from older male rats.
  17. Neonatal muscle-derived extracellular vesicles containing miR-542-3p rejuvenate aged skeletal muscle via a functional microneedle patch.
  18. Contrasting response of polyamine metabolic enzymes underlying fiber-type specific volume regulation in the skeletal muscle with endurance exercise.
  19. The miR-206-3p/Cpeb1 axis delays acetylcholine receptor degradation and preserves neuromuscular junction stability in denervation-induced muscle atrophy.
  20. Acute and Chronic High-Intensity Exercise Differentially Regulate the miRNA Biogenesis Pathway in Human Skeletal Muscle.
  21. Time-Restricted Feeding/Eating and Muscle Aging: Research Progress from Molecular Mechanisms to Personalized Intervention Strategies.
  22. IL-13Rα2 Regulates C2C12 Myoblast Proliferation via the Akt-Cyclin D1-CDK4 Pathway.
  23. Cellular and molecular pathways linking obesity to skeletal muscle dysfunction.
  24. Basal Energetics and Phosphocreatine Recovery Kinetics in Ambulatory Boys With Duchenne Muscular Dystrophy.
  25. Physical exercise mitigates amyloid beta-driven muscle degeneration in Alzheimer's disease.
  26. GPAT3 is associated with lipid deposition and AMPK signaling in skeletal muscle.
  27. Caffeine, skeletal muscle signalling, and exercise adaptation: a narrative review separating acute ergogenic effects from chronic remodelling.
  28. Quantitative interactome mapping of skeletal muscle insulin resistance.
  29. Aerobic exercise is associated with alleviation of skeletal muscle atrophy in CT26 tumor-bearing mice: insights from transcriptomic and weighted gene co-expression network analyses.
  30. High dietary fat causes muscle structural breakdown, mitochondrial dysfunction, and contractile deficits in the absence of carnitine palmitoyltransferase 2.
  31. Zfp36l1 Inhibits DNA Damage by Regulating p21-E2F1-Rad51 Signaling During Myogenic Differentiation.
  32. Dynamic integration of skeletal muscle signals via extracellular vesicles in motor neuron diseases.
  33. THBS1 as a Key Regulator of Myoblasts: Validation of Its Inhibitory Roles in Skeletal Muscle Development.
  34. Three-dimensional imaging reveals preserved intrinsic contractile function in aging human skeletal muscle fibers.
  35. Accumulation of membrane repair-associated proteins and mature myostatin are novel markers of muscle pathophysiology in Pompe disease.
  36. Balanced Essential Amino Acids as Synergistic Therapeutic Agents in Resistance Training: Mechanistic and Clinical Perspectives on Muscle and Metabolic Health.
  37. Phytochemical-Based Therapeutic Strategies for Sarcopenia: From Molecular Mechanisms to Clinical Translation.
  38. Myokines in exercise‑mediated bone homeostasis: Molecular signaling mechanisms and therapeutic implications for bone disorders (Review).
  39. Meta-analysis of DNA methylation aging signatures in 17 human tissues.
  40. Molecular senescence, neuroendocrine metaflammation, and skeletal muscle insulin resistance in type-4 diabetes: from mitochondrial dysfunction to precision therapeutics.
  41. Age-related anabolic resistance and post-absorptive muscle protein synthesis: integrative evidence from a systematic review and meta-analysis.
  42. Kbtbd13 knockdown restores muscle function in a clinically relevant mouse model of nemaline myopathy type 6.
  43. Cellular Senescence Links Muscle Atrophy and Posttraumatic Osteoarthritis after ACL Injury.
  44. Nicotinamide riboside prevents mitochondrial dysfunction in nemaline myopathy type 6.
  45. The Gut-Brain-Muscle Axis: Microbial Regulation of Neuromuscular Aging and Cognitive Frailty.
  46. Skeletal muscle-specific deficiency of Rab geranylgeranyl transferase beta subunit induces myopathy and exacerbates the symptoms caused by HMG-CoA reductase deficiency in mice.
  47. Skeletal muscle‑derived extracellular vesicles in multi‑organ degenerative disease: Mechanisms and therapeutic delivery perspectives (Review).
  48. The Effect of Strength Training During Chemotherapy in Women With Breast Cancer on Serum Cytokine Concentrations and Skeletal Muscle Autophagy-Related Proteins.
  1. bioRxiv. 2026 Jun 11. pii: 2026.06.07.730739. [Epub ahead of print]
    Estrogen-related receptor signaling counters sarcopenia and preserves exercise fitness in naturally aged mice.
    D H Sopariwala, A DeBruine, S Poliakova, E Mosa, E Mann, Citu Citu, Zhongming Zhao, A Kumar, V A Narkar.
       Background: Estrogen-related receptor gamma (ERRγ) drives an exercise mimicking aerobic gene program in the skeletal muscle that could be beneficial in aging. We have investigated the effect of chronic ERRγ activation on minimizing sarcopenia.
    Methods: Experiments were performed in muscle specific ERRγ transgenic (TG) mice and wild type (WT) littermates, at young (4-5 months) and old (24-26 months) age. In the skeletal muscle, global gene expression changes, as well as myofiber histological changes in fiber type, size, vascular supply and neuromuscular junction (NMJ), and mitochondrial content were measured. Functional analysis was performed using in vivo muscle contraction assay. Exercise fitness was measured using treadmill sprint and endurance test. Gene and protein expression was measured using QPCR and Westerns, respectively.
    Results: ERRγ activates a pan-ERR aerobic program in the skeletal muscle to increase expression of 574 genes including ERRα, mitochondrial homeostasis (e.g. Mfn1, Opa1, Drp1, Fis1, and Tfam), vascularization (e.g. Vegfa, Angpt1, Fgf1), and neuromuscular junction (NMJ) (e.g. Nrp1, Aspa, Ptprm, Cxcr4), simultaneously suppressing the expression of atrophy related genes (e.g. Atrogin1, Traf6, Nedd4, Myd88, p21). ERRγ increases mitochondrial content [Mitochondrial area: old TG vs. WT, 2.00 fold; young TG vs. WT, 1.32 fold], oxidative capacity [NADH-TR activity: old TG vs. WT, 1.20 fold; young TG vs. WT, 1.22 fold] and myofiber type [2a: old TG (687±258) vs. WT (252±71); young TG (797±168) vs. WT (440±76); 2x: old TG 1348±87 vs. WT 976±219; young TG 1131±135 vs. WT 936±84; 2b: old TG (798±103) vs. WT (1628±148); young TG (967±133) vs. WT (1623±189)], and capillarity [capillary-to-myofiber ratio: old TG (3.25±0.19) vs. WT (2.41±0.16); young TG (3.41±0.21) vs WT (2.59±0.2)] and [NMJ number [old TG (67±8) vs. WT (40±9); young TG (77±11) vs WT (77±7)], mitigating age-related loss of NMJ and myofiber cross-sectional area [old TG (1570±147µm 2) vs. WT (1692.5±208µm 2 ) WT; young TG (1828.15±132.8µm 2 ) vs. WT (2109.7±296.8µm 2 )]. ERRγ overexpression preserves muscle contractility with aging [Fatigue resistance: 22.72% reduction in force in old vs. young WT; 3.11% reduction in force between old vs. young TG]. Furthermore, ERRγ maintains exercise fitness in old mice [Running: old TG (2964.52±405m) vs. old WT (910.75±6034m); young TG (2232.43±193.64m) vs. young WT (1366.76±60.76m)].
    Conclusions: ERRγ drives a pan-ERR and counter sarcopenic gene program enhancing oxidative myofiber type, mitochondrial content, vasculature, and NMJ in aging muscle. Consequently, ERRγ minimizes myofiber atrophy, preserves contractility, and improves exercise fitness in old mice. Therefore, ERRs are potential translational targets for combating sarcopenia.
    DOI:  https://doi.org/10.64898/2026.06.07.730739
  2. Biomolecules. 2026 Jun 10. pii: 850. [Epub ahead of print]16(6):
    Potential Influence of Myokines on Skeletal Muscle Tissue Hypertrophy Signaling Pathways: A Narrative Review.
    Stephen M Cornish, Jose Peralta-Huertas.
      Sarcopenia is defined as the age-related loss of skeletal muscle strength, power, and size. Understanding the fundamental mechanisms whereby sarcopenia occurs is an area of research that has received much attention due to the aging population. Skeletal muscle tissue is used for locomotion and acts as a major site aiding the regulation of metabolism. Myokines are cytokines released from skeletal muscle tissue that act in an autocrine, paracrine, or endocrine manner. Myokines have been termed the 'exercise factor' or 'work factor' that scientists have long thought communicate between skeletal muscle and various physiological systems, including muscle-to-muscle cross-talk. One area of research that has been underexplored is the effect that myokines may have in an autocrine manner on skeletal muscle tissue itself. Although the myokine role in skeletal muscle hypertrophy and atrophy has been somewhat elucidated in rodent models, relatively little research has been performed in human models to understand the role myokines have on anabolic and catabolic metabolism in an autocrine manner. This review will provide an overview of myokine function within a biological context, some molecular pathways involved in skeletal muscle anabolism, a mechanistic understanding of myokine autocrine action, key evidence in relation to skeletal muscle satellite cell interaction with myokines, how myokines may be involved in skeletal muscle regeneration, and an outline of some key myokines that have the potential to act in an anabolic fashion within skeletal muscle. The review will then emphasize some important areas of research that are needed to understand the role of myokines in maintaining or improving skeletal muscle mass within an aging context.
    Keywords:  aging; anabolism; cytokine; hypertrophy; myokine; skeletal muscle
    DOI:  https://doi.org/10.3390/biom16060850
  3. Am J Physiol Cell Physiol. 2026 Jun 26.
    miR-339-5p impairs myogenic proliferation and differentiation by repressing contractile gene programs in skeletal muscle.
    Xue Yu, Elena Caria, Dimitrius Santiago P S F Guimarães, Maxence Jollet, David Rizo-Roca, Alesandra A Marica, Souren Mkrtchian, Marta Gómez-Galán, Anna Krook, Nicolas J Pillon.
      MicroRNAs (miRNAs) are critical regulators of skeletal muscle development and adaptation, orchestrating the balance between proliferation, differentiation, and tissue repair. Here, we identify miR-339-5p as a previously unrecognized, conserved regulator of skeletal muscle remodeling. Transcriptomic analysis from human, mouse, and rat studies revealed that miR-339-5p is consistently upregulated in skeletal muscle under conditions of stress or injury and declines during myogenic differentiation in vitro. Gain-of-function experiments demonstrated that miR-339-5p overexpression impairs expression of genes associated with myogenic differentiation and promotes expression of proliferative markers in both primary human myotubes and mouse C2C12 cells. Transcriptomic profiling confirmed widespread repression of pathways involved in cytoskeletal organization, myofibrillar assembly, and mitochondrial function. In vivo, electroporation-mediated overexpression of miR-339-5p in mouse tibialis anterior altered regeneration-associated gene expression and increased the number of immature fibers, therefore modulating tissue remodeling during post-injury growth. Integrated analyses combining target prediction algorithms, differentiation-associated correlations, and overexpression datasets identified seven conserved high-confidence miR-339-5p targets, among which the autophagy-associated phosphatase MTMR3 emerged as the most consistently regulated candidate. Collectively, our data demonstrate that miR-339-5p functions as a conserved inhibitor of myogenic progression, linking injury-induced stress responses to delayed differentiation and altered muscle remodeling. These findings establish miR-339-5p as a potential therapeutic target in conditions characterized by impaired muscle regeneration or dysregulated tissue remodeling.
    Keywords:  microRNA; myogenesis; skeletal muscle; tissue remodeling
    DOI:  https://doi.org/10.1152/ajpcell.00898.2025
  4. Pharmaceuticals (Basel). 2026 May 30. pii: 868. [Epub ahead of print]19(6):
    The Dual Role of Interleukin-6 in the Pathophysiology of Skeletal Muscle: Mechanisms, Challenges, and Therapeutic Prospects.
    Yingyu Wang, Jitai Zhang, Jie Wang, Yijie Zhang, Jiacheng Sun, Jiahuan Gong, Xinlei Yao, Hualin Sun.
      Interleukin-6 (IL-6) is a cytokine with multiple biological effects. It plays a complex and seemingly paradoxical central role in both the physiological homeostasis and pathological processes of skeletal muscle. Under physiological conditions, particularly during acute exercise, IL-6 produced and secreted by the contracting skeletal muscle itself acts as an important "myokine." It operates in an autocrine, paracrine, or endocrine manner to regulate systemic energy metabolism, insulin sensitivity, muscle regeneration, and adaptive hypertrophy. This function is crucial for the health benefits conferred by exercise. However, under various pathological conditions-such as cancer cachexia, sepsis, muscular dystrophy, denervation, disuse atrophy, and chronic inflammatory diseases-persistently elevated systemic or local IL-6 levels become a key mediator driving skeletal muscle atrophy, metabolic disorders, and functional decline. This review systematically elaborates on the dual role of IL-6 in skeletal muscle. It provides an in-depth analysis of its downstream signaling pathways (e.g., JAK/STAT, gp130, MAPK, PI3K-Akt) and upstream regulatory mechanisms (e.g., the Piezo1/KLF15 axis, calcium signaling, mitochondrial function, oxidative stress). A particular focus is placed on discussing the distinct biological effects of classical IL-6 signaling versus trans-signaling. Furthermore, we address current challenges in research and practice, including the cell specificity of IL-6 signaling, the complexity of its temporal regulation, the definition of physiological versus pathological concentrations, discrepancies between animal models and human diseases, and the plasticity of its function across different pathological contexts. Finally, this review explores the potential of targeting the IL-6 signaling pathway as a therapeutic strategy for skeletal muscle atrophy and related metabolic diseases. Potential interventions include IL-6/IL-6R monoclonal antibodies, JAK/STAT inhibitors, gp130 modulators, exercise interventions, and nutritional strategies. This aims to provide a theoretical foundation and novel perspectives for future translational research and clinical interventions.
    Keywords:  interleukin-6; muscle atrophy; myokine; skeletal muscle; therapeutic strategy
    DOI:  https://doi.org/10.3390/ph19060868
  5. Biochem Biophys Res Commun. 2026 Jun 20. pii: S0006-291X(26)00947-2. [Epub ahead of print]829 154183
    CIRBP maintains skeletal muscle mitochondrial energy homeostasis via mt-ATP6 to ameliorate sarcopenia.
    Zhouyi Wang, Yang Guo, Zhen Hu, Hongyong Zhang, Qingmei Liu.
      Sarcopenia, characterized by progressive loss of skeletal muscle mass and function, represents a major public health challenge in aging societies; its underlying molecular mechanisms remain incompletely understood, and no approved disease-specific pharmacotherapy exists. Here, we demonstrate that CIRBP is essential for skeletal muscle homeostatic maintenance during aging. Eighteen-month-old Cirbp-/- mice exhibited a canonical sarcopenic phenotype-reduced compound muscle action potential amplitude, decreased grip strength, accelerated fatigue, and prominent myofiber atrophy-accompanied by coordinate upregulation of the ubiquitin-proteasome effectors Atrogin-1, MuRF1, and Myostatin. Whole-transcriptome RNA sequencing identified 814 differentially expressed genes, predominantly downregulated, among which mt-Atp6-encoding mitochondrial ATP synthase subunit 6-exhibited the most pronounced reduction in absolute expression. CIRBP deficiency led to coordinate downregulation of Atp6 mRNA and ATP6 protein, accompanied by severe mitochondrial cristae disruption and oxidative phosphorylation dysfunction, collectively producing chronic energy insufficiency that drove protein degradation pathway activation and progressive myofiber atrophy. Conversely, AAV-mediated CIRBP overexpression simultaneously upregulated ATP6 expression, suppressed protein degradation pathway activation, and substantially improved skeletal muscle function in aged mice at both electrophysiological and mechanical levels. This study establishes the CIRBP-Atp6 mRNA-mitochondrial energy metabolism regulatory axis as a central node in skeletal muscle aging homeostasis, providing a new mechanistic framework and potential therapeutic targets for sarcopenia intervention.
    Keywords:  Cold-inducible RNA-Binding protein; Mitochondrial ATP synthase subunit 6; Mitochondrial dysfunction; Sarcopenia; Skeletal muscle aging
    DOI:  https://doi.org/10.1016/j.bbrc.2026.154183
  6. Front Nutr. 2026 ;13 1803560
    Sarcopenia and satellite cell homeostasis disruption: the dual function of NAD+ metabolism.
    Chenyuan Li, Yue Ai, Jieni Yan, Shuhua Wu.
      Sarcopenia is an age-related syndrome characterized by progressive loss of skeletal muscle mass and function, which is closely associated with impaired regenerative capacity of muscle satellite cells (MuSCs). During aging, the MuSC niche undergoes severe deterioration, including mitochondrial dysfunction, chronic inflammation, and neuromuscular junction (NMJ) degeneration, all of which compromise MuSC quiescence, proliferation, and differentiation. Nicotinamide adenine dinucleotide (NAD+) serves as a critical coenzyme and signaling molecule that governs MuSC homeostasis in a context-dependent, dual-function manner. Moderate NAD+ repletion via precursors such as nicotinamide mononucleotide (NMN) or nicotinamide riboside (NR) activates SIRT1 and SIRT3, enhances mitochondrial bioenergetics, reduces oxidative stress, and promotes MuSC proliferation and myogenic differentiation. In contrast, under pathological or aging conditions, excessive or dysregulated NAD+ signaling activates SIRT2 to deacetylate PAX7 and repress Myogenic Differentiation 1 (MyoD), leading to cell-cycle arrest and MuSC exhaustion. This review adopts a hypothesis-driven framework to systematically summarize the molecular crosstalk between NAD+ metabolism, sirtuin family deacetylases (SIRTs), and MuSC fate regulation. We integrate evidence from nearly 60 representative preclinical and clinical studies, clarify the dual-function role of NAD+, and address current inconsistencies in the field. We also highlight key limitations and propose future directions for developing NAD+-targeted therapies for sarcopenia.
    Keywords:  MuSC homeostasis; NAD+; sarcopenia; satellite cell; sirtuins
    DOI:  https://doi.org/10.3389/fnut.2026.1803560
  7. Cells. 2026 Jun 16. pii: 1091. [Epub ahead of print]15(12):
    Exercise as a Bidirectional Regulator of Drp1: A Goldilocks Principle for Mitochondrial Adaptation in Skeletal Muscle.
    Mei Ma, Jialin Li, Wentao Pang, Ziyi Zhang, Yong Zhang, Hai Bo.
      Dynamin-related protein 1 (Drp1) is essential for mitochondrial dynamics in skeletal muscle, particularly in regulating fission, mitophagy, and maintaining mitochondrial function. Exercise is crucial for sustaining muscle function, promoting mitochondrial adaptations that enhance energy metabolism and oxidative capacity in skeletal muscle. In this Review, we discuss the role of Drp1 in exercise-induced mitochondrial adaptations and its potential implications for skeletal muscle health. We first address the evidence that Drp1 activity must be maintained within a narrow physiological range. Both Drp1 deficiency and overabundance provoke muscle atrophy and dysfunction, establishing a Goldilocks principle for mitochondrial fission. We then examine the multi-layered post-translational modification code that governs Drp1 activity, including canonical phosphorylation, redox-sensing modifications, and the receptor selectivity model that may specify distinct fission programs. A three-stage model of exercise-induced mitochondrial adaptation is presented, describing how Drp1 activity is temporally orchestrated from acute fragmentation through short-term remodeling to long-term network optimization, and how these morphological transitions govern substrate metabolism and determine exercise performance. The pathological consequences of Drp1 dysregulation are examined in metabolic disease, where Drp1 is chronically hyperactivated, and in aging, where Drp1 activity is deficient. Finally, we analyze the ROS-Drp1 signaling axis as the mechanistic basis for the bidirectional regulation of Drp1 by exercise. Moderate exercise-induced ROS production activates Nrf2 and AMPK signaling, which suppress excessive fission in metabolic disease while restoring insufficient fission in aging, thereby moving Drp1 activity toward the physiological Goldilocks zone in both contexts. This context-dependent, bidirectional regulation distinguishes exercise from pharmacological inhibitors and identifies the ROS-Drp1 axis as a therapeutic target for conditions at opposite ends of the Drp1 activity continuum, such as sarcopenia and type 2 diabetes.
    Keywords:  Drp1; ROS; exercise; mitochondrial adaptation; skeletal muscle atrophy
    DOI:  https://doi.org/10.3390/cells15121091
  8. Stem Cell Reports. 2026 Jun 25. pii: S2213-6711(26)00184-0. [Epub ahead of print] 102973
    Resident mesenchymal progenitor cells require autocrine IGF-I in homeostatic and regenerating skeletal muscle.
    Yangyi E Luo, Zoe Abe-Teh, Tarek Y Alsaghir, Li-Ying Kuo, Fahong Yu, Bradley E Stoker, Yumei Zhou, Ambili Bai Appu, Elijah M Dy, Feng Yue, Daniel Kopinke, Elisabeth R Barton.
      Fibro-adipogenic progenitors (FAPs) are muscle-resident mesenchymal stromal cells essential for homeostasis and regeneration but can produce fibrosis or intramuscular fat in pathological conditions. Insulin-like growth factor-I (IGF-I) regulates regeneration through actions on muscle fibers, satellite cells, macrophages, and extracellular matrix (ECM) remodeling but has multiple sources. To assess the role of FAP-derived IGF-I, we generated inducible FAP-specific Igf1-deficient (FID) mice. Following BaCl2 injury, FID muscles displayed impaired regeneration, with smaller fibers, fewer Pax7+ and MyoD+ cells, increased CD68+ macrophages, decreased collagen, and suppressed FAP proliferation. After glycerol-induced injury, FID muscles had reduced fat. Primary FID FAPs displayed blunted proliferation, upregulated immune-regulatory genes, and downregulated ECM and growth genes, with delayed fibrogenic and adipogenic differentiation. scRNA-seq of homeostatic muscle revealed reduced protein translation and ECM indices alongside increased senescence markers in FID samples. Taken together, FAP IGF-I is critical for FAP function, with direct and indirect impact on muscle regeneration.
    Keywords:  PDGFRα; acute injury; adipogenesis; fibro-adipogenic progenitors; fibrosis; insulin-like growth factor I; mesenchymal progenitor cells; senescence; skeletal muscle regeneration
    DOI:  https://doi.org/10.1016/j.stemcr.2026.102973
  9. Stem Cell Reports. 2026 Jun 25. pii: S2213-6711(26)00183-9. [Epub ahead of print] 102972
    Elevated mitochondrial Ca2+ impairs satellite cell pool expansion in response to skeletal muscle injury.
    Ahmed S Shams, Lalitha S Denduluri, Megan K Sumera, Ingrid R Aragon, Lauren LaScala, Jae Hwi Sung, Sydney Peng, Sarah J Cornelius, Sana Ikramuddin, Aiden M Boechler, Eric Batchelor, Michael Kyba, Julia C Liu.
      MICU1 loss-of-function variants in human patients are associated with proximal muscle weakness and myopathy. Mitochondrial Ca2+ levels are basally elevated when MICU1, the gatekeeper of the mitochondrial Ca2+ uniporter, is absent. The importance of regulating mitochondrial Ca2+ in skeletal muscle has generally been studied in mature muscle fibers. How satellite cells are impacted by mitochondrial Ca2+ dysregulation is poorly understood. We investigated Micu1 deletion specifically in Pax7+ satellite cells to address this gap in knowledge. Colony-forming activity in vitro was unaffected in Micu1-deficient satellite cells, but colony sizes were smaller. Although satellite cell homeostasis was not significantly affected 1 month following Micu1 deletion, the regenerative response post-injury was significantly impaired. Satellite cell self-renewal from Micu1-deficient donor cells in transplant recipients was also heavily compromised. Our data suggest that properly gating mitochondrial Ca2+ import via the uniporter is integral to satellite cell activation from quiescence in response to muscle injury.
    Keywords:  MICU1; activation; calcium; mitochondria; myogenesis; quiescence; respiration; satellite cells; self-renewal; transplantation
    DOI:  https://doi.org/10.1016/j.stemcr.2026.102972
  10. J Physiol Biochem. 2026 Jun 23. pii: 59. [Epub ahead of print]82(1):
    The two faces of mitochondrial Ca2+ dysregulation in skeletal muscle: overload and deficiency.
    Mikhail V Dubinin, Konstantin N Belosludtsev.
      Mitochondrial Ca²⁺ dysregulation is a central pathogenic event in skeletal muscle disorders, yet the dichotomy between overload and deficiency is often overlooked. This review summarizes mechanisms governing mitochondrial Ca²⁺ transport and sarcoplasmic reticulum-mitochondria communication. We examine prerequisites of Ca²⁺ overload, including RyR1/SERCA dysfunction and mitochondrial calcium uniporter (MCU) complex remodeling, leading to suppressed ATP synthesis, reactive oxygen species overproduction, and necrosis. Conversely, we address mitochondrial Ca²⁺ deficiency in aging, sarcopenia, and diabetes, resulting from altered MCU stoichiometry and reduced organelle tethering, causing metabolic inflexibility and impaired antioxidant defense. Additionally, therapeutic strategies limiting Ca²⁺ overload and prospects of pharmacological MCU activation to enhance bioenergetics in sarcopenia are discussed.
    Keywords:  Calcium signaling; MCU complex; Mitochondrial Ca²⁺ deficiency; Mitochondrial Ca²⁺ overload; Sarcoplasmic reticulum-mitochondria coupling; Skeletal muscle
    DOI:  https://doi.org/10.1007/s13105-026-01197-9
  11. Cells. 2026 Jun 10. pii: 1061. [Epub ahead of print]15(12):
    Regulation of Myogenic Cell Apoptosis, UPS, and Autophagy During Mammalian Skeletal Myogenesis.
    Binglin Yue, Wen Hu, Shuo Zhu, Du'an Chen, Huanyu Guan, Zhuoying Zhao, Hui Wang, Jiabo Wang, Jincheng Zhong, Haitao Shi.
      Skeletal myogenesis is an extremely complex process that mononuclear myoblasts undergo proliferation, differentiation, and fusion to form multinucleated contractile muscle fibers, involving a balance between synthesis and degradation metabolism. Skeletal muscle requires an effective mechanism to balance rapid proliferation by degrading supernumerary or damaged organelles/proteins, or by activating cellular signals to regulate subsequent muscle differentiation. In recent years, three important cellular processes-apoptosis, ubiquitin-proteasome system (UPS), and autophagy-have received extensive attention in skeletal myogenesis. The UPS supports the early differentiation process and initiates apoptosis, and the increase in apoptosis activates autophagy to clear damaged organelles and proteins, which in turn inhibits apoptosis, preventing excessive cell death and maintaining cellular stability. The coordination among apoptosis, UPS, and autophagy is more intricate, as they interact through a dynamic balancing mechanism, determining the balance between cell death and survival, and enabling proper muscle differentiation. Here, we explore the molecular signals that mediate apoptosis, UPS, and autophagy, with a focus on analyzing their interrelationship in skeletal myogenesis. Studying the regulatory mechanisms of these molecules will help in understanding the role of cell death in skeletal muscle development, especially how they affect muscle cell differentiation, providing new insights into mammalian skeletal myogenesis.
    Keywords:  UPS; apoptosis; autophagy; skeletal myogenesis
    DOI:  https://doi.org/10.3390/cells15121061
  12. Front Physiol. 2026 ;17 1818866
    Intrinsic exercise capacity is associated with skeletal muscle clock gene and IGF-1 signaling in aged low- and high-running capacity rats.
    Hyeon-Ki Kim, Takuji Kawamura, Zoltan Bori, Lauren Gerard Koch, Steven Loyal Britton, Zsolt Radak.
       Background: Intrinsic exercise capacity is a strong predictor of health and longevity and is independently associated with aging- and disease-related outcomes. Although previous studies using low- and high-capacity runner (LCR and HCR) rats have demonstrated organ-specific patterns of epigenetic aging, the molecular mechanisms linking intrinsic aerobic capacity to skeletal muscle signaling remain incompletely understood.
    Objective: This study investigated whether intrinsic exercise capacity is associated with alterations in skeletal muscle clock gene expression and insulin-like growth factor-1 (IGF-1)-related signaling pathways.
    Methods: Female LCR and HCR rats (23-24 months old, 44th generation) underwent maximal oxygen uptake (VO2max) testing, followed by molecular analyses of plantaris and soleus muscles using quantitative PCR and Western blotting.
    Results: VO2max was significantly higher in HCR rats. In skeletal muscle, LCR rats exhibited higher mRNA expression levels of Cry1, Bmal1, Igf1, and Igf1Ec measured at ZT2-ZT3, whereas expression of Cry2, Pdk4, and MuRF-1 did not differ between phenotypes. Despite increased Igf1 expression in LCR rats, the phosphorylated-to-total JAK2 ratio was reduced, while STAT5 phosphorylation was unchanged. Correlation analyses demonstrated significant negative associations between VO2max and Igf1, Igf1Ec, Cry1, and Bmal1 expression.
    Conclusion: These findings indicate that low intrinsic exercise capacity is associated with coordinated alterations in skeletal muscle clock gene expression and IGF-1- related signaling, suggesting altered IGF-1-related signaling balance in aging skeletal muscle. These results provide mechanistic insight into how intrinsic aerobic capacity may influence muscle biology and health trajectories during aging.
    Keywords:  IGF-1 signaling; aging; circadian clock genes; intrinsic exercise capacity; low- and high-capacity runner rats; skeletal muscle
    DOI:  https://doi.org/10.3389/fphys.2026.1818866
  13. Acta Neuropathol. 2026 Jun 26. pii: 73. [Epub ahead of print]151(1):
    VMA21 deficiency leads to autophagic dysregulation and altered vesicle trafficking in X-linked myopathy with excessive autophagy.
    Christian A Suarez, Sara K Pittman, Michio Inoue, Eileen M Lynch, Andrew Moran, Angèle N Merlet, Emmanuelle Lacenne, Teresinha Evangelista, Conrad C Weihl.
      X-Linked myopathy with excessive autophagy (XMEA) is a rare vacuolar myopathy caused by mutations in Vma21, an assembly chaperone required for vacuolar H⁺-ATPase (V-ATPase) function. However, the mechanisms linking Vma21 deficiency to progressive muscle pathology remain poorly understood, in part due to the lack of suitable animal models. To address this gap, we generated conditional Vma21 knockout mouse models to investigate the consequences of Vma21 loss in striated muscle. Combined deletion of Vma21 in skeletal and cardiac muscle resulted in early lethality driven by severe cardiomyopathy associated with autophagic dysregulation, preceding the development of skeletal muscle pathology. In contrast, inducible skeletal muscle-specific deletion of Vma21 produced progressive muscle weakness and myopathy characterized by centralized nuclei, fiber splitting, and increased fiber size variability. Affected skeletal muscle also recapitulated defining pathological hallmarks of XMEA, including basal lamina reduplication and autophagic vacuoles with sarcolemmal features (AVSFs). Ultrastructural analysis revealed membrane-bound vacuoles containing partially undegraded material that frequently accumulated at the subsarcolemmal region, together with clusters of vesicular structures. Notably, mutant muscle exhibited increased staining for the late endosomal/exosomal marker CD63, which strongly colocalized with the complement membrane attack complex C5b-9. A similar increase in CD63 staining and its colocalization with C5b-9 were observed in skeletal muscle biopsies from patients with XMEA. Together, these models faithfully recapitulate key pathological features of XMEA and identify the accumulation of CD63-positive structures and their colocalization with C5b-9 as previously unrecognized features of Vma21-deficient skeletal muscle, implicating altered vesicle trafficking in XMEA pathogenesis.
    Keywords:  Autophagy; Membrane attack complex; VMA21; Vacuolar myopathy; Vesicle trafficking; XMEA
    DOI:  https://doi.org/10.1007/s00401-026-03044-z
  14. Int J Mol Sci. 2026 Jun 20. pii: 5594. [Epub ahead of print]27(12):
    Regular Aerobic Exercise Can Effectively Ameliorate the Skeletal Muscle and Mitochondrial Function Impairments Caused by bves Deficiency in Zebrafish.
    Wanwan Cai, Wanbang Zhou, Xiushan Wu, Junrong Lei, Haochen Wang, Qiong Wu, Song Zhou, Kang Sun, Xiuyan Li, Zhilong Zhang, Jisheng Zhang, Jingying Ouyang, Yongqing Li, Zhigang Jiang, Xianchu Liu, Wuzhou Yuan, Lan Zheng.
      The Popeye domain-containing protein 1 (Popdc1), also known as Bves, plays a crucial role in maintaining skeletal muscle homeostasis, with its variants leading to limb-girdle muscular dystrophy type R25. Skeletal muscles of patients with the homozygous missense variant of Bves exhibit impaired membrane trafficking, while skeletal muscle fibers in bvesS191F homozygous mutant zebrafish are significantly reduced and disorganized. However, the mechanism by which the absence of bves induces skeletal muscle atrophy remains unclear. In this study, we discovered a novel mechanism whereby bves deficiency drives skeletal muscle atrophy by disrupting mitochondrial structure and function. Our findings indicate that bves knockout leads to a significant decrease in zebrafish's ability to swim, atrophy of skeletal muscle tissue, loss of cell membrane localization signals, and abnormalities in mitochondrial structure and function. After an 8-week intervention of regular aerobic exercise, the symptoms of skeletal muscle atrophy in bves knockout zebrafish were significantly alleviated, and the expression levels of genes and proteins related to mitochondrial were effectively rescued. These findings establish a connection between bves deficiency-induced disruption of mitochondrial structure and function and the onset and progression of skeletal muscle tissue atrophy symptoms, thereby laying a molecular foundation for exercise rehabilitation strategies in atrophic myopathy.
    Keywords:  CRISPR-Cas9; bves; mitochondrial dysfunction; regular aerobic exercise; skeletal muscle atrophy
    DOI:  https://doi.org/10.3390/ijms27125594
  15. Autophagy. 2026 Jun 25. 1-16
    Efficient pharmacological modulation of autophagy in isolated muscle fibers: impact on excitation-contraction coupling.
    Julie Gaillard, Céline Malleval, Camille Dauvois, Lina Gueloua, Jonathan Schreiber, Carole Kretz-Remy, Yann-Gaël Gangloff, Bruno Allard, Christine Berthier, Vincent Jacquemond.
      Macroautophagy/autophagy is a key regulator of muscle mass and of muscle adaptation to stress and defective autophagy is a feature of many muscle disorders. Still, how changes in autophagic flux influence the integrity and function of differentiated muscle fibers remains under-documented. Specifically, links between autophagy and mechanisms involved in Ca2+ homeostasis and excitation-contraction coupling are largely unexplored. We developed an assay to monitor autophagy modulation in mouse muscle fibers maintained in culture. Exposure to 3-methyladenine, an inhibitor of autophagy initiation, reduced the density of autophagic vesicles. Conversely, hydroxychloroquine, a blocker of autolysosome formation, as well as two MTOR inhibitors that activate autophagy, rapamycin and torin-1, enhanced the vesicle density. The density of lysosomal vesicles was increased by MTOR inhibitors and by hydroxychloroquine, but insensitive to 3-methyladenine. Measurements of Ca2+ signals associated with contractile activation revealed that voltage-activated sarcoplasmic reticulum Ca2+ release was unaffected by torin-1 but was depressed in 3-methyladenine- and in hydroxychloroquine-exposed fibers, suggesting that restraining autophagic flux is detrimental to excitation contraction coupling. The density of the inner plasma membrane network that carries the electrical excitation was depressed by 3-methyladenine and hydroxychloroquine, likely contributing to the function defect. Results establish that autophagic flux is preserved and can be manipulated in cultured muscle fibers, and revealed the power of the approach to tackle the cellular and subcellular consequences of autophagy modulation. They also uncover the possibility that autophagy is a determinant of maintenance and/or function of excitation-contraction coupling, with a potential role in several muscle disease situations.Abbreviations: 3-MA: 3-methyladenine; EC: excitation-contraction; HCQ: hydroxychloroquine; MTM1: myotubularin 1; RYR1: ryanodine receptor 1.
    Keywords:  3-methyladenine; rapamycin; ryanodine receptor; sarcoplasmic reticulum Ca2+ release; skeletal muscle; torin-1
    DOI:  https://doi.org/10.1080/15548627.2026.2693256
  16. Exp Gerontol. 2026 Jun 23. pii: S0531-5565(26)00191-9. [Epub ahead of print]222 113212
    Calorie restriction and exercise differentially regulate AMP-activated protein kinase across subcellular compartments in skeletal muscle from older male rats.
    Haiyan Wang, Jiwei Hao, Jun-Hyun Bae, Gregory D Cartee.
      AMP-activated protein kinase (AMPK) is a crucial energy sensor that regulates a wide range of important processes in skeletal muscle. AMPK is present in several subcellular compartments (including the cytosol, nucleus, and mitochondria). However, the influence of physiologically relevant interventions on AMPK's localization in skeletal muscle is not well understood, especially during older age. Accordingly, this study examined AMPK signaling in skeletal muscle from aged male rats (24-25-months-old) subjected to either eight-weeks of calorie restriction (CR; consuming 65% of ad libitum intake) or a single swim-exercise session. Phosphorylation of AMPK and its substrate acetyl-CoA carboxylase (ACC), as well as abundance of AMPK subunits (α1, α2, β1, β2, γ1, γ3), were assessed by immunoblotting in whole muscle lysates and cytosolic, nuclear, and mitochondrial-enriched fractions obtained by differential centrifugation. CR increased phosphorylation of AMPK and ACC in whole muscle lysates, but not in the three subcellular fractions that were tested, suggesting AMPK-activation occurs in other, currently unidentified compartments. In contrast, exercise significantly increased AMPK phosphorylation in the cytosolic fraction and ACC phosphorylation in whole lysates and all three subcellular fractions. AMPK-γ1 abundance was greater in the mitochondrial-enriched fraction of CR versus ad libitum muscles. These findings revealed strikingly different patterns of AMPK activation within key subcellular compartments in response to two important physiological interventions. This study substantially advances current knowledge and provides a foundation for future research on AMPK's compartment-specific roles in skeletal muscle physiology and aging.
    Keywords:  AMP-activated protein kinase; Acetyl-CoA carboxylase; Cytosol; Mitochondria; Nucleus
    DOI:  https://doi.org/10.1016/j.exger.2026.113212
  17. Bioact Mater. 2026 Nov;65 573-592
    Neonatal muscle-derived extracellular vesicles containing miR-542-3p rejuvenate aged skeletal muscle via a functional microneedle patch.
    Feifei Yuan, Yong Chen, Wenjie Li, Lin Zhang, Ruixue Du, Sheng Xu, Zhiyu Hu, Tao Zhang, Ling Qin, Hongbin Lu, Chengjun Li.
      Age-related skeletal muscle aging can lead to sarcopenia and is closely associated with cellular senescence and mitochondrial dysfunction. Neonatal mammalian muscle exhibits a strong regenerative capacity, and neonatal muscle extracellular vesicles (NMEVs) show therapeutic potential against skeletal muscle aging. In this study, we isolated NMEVs for the first time and found that they significantly alleviated palmitic acid (PA)-induced senescence, mitochondrial dysfunction, and lipid accumulation in C2C12 cells. in vivo, we developed a bilayer microneedle (MN) system loaded with NMEVs (NMEVs@PLGA@Fucoidan-HA MN) and applied it to aged mice. The MN effectively enhanced mitochondrial function, reduced muscle aging and fibrosis, and decreased lipid deposition. Mechanistically, miR-542-3p enriched in NMEVs directly targeted and downregulated Asxl2-PPARγ, leading to reduced lipid accumulation. At the same time, it suppressed Eef1a1 to activate the AMPK pathway, thereby improving mitochondrial function and attenuating cellular senescence. Our findings demonstrate the protective role of NMEVs delivered via an innovative MN system against muscle aging, where miR-542-3p plays a central role by concurrently targeting Eef1a1 and Asxl2 to mitigate senescence and lipid dysregulation. This study reveals a novel molecular mechanism underlying the anti-aging potential of NMEVs and offers a promising therapeutic strategy for skeletal muscle aging.
    Keywords:  Cellular senescence; Microneedle patch; Neonatal muscle extracellular vesicles; Skeletal muscle aging; miR-542-3p
    DOI:  https://doi.org/10.1016/j.bioactmat.2026.06.011
  18. J Physiol Sci. 2026 Jun 17. pii: S1880-6546(26)00029-6. [Epub ahead of print]76(2): 100083
    Contrasting response of polyamine metabolic enzymes underlying fiber-type specific volume regulation in the skeletal muscle with endurance exercise.
    Maki Yamaguchi, Makiko Ohkido, Naoya Nakahara, Kazuhiro Hirano, Shigeru Morimoto, Michiaki Ikeda, Toshiko Yamazawa, Hideki Yamauchi.
      To explore the role of polyamine metabolism in muscle-type-specific hypertrophy, we analyzed changes in the expression profiles of polyamine metabolic enzymes and key enzymes for muscle metabolism induced by voluntary wheel running exercise in different muscle types. Effect of the polyamine precursor, putrescine, which was reported to have potential to regulate muscle volume, was also tested. Polyamine synthetic enzymes were upregulated in hypertrophic soleus muscle whereas polyamine catabolic enzymes were upregulated in non-hypertrophic plantar muscle by exercise in correlation with increased mitochondria-related protein expression. The increased catabolic enzymes of polyamines in the plantar muscle were hypothesized to be possibly involved in restriction of hypertrophy in fast-type skeletal muscles correlating with increased aerobic metabolism. Putrescine administration minimally affected polyamine metabolism and muscle volume indicating that it did not effectively regulate muscle hypertrophy. Polyamine oxidase localized in the perinuclear and inter-myofibrillar region suggesting a correlation between aerobic metabolism and polyamine catabolism.
    Keywords:  Aerobic metabolism; Endurance training; Hypertrophy; Polyamine; Putrescine
    DOI:  https://doi.org/10.1016/j.jphyss.2026.100083
  19. Cell Mol Life Sci. 2026 Jun 23.
    The miR-206-3p/Cpeb1 axis delays acetylcholine receptor degradation and preserves neuromuscular junction stability in denervation-induced muscle atrophy.
    Guohua Jiang, Long Li, Yanhua Wang, Tianjing Zhao, Hao Guo, Han Yan, Jianwen Xu, Canjun Zeng, Yijun Liu.
      Peripheral nerve injury leads to progressive neuromuscular junction (NMJ) destabilization and acetylcholine receptor (AChR) degradation, which are critical drivers of denervation-induced muscle atrophy and impaired motor recovery. However, the post-transcriptional mechanisms regulating AChR stability during denervation remain poorly understood. Here, we investigated the role of miR-206-3p in NMJ maintenance and muscle preservation after denervation, with a focus on its interaction with the RNA-binding protein cytoplasmic polyadenylation element binding protein 1 (Cpeb1). Using C2C12 myoblasts and a sciatic nerve transection mouse model, we demonstrate that miR-206-3p promotes myogenic differentiation, enhances AChR clustering, and preserves postsynaptic AChR morphology. miR-206-3p directly targets the 3' untranslated region of Cpeb1, suppressing its expression, as confirmed by dual-luciferase reporter assays. In vivo, adeno-associated virus-mediated overexpression of miR-206-3p delayed denervation-induced AChR fragmentation, attenuated muscle atrophy, and significantly improved motor function recovery. Conversely, Cpeb1 overexpression accelerated AChR degradation and muscle wasting, whereas co-overexpression of miR-206-3p mitigated these detrimental effects, indicating that Cpeb1 is a key downstream effector of miR-206-3p. Collectively, our findings identify the miR-206-3p/Cpeb1 axis as a previously unrecognized regulator of NMJ stability and muscle integrity after denervation, providing mechanistic insight and a potential therapeutic target for preserving neuromuscular function during prolonged denervation.
    Keywords:  Acetylcholine receptor; Cpeb1; MiR-206-3p; Muscle atrophy; Neuromuscular junction; Peripheral nerve injury
    DOI:  https://doi.org/10.1007/s00018-026-06302-1
  20. Genes (Basel). 2026 May 29. pii: 626. [Epub ahead of print]17(6):
    Acute and Chronic High-Intensity Exercise Differentially Regulate the miRNA Biogenesis Pathway in Human Skeletal Muscle.
    Zeyu Wu, Eveline S Menezes, Natalia de M Lyra E Silva, Benjamin B Arhen, Lucas P R Beaupre, Craig A Simpson, Chris McGlory, Fernanda G De Felice, Brendon J Gurd.
      Background/Objectives: MicroRNAs (miRNAs) are key regulators of skeletal muscle adaptation; however, the extent to which exercise modulates the miRNA biogenesis pathway remains poorly understood. To investigate the impact of acute and chronic high-intensity exercise on components of miRNA biogenesis, and whether such changes are reflected in miRNA expression across stages of their biogenesis, we performed secondary analyses of muscle biopsy samples from two previously published studies. Methods: Muscle biopsies were analyzed from the following protocols: nine men and eight women pre- and 3 h post- a bout of high-intensity interval cycling exercise (HIIE), and eleven men and eight women pre- and post- a 6-week period of high-intensity interval training (HIIT) or non-exercise control. mRNA expression of components of miRNA biogenesis including Drosha, Exportin-5, Dicer, and Ago2 were assessed following HIIE using RT-qPCR and their protein abundance was measured following HIIT using Western blotting. Primary (pri-miR-133a1, -133a2, -133b) and mature (miR-133a-3p, -133a-5p, -133b) miRNA expression were quantified following HIIT. Results: An acute bout of HIIE significantly decreased Drosha mRNA (p < 0.05) and resulted in a reduction in Dicer mRNA that approached significance (p < 0.10). Following 6 weeks of HIIT, no significant changes were detected in the protein abundance of Drosha, Exportin-5, Dicer, or Ago2. HIIT did not alter miR-133 expression at either the primary or mature transcript level across all isoforms. Conclusions: This study highlights the complexity of miRNA regulation in skeletal muscle and underscores the need for further research examining the temporal and mechanistic control of miRNA biogenesis in response to exercise.
    Keywords:  exercise; miR-133; microRNA biogenesis; training
    DOI:  https://doi.org/10.3390/genes17060626
  21. Nutr Rev. 2026 Jun 24. pii: nuag095. [Epub ahead of print]
    Time-Restricted Feeding/Eating and Muscle Aging: Research Progress from Molecular Mechanisms to Personalized Intervention Strategies.
    Jin Liu, Kai Huang, Jun Qian, Qiaocheng Zhai.
      Sarcopenia, the age-related progressive decline of muscle mass and function, poses a severe public health challenge closely linked to metabolic disorders and reduced mobility. Time-restricted feeding or eating (TRF/TRE), which refers to confining daily food intake to a specific window regardless of specific caloric or nutrient requirements, has emerged as a pro8mising dietary strategy to regulate metabolism and delay aging. In this review, recent evidence is synthesized on TRF/TRE's regulation of muscle mass and function, and its potential as a nonpharmacological intervention for muscle aging is evaluated. A targeted literature search was conducted in PubMed. Retrieved articles were manually screened, and those highly relevant to the effects of TRF/TRE on skeletal muscle mass, function, and any underlying molecular and cellular mechanisms (such as circadian rhythm regulation, autophagy, and mitochondrial function) were included. The impact of TRF/TRE on muscle health is heterogeneous. Standalone TRF/TRE promotes fat loss; however, younger adults are particularly susceptible to lean mass attrition without concurrent exercise, whereas older cohorts show greater resilience. Combining TRF/TRE with resistance training or supplementation effectively counteracts this catabolic risk, preserving muscle integrity and function. Mechanistically, TRF/TRE mitigates muscle aging by reinforcing circadian rhythms, enhancing mitochondrial function, activating autophagy, reducing chronic inflammation, remodeling the gut microbiota, and regulating AMPK and mechanistic target of rapamycin signaling pathways. Although TRE holds broad application prospects as a nonpharmacological intervention, its successful clinical translation requires personalized strategies tailored to individual factors like age, sex, baseline metabolic phenotypes, and physical activity levels. Future research and clinical applications should focus on optimizing individualized parameters, including determining precise age-specific time windows, ensuring adequate protein timing, and combining TRE with resistance training and nutritional supplementation to effectively prevent and treat muscle aging.
    Keywords:  circadian rhythm; sarcopenia; skeletal muscle; time-restricted eating; time-restricted feeding
    DOI:  https://doi.org/10.1093/nutrit/nuag095
  22. Int J Mol Sci. 2026 Jun 21. pii: 5600. [Epub ahead of print]27(12):
    IL-13Rα2 Regulates C2C12 Myoblast Proliferation via the Akt-Cyclin D1-CDK4 Pathway.
    Mitsutoshi Kurosaka, Kazuhisa Kohda.
      Interleukin-13 receptor α2 (IL-13Rα2) has traditionally been considered a decoy receptor; however, its cellular functions beyond the immune system remain unclear. We aimed to investigate the role of IL-13Rα2 in C2C12 myoblast proliferation and differentiation. IL-13Rα2 expression was knocked down in C2C12 cells using siRNA. Myogenic differentiation was evaluated by myosin heavy chain (MyHC) immunostaining and by quantifying the expression of myogenic regulatory and fusion-related genes. Myoblast proliferation was assessed using BrdU incorporation and cell number analyses, and signaling events induced by IL-13Rα2 knockdown were analyzed via immunoblotting and immunocytochemical analysis. IL-13Rα2 knockdown did not alter myogenic differentiation or the expression of fusion-associated genes. In contrast, IL-13Rα2 knockdown significantly increased BrdU incorporation and cell number, accompanied by increased Akt phosphorylation and decreased ERK phosphorylation. Cyclin D1 and cyclin-dependent kinase 4 (CDK4) levels were also increased. Akt inhibition abolished the enhanced proliferation and normalized Cyclin D1/CDK4 levels, whereas ERK activation did not further modify the knockdown-associated phenotype. These findings demonstrate that IL-13Rα2 negatively regulates myoblast proliferation by modulating the Akt-Cyclin D1-CDK4 signaling pathway, while being dispensable for myogenic differentiation.
    Keywords:  Akt signaling; Cyclin D1; IL-13Rα2; cytokine signaling; myoblast proliferation; skeletal muscle
    DOI:  https://doi.org/10.3390/ijms27125600
  23. Mol Biol Rep. 2026 Jun 23. pii: 978. [Epub ahead of print]53(1):
    Cellular and molecular pathways linking obesity to skeletal muscle dysfunction.
    Diego Pinheiro, Anabelle Silva Cornachione.
      Obesity is increasingly recognized as a condition that directly impairs skeletal muscle structure, metabolism, and endocrine function through complex molecular and cellular mechanisms extending beyond the classical concept of sarcopenic obesity. This narrative review aimed to synthesize current evidence regarding the intracellular signaling pathways, metabolic alterations, and endocrine interactions involved in obesity-induced skeletal muscle dysfunction independent of overt sarcopenia. Relevant literature from experimental, clinical, and review studies was identified through searches of PubMed, Scopus, and Web of Science databases, focusing on obesity-associated alterations in skeletal muscle metabolism, ectopic lipid accumulation, inflammatory signaling, mitochondrial dysfunction, and adipose-muscle crosstalk. Current evidence indicates that obesity per se promotes skeletal muscle dysfunction through ectopic lipid deposition, lipotoxicity, mitochondrial impairment, and chronic low-grade inflammation mediated by dysregulated intracellular signaling pathways. Altered adipomyokine signaling, including interleukin-6 and tumor necrosis factor-α, further contributes to impaired insulin signaling, reduced metabolic flexibility, oxidative stress, and compromised muscle integrity. These molecular and cellular alterations reinforce skeletal muscle as both a target and an active regulator of obesity-associated metabolic inflammation. Collectively, these findings support the concept that obesity intrinsically disrupts skeletal muscle metabolic and endocrine homeostasis independently of sarcopenic obesity and highlight the importance of targeted strategies aimed at preserving skeletal muscle metabolic function and overall metabolic health.
    Keywords:  Insulin resistance; Lipotoxicity; Metabolic inflammation; Myokines; Obesity; Skeletal muscle
    DOI:  https://doi.org/10.1007/s11033-026-12146-6
  24. NMR Biomed. 2026 Aug;39(8): e70336
    Basal Energetics and Phosphocreatine Recovery Kinetics in Ambulatory Boys With Duchenne Muscular Dystrophy.
    Pratiksha P Awale, Christophor Lopez, Tanja Taivassalo, Krista Vandenborne, Glenn A Walter, Sean C Forbes.
      Duchenne muscular dystrophy (DMD) is an X-linked recessive condition that is characterized by muscle deterioration, loss of functional abilities, and shortened lifespan. There is growing evidence of skeletal muscle mitochondrial impairments in DMD, and 31phosphorous magnetic resonance spectroscopy (31P-MRS) provides a noninvasive marker of functional oxidative capacity of muscle. Therefore, the purpose of this study was to examine 31P-MRS indices of energetic status and oxidative capacity in DMD and correlate with clinical functional measures. In this study, we evaluated ambulatory participants with DMD (n = 21, 8.7 ± 1.9 years) and unaffected age-matched controls (n = 20, 9.0 ± 2.8 years) using a 3T MR system. 31P-MRS was used to measure relative changes in high-energy phosphates and muscle pH of the anterior compartment of the lower leg during and following isometric dorsiflexion muscle contractions (120 s rest, 60 s of contractions at 0.5 Hz, and 420 s recovery). Data were analyzed with jMRUI (v7.0), and a mono-exponential model was used to estimate the time constant (tau) of PCr recovery (PCrτ). We observed that relative concentrations of inorganic phosphate to phosphocreatine (Pi/PCr) and phosphodiesters to ATP (PDE/ATP) were elevated (p < 0.05) in DMD compared to controls, and the PCrτ recovery was slower (p < 0.01) in DMD than controls. PCrτ recovery was correlated with the distance covered in the 6-min walk test (6MWT) (ρ = -0.61, p < 0.01) and other timed functional measures (ρ = 0.54-0.67, p < 0.05). The findings from this study demonstrated that energetic status is altered and PCr recovery time is impaired in ambulatory boys with DMD indicating reduced oxidative capacity compared to unaffected controls. Overall, these findings support the use of 31P-MRS as a valuable noninvasive tool to evaluate skeletal muscle energetics and mitochondrial function in individuals with DMD.
    Keywords:  31phosphorus magnetic resonance spectroscopy; Duchenne muscular dystrophy; acid–base status; energetics; metabolism; oxidative capacity; skeletal muscle
    DOI:  https://doi.org/10.1002/nbm.70336
  25. J Adv Res. 2026 Jun 21. pii: S2090-1232(26)00500-X. [Epub ahead of print]
    Physical exercise mitigates amyloid beta-driven muscle degeneration in Alzheimer's disease.
    Ling-Ling Yang, Ya-Xi Luo, Dan Song, Na Liu, Li-Huan Gong, Tian Heng, Xiao-Han Zhou, Ya-Xing Li, Jia-Hui Chen, Zheng-Xi Song, Yang Li, Yu-Le Wang, Chuan-Chuan Bai, Rui He, Peng Hu, Yang Zhou, Gong-Wei Jia, Xiu-Qing Yao.
       INTRODUCTION: Alzheimer's disease (AD) is increasingly recognized as a systemic disorder, with skeletal muscle dysfunction contributing substantially to frailty and functional decline. Although amyloid-β (Aβ) has been detected in peripheral tissues, including skeletal muscle, how it drives muscle degeneration and whether exercise can counteract this process remain to be elucidated.
    OBJECTIVES: This study aimed to define the molecular mechanisms underlying Aβ-induced skeletal muscle degeneration in AD and assess the potential of high-intensity interval training (HIIT) to alleviate muscle dysfunction and related pathology.
    METHODS: We combined a small-scale exploratory clinical cohort with the 5 × FAD mouse model, integrating transcriptomic and metabolomic profiling with in vitro and in vivo functional assays to dissect Aβ-induced muscle pathology and the protective mechanisms of HIIT.
    RESULTS: AD patients in the exploratory cohort showed a trend toward reduced handgrip strength, mirroring the progressive muscle weakness, myofiber atrophy, and intramuscular Aβ accumulation observed in 5 × FAD mice. Mechanistically, Aβ activated RAGE/NF-κB signaling, driving inflammation and oxidative stress in myofibers. HIIT reversed these pathological changes and concomitantly lowered Aβ levels. Transcriptomic profiling identified fibroblast growth factor 10 (FGF10) as a key exercise-induced mediator: FGF10 activated the FGFR2-AKT-ADAM10 axis to promote RAGE ectodomain shedding, generating soluble RAGE that suppressed Aβ-mediated inflammatory and injury signaling.
    CONCLUSION: Our findings define an Aβ-RAGE axis driving AD-associated muscle degeneration and reveal an exercise-responsive FGF10-RAGE protective pathway, reframing AD as a brain-muscle axis disorder and highlighting FGF10 as a promising target for systemic therapeutic intervention.
    Keywords:  Alzheimer’sdisease; Amyloid-β; FGF10; High-intensity interval training; RAGE signaling; Skeletal muscle dysfunction
    DOI:  https://doi.org/10.1016/j.jare.2026.06.018
  26. Biochem Biophys Res Commun. 2026 Jun 18. pii: S0006-291X(26)00936-8. [Epub ahead of print]829 154172
    GPAT3 is associated with lipid deposition and AMPK signaling in skeletal muscle.
    Mengxuan Wang, Wanshan Gu, Zhengyao Sheng, Guoqiang Fan, Xiaojing Yang.
      As metabolic disorders associated with excessive lipid deposition in skeletal muscle rise, strategies to alleviate this accumulation have emerged as a major focus in metabolic research. Glycerol-3-phosphate acyltransferase 3 (GPAT3) is a key enzyme in triglyceride biosynthesis; however, its role in muscle lipid metabolism remains unclear. In this study, we overexpressed or knocked down GPAT3 in C2C12 myoblasts to evaluate its effects on muscle lipid metabolism and then validated the findings in GPAT3 knockout (KO) mice. GPAT3 deficiency significantly reduced lipid deposition in muscle cells. In C2C12 cells, changes in GPAT3 expression were accompanied by alterations in AMPK signaling activity. These results demonstrate that GPAT3 promotes lipid deposition in skeletal muscle. Our in vitro data reveal a correlation between GPAT3 and AMPK signaling; further in vivo validation and functional assays are required to clarify the role of AMPK in this process. This study highlights GPAT3 as a potential therapeutic target for metabolic diseases characterized by excessive intramuscular lipids.
    Keywords:  AMPK signaling; GPAT3; Lipid metabolism; Muscle physiology
    DOI:  https://doi.org/10.1016/j.bbrc.2026.154172
  27. Front Physiol. 2026 ;17 1875283
    Caffeine, skeletal muscle signalling, and exercise adaptation: a narrative review separating acute ergogenic effects from chronic remodelling.
    Zhifeng Liu, Huakun Zheng, Hengzhi Deng, Mingrui Wang, Wenxin Du, Ming Chen, Zike Zhang, Bitai Wu.
      Caffeine is one of the most widely used and extensively studied ergogenic aids in sport, yet whether its well-established acute benefits extend to the chronic remodelling of skeletal muscle remains unresolved. In this narrative review, we distinguish the acute ergogenic effects of caffeine from its potential influence on chronic skeletal muscle remodelling, because the mechanisms that improve acute performance need not be those that govern repeated tissue adaptation. The evidence for acute ergogenicity rests on a large human literature, in which adenosine receptor antagonism is the probable dominant mediator, with additional contributions from potassium handling, ryanodine receptor 1 (RyR1) sensitisation, altered contractile behaviour, and reduced perceived effort. Evidence that repeated caffeine exposure around exercise modifies chronic skeletal muscle adaptation in humans remains limited; available training trials are short, narrow in modality, and lack muscle biopsy endpoints, and several acute endurance studies under substrate restriction are better interpreted as training quality mediator evidence. Preclinical work is more mechanistic but directionally mixed, supporting Ca²+ linked CaMKKβ (Ca²+/calmodulin-dependent protein kinase kinase β) and AMP-activated protein kinase (AMPK) signalling, autophagy, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) related transcription, and mitochondrial quality control on one side, and raising an attenuation hypothesis through protein synthesis, recovery, and tissue-specific remodelling on the other. We therefore evaluate three working models in which caffeine acts as an amplifier, a partial mimic, or an attenuator of exercise-related signalling. Current human evidence is most compatible with partial mimicry and training quality mediation rather than direct amplification or impairment of long-term tissue adaptation. Resolving this question will require human training studies that combine muscle biopsy endpoints, caffeine-abstinent post-training testing, objective sleep monitoring, and explicit control of external training load. On balance, the current evidence supports interpreting caffeine as a reliable acute ergogenic aid and a plausible mediator of training quality, rather than as a proven direct modifier of chronic skeletal muscle adaptation.
    Keywords:  AMPK; PGC-1α; caffeine; mitochondrial biogenesis; molecular signalling; narrative review; skeletal muscle adaptation; training quality
    DOI:  https://doi.org/10.3389/fphys.2026.1875283
  28. Mol Syst Biol. 2026 Jun 23.
    Quantitative interactome mapping of skeletal muscle insulin resistance.
    Yaan-Kit Ng, Ronnie Blazev, Julian P H Wong, Nichollas E Scott, Jeffrey Molendijk, Benjamin L Parker.
      Protein-protein interactions (PPIs) are dynamic and critical to adaptive homeostasis. While there have been massive efforts to catalogue proteome-wide PPIs, global quantification of changes remains a challenge. Here, we integrate dynamic protein correlation profiling - mass spectrometry (PCP-MS) and quantitative cross linking-mass spectrometry (qXL-MS) using multiplexed stable isotope labelling to characterise global PPI remodelling following the development of chronic skeletal muscle insulin resistance (IR) with or without acute insulin stimulation. We quantify >7,000 unique PPIs amongst 5,346 proteins and show changes in the interactome network dominate the proteome response. Our data show the dysregulation of protein processing in the endoplasmic/sarcoplasmic reticulum involving changes in PPIs with protein chaperones and disulfide isomerases is a major hallmark of skeletal muscle IR. Mechanistically, we show the dysregulation of PPIs with Protein-Disulfide Isomerase 6 (PDIA6) regulates cysteine oxidation and insulin sensitivity. Taken together, we show in vivo quantitative interactome mapping is a powerful approach to understand disease mechanisms and provide new insights into protein network re-organisations with IR.
    DOI:  https://doi.org/10.1038/s44320-026-00224-7
  29. BMC Musculoskelet Disord. 2026 Jun 26.
    Aerobic exercise is associated with alleviation of skeletal muscle atrophy in CT26 tumor-bearing mice: insights from transcriptomic and weighted gene co-expression network analyses.
    Jiahao Lv, Junwei Wang, Jia Fan, Junzhi Sun, Yang Liu, Shuling Zhang.
       BACKGROUND: Cancer-associated skeletal muscle atrophy is a major manifestation of cachexia and is closely associated with inflammation, metabolic disturbance, and muscle structural deterioration. Aerobic exercise has been considered a promising non-pharmacological intervention, but its molecular mechanisms in tumor-associated muscle wasting remain incompletely understood. This study aimed to investigate transcriptomic changes associated with the effects of aerobic exercise on skeletal muscle wasting-related alterations in CT26 tumor-bearing mice and to identify candidate hub genes using weighted gene co-expression network analysis.
    METHODS: Eight-week-old specific pathogen-free male BALB/c mice were randomly assigned to four groups: control, exercise, tumor-bearing, and tumor-bearing plus exercise. CT26 cells were subcutaneously inoculated to establish the tumor-bearing model. Mice in the exercise groups underwent treadmill-based aerobic training for 4 weeks. Gastrocnemius muscles were collected for hematoxylin-eosin staining and transcriptome sequencing. Differentially expressed genes were identified, followed by Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and gene set enrichment analyses. Weighted gene co-expression network analysis was further performed to identify phenotype-related modules and candidate hub genes.
    RESULTS: Tumor-bearing mice showed reduced gastrocnemius wet weight and histological abnormalities characterized by disorganized muscle fiber arrangement and structural damage. Compared with the tumor-bearing group, the tumor-bearing plus exercise group exhibited a significant increase in gastrocnemius wet weight alongside a qualitative trend toward histomorphological recovery. Transcriptomic analysis showed that tumor burden upregulated pathways related to inflammation and protein degradation, while downregulating pathways associated with energy metabolism and maintenance of muscle structure. Aerobic exercise was associated with partial reversal of these transcriptional trends. Enrichment analyses indicated that the differentially expressed genes were mainly involved in the PI3K-Akt, NF-kappa B, and IL-17 signaling pathways. Weighted gene co-expression network analysis identified an inflammation-related module closely associated with the tumor-bearing phenotype, in which S100a8 was recognized as a candidate hub gene.
    CONCLUSIONS: Aerobic exercise was associated with a significant improvement in gastrocnemius wet weight and a mitigating trend in histomorphological abnormalities in CT26 tumor-bearing mice, which may be associated with remodeling of inflammation- and metabolism-related transcriptional networks. S100a8 may represent a candidate hub gene associated with this process, although further functional validation is required.
    Keywords:  Aerobic exercise; CT26 tumor-bearing mice; Cancer cachexia; S100a8; Skeletal muscle atrophy; Transcriptome; Weighted gene co-expression network analysis
    DOI:  https://doi.org/10.1186/s12891-026-10131-5
  30. Mol Genet Metab. 2026 Jun 22. pii: S1096-7192(26)00480-4. [Epub ahead of print]148(4): 110197
    High dietary fat causes muscle structural breakdown, mitochondrial dysfunction, and contractile deficits in the absence of carnitine palmitoyltransferase 2.
    Andrea S Pereyra, Filip Jevtovic, Adam J Amorese, Chien-Te Lin, P Darrell Neufer, Espen E Spangenburg, Jessica M Ellis.
      Carnitine palmitoyltransferase 2 (CPT2) deficiency is an inherited autosomal recessive disorder of fatty acid oxidation, which commonly manifests in adolescences and adulthood as muscle weakness and recurrent rhabdomyolysis, limiting physical activity and compromising quality of life. Despite the recognition and avoidance of known triggers such as exercise, fasting, and stress, many patients suffer unexplained periodic episodes of muscle breakdown. While avoidance of fatty meals is recommended, the impact of high-fat consumption alone on muscle biology of CPT-deficient patients is not well defined. Mice with muscle specific CPT2-deletion (Cpt2Sk-/-) and control littermates, were placed on control or high-fat diet (HFD) (60% kcal) for up to 8 weeks. Muscle contractility, transcriptional and protein signatures, mitochondrial metabolic capacity, and histopathology were determined. After 8 weeks on the diet, Cpt2Sk-/- ex vivo muscle force production was significantly reduced by high-fat feeding in the glycolytic EDL and oxidative soleus muscles. In response to HFD, Cpt2Sk-/- muscle mitochondrial respiratory capacity was significantly reduced, despite increased mitochondrial biogenesis, across various muscles. Importantly, HFD further deteriorated the structural integrity of oxidative soleus muscle in CPT2-deficient mice, characterized by reduced fiber size and the presence of ragged red fibers. Together, these data indicate that chronic high dietary fat intake exacerbates the underlying mitochondrial and myopathic dysfunction caused by CPT2 deficiency. This diet-induced worsening of muscle pathology may provide a mechanistic explanation for the symptom exacerbation experienced by individuals with CPT2 deficiency following fatty food consumption.
    Keywords:  Carnitine palmitoylcarnitine transferase 2; Contraction; Fatty acid oxidation disorders; High-fat diet; Mitochondria; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.ymgme.2026.110197
  31. Int J Mol Sci. 2026 Jun 12. pii: 5319. [Epub ahead of print]27(12):
    Zfp36l1 Inhibits DNA Damage by Regulating p21-E2F1-Rad51 Signaling During Myogenic Differentiation.
    Yi Liu, Xiaoyu Jiang, Jingxin Sun, Luyao Wang, Jialong Li, Honglin Liu, Aiwen Jiang, Shenglong Wu, Wenbin Bao.
      Skeletal muscle differentiation relies on transient DNA strand breaks (DSBs), yet excessive DNA damage remains harmful to myogenic progression. The RNA-binding protein Zfp36l1 is expressed in skeletal muscle and contributes to muscle regeneration; nevertheless, its role in preserving genome stability during myogenic differentiation has not been defined. Here, we investigated the role and mechanism of Zfp36l1 in regulating DNA damage using C2C12 myoblast cells, combining loss- and gain-of-function assays, RNA-seq, and rescue experiments. The results revealed that Zfp36l1 expression is strongly induced during early myogenic differentiation, coinciding with the onset of physiological DSBs. Functional assays revealed that silencing Zfp36l1 aggravates DSB accumulation, reinforces G0/G1 cell cycle arrest, and promotes apoptosis, whereas Zfp36l1 overexpression attenuates these abnormalities. Transcriptomic profiling shows that Zfp36l1 knockdown impairs homologous recombination (HR)-mediated DNA repair by downregulating core repair factors, including Rad51 and Brca1. Gene set enrichment analysis further confirms significant suppression of the HR-dependent DSB repair pathway. Mechanistically, Zfp36l1 regulates HR repair by suppressing p21 expression, thereby relieving inhibition of E2F1-mediated Rad51 transcription. Co-silencing p21 restores Rad51 expression and reduces DNA damage in Zfp36l1-knockdown cells. Collectively, these findings identify Zfp36l1 as an essential safeguard of genome stability during myogenic differentiation by balancing DNA damage levels through the p21-E2F1-Rad51 signaling axis, and provide new insights into the regulatory basis of muscle development and genomic instability-associated muscle diseases.
    Keywords:  DNA damage; Zfp36l1; homologous recombination; myogenic differentiation; p21
    DOI:  https://doi.org/10.3390/ijms27125319
  32. Acta Neuropathol Commun. 2026 Jun 26.
    Dynamic integration of skeletal muscle signals via extracellular vesicles in motor neuron diseases.
    Flaminia Riggio, Gianmarco Fenili, Daniela Caporossi, Maria Paola Paronetto.
      Extracellular vesicles (EVs) are heterogenous lipid bilayer-enclosed particles secreted by virtually all cell types. They encapsulate a diverse array of bioactive molecules, including proteins, lipids, nucleic acids, and metabolites, which can be transferred to recipient cells, thereby modulating their function and phenotype. In recent years, skeletal muscle-derived EVs (SkM-EVs) have emerged as key players in the bidirectional communication between skeletal muscle and motor neurons, contributing to the establishment and maintenance of neuromuscular homeostasis. Disruptions in this intercellular signalling have been implicated in the pathophysiology of motor neuron diseases (MNDs) such as spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS). In these contexts, SkM-EVs may contribute to disease progression by delivering pathogenic cargo, including misfolded proteins and aberrant RNAs, to motor neurons. A comprehensive understanding of SkM-EV biology, particularly their roles in neuromuscular communication, could offer critical insights into disease mechanisms and identify novel opportunities for biomarker discovery and therapeutic intervention. This review synthesizes current knowledge on the functional roles of SkM-EVs in motor neuron health and disease and evaluates their potential as diagnostic tools and therapeutic vectors in the context of MNDs.
    Keywords:  ALS; Extracellular vesicles; Motor neuron; Neurodegenerative diseases; SMA
    DOI:  https://doi.org/10.1186/s40478-026-02356-1
  33. Genes (Basel). 2026 Jun 21. pii: 720. [Epub ahead of print]17(6):
    THBS1 as a Key Regulator of Myoblasts: Validation of Its Inhibitory Roles in Skeletal Muscle Development.
    Ji Qi, Xinlin Jin, Jing Wang, Yunzhou Wang, Wei Chen, Hongzhen Cao, Jingsen Huang, Hui Tang, Junfeng Chen, Baosong Xing, Yongqing Zeng.
       BACKGROUND: Thromboxane B2 Synthase 1 (THBS1), also known as TSP-1, is a multifunctional glycoprotein involved in various cellular processes that plays a crucial role in skeletal muscle development and repair. It acts as a key physiological activator of transforming growth factor-β1 (TGF-β1), both in vivo and in vitro.
    METHODS: This study aimed to investigate the effects of THBS1 on myoblast proliferation and differentiation using the mouse skeletal muscle satellite cell line C2C12 and to reveal its regulatory relationship with the TGF-β signaling pathway through a series of cellular and molecular experiments.
    RESULTS: Overexpression or knockout of THBS1 in C2C12 cells regulates and upregulates the activity of the TGF-β signaling pathway, thereby inhibiting the proliferation and differentiation of C2C12 cells.
    CONCLUSIONS: These results provide a theoretical foundation for future research aimed at enhancing skeletal muscle quality in livestock and poultry and lay the groundwork for developing therapeutic strategies for skeletal muscle disorders.
    Keywords:  TGF-β signaling pathway; THBS1; cellular differentiation; myoblasts; skeletal muscle
    DOI:  https://doi.org/10.3390/genes17060720
  34. bioRxiv. 2026 Jun 12. pii: 2026.06.09.730973. [Epub ahead of print]
    Three-dimensional imaging reveals preserved intrinsic contractile function in aging human skeletal muscle fibers.
    Carlos S Zepeda, Laura E Teigen, Isabell Dobrzycki, Yuan Wen, Christopher W Sundberg.
      Age-related reductions in muscle fiber size and contractile function, particularly in fibers expressing fast myosin heavy chains, contribute to declines in whole-muscle power. However, methodological limitations in estimating fiber size during contractile experiments have likely contributed to conflicting findings regarding whether reduced single-fiber force and power in older adults reflects their smaller size and/or impaired intrinsic contractile function. To address this, we coupled single-fiber contractile experiments with 3D-imaging in 7 young (19-40yrs) and 6 older (69-84yrs) males to assess intrinsic contractile function and compare agreement between 3D-derived cross-sectional area (CSA) and CSA estimates obtained either in air or solution. Fast fiber CSA from older males were ∼28-45% smaller across measurement conditions compared with young, whereas slow fiber CSA did not differ. Accordingly, absolute force and power of fast fibers were 41% and 37% lower. When normalized to CSA from measurements in air or 3D-imaging, size-specific force and power either did not differ or were greater in older adults, indicating preserved intrinsic contractile function in both fiber types. This was supported by no age-related differences in the rate of tension redevelopment (k tr ), a size-independent measure of intrinsic contractile function. In contrast, size-specific force and power calculated using solution-based CSA estimates were lower in older compared with young adults, and Bland-Altman analyses demonstrated the poorest agreement between solution-based and 3D CSA measurements. These findings indicate that intrinsic contractile function is preserved with aging and suggest that methodological differences in CSA measurement contributes to the disparate findings in the literature.
    DOI:  https://doi.org/10.64898/2026.06.09.730973
  35. Acta Neuropathol Commun. 2026 Jun 23.
    Accumulation of membrane repair-associated proteins and mature myostatin are novel markers of muscle pathophysiology in Pompe disease.
    LYSAUMI Consortium
      Pompe disease is an autosomal recessive metabolic disorder caused by acid alpha-glucosidase deficiency, characterized by progressive skeletal muscle weakness and respiratory insufficiency. Affected muscles exhibit glycogen-filled lysosomes, autophagic build-up, and mitochondrial abnormalities. Despite global myofibrillar disorganization, satellite cells (SCs) fail to activate, due to mechanisms that remain unclear. This study aimed to further characterize the muscle phenotype in Pompe disease, with particular attention to proteins associated with membrane repair processes, as membrane damage is a primary trigger for SC activation. Longitudinal transcriptomic analysis of skeletal muscle from a Pompe disease mouse model, combined with immunohistochemical and biochemical approaches, showed early and sustained overexpression of dysferlin (DYSF), annexin A2 (ANXA2), and AHNAK2. These membrane repair-associated proteins displayed abnormal localization during disease progression, with sarcoplasmic accumulation associated with T-tubules, lysosomes and autophagosomes, respectively. Analysis of muscle biopsies from some patients with late-onset Pompe disease (LOPD) identified similar expression patterns in moderately affected cases, whereas these patterns were less evident or absent in the most severe samples, suggesting stage-dependent redistribution associated with advanced myoarchitectural disorganization. Furthermore, in the mouse model, we observed persistent post-transcriptional accumulation of mature myostatin (MSTN), a key negative regulator of muscle growth, alongside a decrease in the phospho-SMAD3/SMAD3 ratio and reduced SMAD7 expression, which point toward a more complex modulation of its canonical bioactivity rather than a simple increase. Altogether, these findings identify modified distribution proteins linked to membrane repair and dysregulation of MSTN as features of muscle remodeling in Pompe disease.
    Keywords:  Autophagosome; Lysosome; Membrane repair-associated protein; Myostatin; Pompe disease; Satellite cell; Skeletal muscle; T-tubule
    DOI:  https://doi.org/10.1186/s40478-026-02348-1
  36. Nutrients. 2026 Jun 19. pii: 1990. [Epub ahead of print]18(12):
    Balanced Essential Amino Acids as Synergistic Therapeutic Agents in Resistance Training: Mechanistic and Clinical Perspectives on Muscle and Metabolic Health.
    Jiwoong Jang, Robert R Wolfe, Il-Young Kim.
      Declines of skeletal muscle mass and functions are implicated in the progression of various clinical conditions such as cancers, obesity, insulin resistance, diabetes, and osteoporosis. While no effective and safe drugs against muscle wasting, such as sarcopenia and disease-associated cachexia, have been discovered, it is well documented that dietary essential amino acids (EAAs) or high-quality protein work synergistically to enhance the anabolic effect of resistance exercise training (RT), leading to gains in muscle mass, strength, and muscle quality. Dietary EAAs serve as precursors and signaling molecules for the synthesis of new muscle proteins (both contractile and mitochondrial) and stimulate neuromuscular junction remodeling. Furthermore, EAAs consumed in the post-absorptive state improve endurance capacity via stimulation of mitochondrial biogenesis (independent of PGC1-α) and mitochondrial dynamics (mitochondrial protein synthesis and fission). Here, we discuss (1) traditional molecular mechanisms regulating the muscle proteome through constant turnover (synthesis and breakdown), (2) novel mechanisms by which dietary supplementation of EAAs during RT simultaneously improves muscle strength and endurance, (3) stable isotope tracer methodologies that enable understanding of the dynamic muscle proteome and accurate assessment of functional muscle mass, and finally, (4) clinical implications of combined EAA and RT interventions in the context of muscle and metabolic dysfunction, including sarcopenia, cachexia, obesity, and chronic disease. Collectively, current evidence underscores the potential of balanced EAAs, particularly when combined with resistance training, as a safe, effective, and translationally relevant nutritional strategy to preserve and enhance muscle and metabolic health across healthy and clinical populations.
    Keywords:  essential amino acids; physical function; protein turnover; resistance exercise; stable isotope tracer methodology
    DOI:  https://doi.org/10.3390/nu18121990
  37. Pharmaceuticals (Basel). 2026 Jun 07. pii: 905. [Epub ahead of print]19(6):
    Phytochemical-Based Therapeutic Strategies for Sarcopenia: From Molecular Mechanisms to Clinical Translation.
    Gengyun Le-Chan, Nicole Q Amoah, Hailey M Sofia, Aidan H Quee, Sunny S K Chan, Cindy A Thomas-Charles.
      Sarcopenia is a progressive, age-related musculoskeletal disorder characterized by the loss of skeletal muscle mass, strength, and physical performance, which contributes to frailty, disability, and mortality in older adults. Although resistance exercise and optimized protein intake remain first-line interventions, effective pharmacological therapies are limited, highlighting the need for novel adjunctive strategies. Increasing interest has focused on phytochemicals, plant-derived bioactive compounds with antioxidant, anti-inflammatory, and metabolic regulatory properties that may target multiple mechanisms underlying muscle aging. This review summarizes the molecular and translational potential of phytochemicals in sarcopenia management. Experimental and emerging clinical evidence indicates that flavonoids, polyphenols, alkaloids, and terpenoids modulate key pathways involved in sarcopenia pathogenesis, including PI3K/Akt/mTOR-mediated anabolic signaling, AMPK-SIRT3-PGC-1α-dependent mitochondrial biogenesis, NF-κB-driven inflammation, oxidative stress responses, autophagy, and satellite cell function. Through these pleiotropic effects, phytochemicals may attenuate the anabolic resistance, mitochondrial dysfunction, chronic inflammation, and impaired muscle regeneration associated with aging. Despite promising mechanistic evidence, clinical translation remains limited by poor bioavailability, variability in formulation and dosing, a lack of long-term randomized trials, and inconsistent functional outcome measures. Current evidence suggests that phytochemicals are most effective when integrated with resistance exercise and nutritional support rather than used as stand-alone therapies. Overall, phytochemicals represent promising complementary candidates for sarcopenia prevention and management. Future studies should prioritize standardized formulations, biomarker-guided approaches, and rigorously designed clinical trials focused on clinically meaningful functional outcomes to establish their efficacy, safety, and translational relevance in aging populations.
    Keywords:  aging; muscle; pharmaceutical; phytochemical; sarcopenia
    DOI:  https://doi.org/10.3390/ph19060905
  38. Int J Mol Med. 2026 Aug;pii: 231. [Epub ahead of print]58(2):
    Myokines in exercise‑mediated bone homeostasis: Molecular signaling mechanisms and therapeutic implications for bone disorders (Review).
    Bin Tian, Xuesong Chen, Jiang Zheng, Xin Kang.
      Skeletal muscle functions as an endocrine organ, secreting myokines that mediate interorgan communication with bone. Exercise‑induced myokines regulate bone homeostasis by orchestrating osteoblast differentiation, osteoclastogenesis, and osteocyte mechano‑sensing through key signaling pathways, including the Wnt/β‑catenin, mitogen‑activated protein kinase, phosphatidylinositol‑3‑kinase/AKT, nuclear factor kappa B and transforming growth factor‑beta/bone morphogenetic protein pathways. The present review provides a critical synthesis of the current evidence and proposes a conceptual framework for the tripartite muscle‑bone‑immune axis, which has not been systematically integrated into previous reviews. Emerging evidence highlights a tripartite muscle‑bone immune axis, wherein myokines modulate immune cells within the bone niche, with dysregulation contributing to age‑related osteoporosis and sarcopenia. Methodological innovations such as multi‑omics, single cell and spatial transcriptomics, organ‑on‑a‑chip platforms, and artificial intelligence are accelerating discovery. The present review synthesizes current knowledge on myokine mediated muscle‑bone crosstalk and evaluates the therapeutic implications for bone disorders.
    Keywords:  bone homeostasis; exercise; muscle bone crosstalk; myokines; osteoporosis; sarcopenia; signaling pathways; therapeutic targets
    DOI:  https://doi.org/10.3892/ijmm.2026.5902
  39. Nat Aging. 2026 Jun 26.
    Meta-analysis of DNA methylation aging signatures in 17 human tissues.
    Macsue Jacques, Kirsten Seale, Sarah Voisin, Anna Lysenko, Robin Grolaux, Bernadette Jones-Freeman, Severine Lamon, Mandhri Abeysooriya, Itamar Levinger, Carlie Bauer, Adam P Sharples, Aino Heikkinen, Elina Sillanpaa, Miina Ollikainen, Cassandra Smith, James R Broatch, Navabeh Zarekookandeh, Linn Gillberg, Ida Blom, Jesse R Poganik, Mahdi Moqri, Vadim N Gladyshev, Matthew Taper, Cassandra Malecki, Sean Lal, Nathalie Saurat, Steve Horvath, Andrew Teschendorff, Nir Eynon.
      Epigenetic changes, in particular DNA methylation, accumulate with age across different tissues, but whether these changes follow consistent patterns across different organs remains poorly understood. Here we show, through a meta-analysis of more than 15,000 human methylation profiles spanning 17 tissues, that aging produces both conserved and tissue-specific epigenetic signatures. We identify systemic shifts in methylation levels, increases in methylation variability, and growing molecular disorder across tissues. Network analysis revealed tightly connected gene clusters that are not modified by beneficial interventions, alongside a more modifiable cluster linked to NAD+ metabolism, supporting NAD+ as a potential therapeutic target in aging. A gene encoding a cell-adhesion protein, PCDHGA1, emerged as a conserved hub across tissues, implicating cell-to-cell communication pathways in aging across multiple organs. Our methylation atlas therefore provides a resource for dissecting the molecular basis of human aging and for identifying potential biomarkers and translational therapies.
    DOI:  https://doi.org/10.1038/s43587-026-01164-5
  40. Diabetes Res Clin Pract. 2026 Jun 21. pii: S0168-8227(26)00306-2. [Epub ahead of print]238 113386
    Molecular senescence, neuroendocrine metaflammation, and skeletal muscle insulin resistance in type-4 diabetes: from mitochondrial dysfunction to precision therapeutics.
    Bhanu Pratap Singh, Ravinder Kumar Mehra, Shakir Siddiqui, Km Kahkasha, Dinesh Kumar Gupta, Shatakshi Kushwaha.
      With the global population aged 65 years and older projected to exceed 1.5 billion by 2050, sarcopenia-driven insulin resistance is emerging as an urgent yet still under-recognised contributor to the diabetes burden in older adults, underscoring the timeliness of a focused molecular synthesis of this entity for guiding both diagnostic recognition and therapeutic prioritisation. Molecularly different, age-driven insulin resistance promotes skeletal muscle ageing, mitochondrial bioenergetic collapse, and prolonged neuroendocrine metaflammation in type-4 diabetes (T4DM). In ageing myocytes, poor IRS-1/PI3K/Akt signalling, GLUT4 trafficking anomalies, AMPK suppression, ROS-mediated mtDNA instability, and decreased OXPHOS capacity induce T4DM. Senescent muscle cells generate IL-6, TNF-α, and MCP-1 when p16INK4a/p21 checkpoints activate, forming a self-reinforcing inflammatory cycle. Myostatin overactivation, irisin decrease, and FGF21 imbalance influence glucose homeostasis. Metabolism declines due to hypothalamic insulin resistance, microglial inflammation, gut dysbiosis-driven TLR4/NF-κB signalling, and epigenetic remodelling via miR-29, miR-34a, and l Using precision biomarkers like GDF-15, β2-microglobulin, and p16INK4a with multi-omics phenotyping may change diagnosis. Senolytics, NAD⁺ replenishment, SIRT1 activators, mitophagy inducers, anti-myostatin medicines, and exosome-based therapies shift metabolic care towards senescence. T4DM's molecular architecture and precision geriatric endocrinology translational targets are reviewed here.
    Keywords:  Ageing skeletal muscle; Immunometabolism; Insulin resistance; Metaflammation; Mitochondrial senescence; Myokines; Precision metabolism; Sarcopenia; Senolytics; Type-4 diabetes
    DOI:  https://doi.org/10.1016/j.diabres.2026.113386
  41. Front Physiol. 2026 ;17 1740284
    Age-related anabolic resistance and post-absorptive muscle protein synthesis: integrative evidence from a systematic review and meta-analysis.
    Jonas Boritz Kristiansen, Kristian Vissing, Jakob Lindberg Nielsen.
       Introduction: Age-related declines in skeletal muscle mass and function are partly attributed to anabolic resistance, a diminished stimulation of muscle protein synthesis (MPS) following nutrient intake or exercise. However, the magnitude and physiological specificity of this phenomenon remain incompletely defined. This systematic review and meta-analysis examined age-related differences in MPS across post-absorptive, post-prandial, post-exercise, and combined post-prandial/-exercise states in healthy adults.
    Methods: A systematic literature search was conducted in November 2025 across major databases. Eligible studies compared MPS between young (18-35 years) and older (≥60 years) adults using stable isotope tracer techniques under controlled conditions. Random-effects meta-analyses were conducted for post-absorptive and post-prandial conditions, while post-exercise and combined post-prandial/-exercise findings were synthesized qualitatively due to substantial methodological heterogeneity. Meta-regression explored potential moderators, and risk of bias was assessed using the ROBINS-I tool.
    Results: Forty-six studies including 1,280 participants (700 older adults, 580 young) met the inclusion criteria. Post-absorptive MPS was significantly lower in older compared with younger adults (SMD = -0.167; 95% CI: -0.313 to -0.021; p = 0.025; I² = 18.4%). Post-prandial MPS was also reduced in older adults (SMD = -0.348; 95% CI: -0.627 to -0.070; p = 0.014; I² = 83.4%), with consistent directionality across sensitivity analyses. Post-exercise (5/8) and combined post-prandial/-exercise (7/9) studies reported no significant age-related difference. Overall risk of bias was low to moderate.
    Discussion: These findings demonstrate modest but significant reductions in both post-absorptive and post-prandial MPS with aging, consistent with basal and nutrient-related anabolic resistance. However, the preserved MPS response to exercise suggests maintained anabolic potential when appropriate stimuli are provided. Evidence for combined post-exercise MPS remains mixed, with evidence leaning toward a similar response in young and older adults. Standardization of tracer protocols and sex-specific analyses are warranted to refine mechanistic understanding of age-related anabolic heterogeneity.
    Keywords:  aging; amino acid metabolism; anabolic resistance; exercise; muscle protein breakdown; muscle protein synthesis; postprandial metabolism; stable isotope tracers
    DOI:  https://doi.org/10.3389/fphys.2026.1740284
  42. Sci Transl Med. 2026 Jun 24. 18(855): eadx2116
    Kbtbd13 knockdown restores muscle function in a clinically relevant mouse model of nemaline myopathy type 6.
    Ricardo A Galli, Leander A Vonk, Rianne J Baelde, Anita van den Heuvel, Sylvia Bogaards, Stefan Conijn, Emma Siteur, Olga Alekhina, Henk Granzier, Thomas Irving, Weikang Ma, Karlijn Bouman, Baziel van Engelen, Silvère M van der Maarel, Tyler J Kirby, Nicol Voermans, Josine de Winter, Coen A C Ottenheijm.
      Nemaline myopathy type 6 (NEM6) is a rare neuromuscular disorder caused by pathogenic variants in the Kelch repeat and BTB domain-containing 13 (KBTBD13) gene. Patients experience muscle weakness, excessive fatigue, and impaired muscle relaxation that affect their daily activities related to abnormal protein aggregation in muscle cells and a predominance of slow-twitch myofibers, and no specific therapies are available. Here, we studied a clinically relevant Kbtbd13:p.Arg408Cys knockin mouse model to elucidate the molecular changes driving disease pathogenesis through measurements of muscle contractility, single myofiber assays, super-resolution microscopy, and x-ray diffraction. Kbtbd13:p.Arg408Cys knockin mice closely phenocopied human NEM6 pathology at the morphological, functional, and transcriptional levels, with the p.Arg408Cys variant causing mislocalization of KBTBD13 in the muscle sarcomere, associated with disease onset between 1 and 3 months of age, plateauing by 9 months, and with little progression at 18 months. As a potential therapeutic approach, we knocked down Kbtbd13 using short hairpin RNA against Kbtbd13 delivered intramuscularly via an adeno-associated virus 9 vector at either the prephenotype (1-month-old) or peak-phenotype (3- or 7-month-old) stages. A single treatment at the prephenotype stage prevented the development of impaired relaxation kinetics, nemaline rod aggregation, and slow-twitch myofiber predominance at 3 months of age. A single treatment at 3 months of age, after onset of disease, restored muscle morphology, contractility, and muscle-relaxation kinetics over 6 months. These data provide insights into NEM6 pathogenesis and suggest that Kbtbd13 knockdown might be a promising therapeutic strategy for patients with NEM6.
    DOI:  https://doi.org/10.1126/scitranslmed.adx2116
  43. Function (Oxf). 2026 Jun 25.
    Cellular Senescence Links Muscle Atrophy and Posttraumatic Osteoarthritis after ACL Injury.
    Alexander R Keeble, Allison Owen, Sara Gonzalez-Velez, Nicholas T Thomas, Camille Brightwell, Peyton Balawender, Madeline O'Daniel, Helena Weiss, Haley Noehren, Heather Thompson, Karen Zuluaga-Osorio, Zane Bates, Lauren Gottlieb, Douglas Long, Douglas Harrison, Philip Kern, Caitlin Conley, Michael Samaan, Stephen Duncan, Austin Stone, Darren Johnson, Yuan Wen, Brian Noehren, Cory Dungan, Christopher S Fry.
      Traumatic knee injury leads to posttraumatic osteoarthritis (PTOA) and significant skeletal muscle weakness, resulting in chronic disability. The current standard of care frequently fails to prevent musculoskeletal dysfunction, underscoring the need to identify therapeutic mechanisms of PTOA. Using an established preclinical anterior cruciate ligament (ACL) transection model of PTOA and leveraging an innovative SPiDER-senescence associated β-galactosidase stain to discern senescent cells, we investigated cellular senescence at single-cell resolution and identified anti-inflammatory macrophages as a predominant contributor to the senescent cell burden in both muscle and knee joint after injury. Clearance of senescent cells using the senolytic dasatinib and quercetin (D+Q) mitigated injury-induced muscle atrophy and cartilage degradation, with greater senescent cell clearance within muscle compared to cartilage. We also provide clinical evidence of elevated senescent cell burden in muscle of patients following ACL injury and with PTOA, which is obstinate to standard of care, highlighting cellular senescence as a strong therapeutic target to improve functional recovery after traumatic joint injury.
    Keywords:  fibro-adipogenic progenitor cells; keletal muscle; muscle fibrosis; quadriceps; senolytic
    DOI:  https://doi.org/10.1152/function.017.2026
  44. Hum Mol Genet. 2026 Jun 12. pii: ddag023. [Epub ahead of print]35(12):
    Nicotinamide riboside prevents mitochondrial dysfunction in nemaline myopathy type 6.
    Rianne J Baelde, Leander A Vonk, Edgar E Nollet, Ricardo A Galli, Alexcia Fortes Monteiro, Sultan Bastu, Bornale Das, Michel van Weeghel, Bauke V Schomakers, Kasper T Vinten, Marloes van den Berg, Jolanda van der Velden, Riekelt H Houtkooper, Nicol C Voermans, Edoardo Malfatti, Coen A C Ottenheijm, Josine M de Winter.
      Nemaline Myopathy type 6 (NEM6) is a congenital myopathy caused by variants in Kelch-repeat-and-BTB-(POZ)-Domain-Containing-13 (KBTBD13). The majority of the NEM6 patients harbor the Dutch founding variant KBTBD13R408C (c.1222C > T, p.Arg408Cys) and experience skeletal muscle weakness and sarcomere-based hypercontractility. Histological characterization of NEM6 patient biopsies by NADH staining shows the presence of cores, suggesting mitochondrial dysfunction. We aimed to elucidate the role of mitochondrial dysfunction in NEM6 pathology and tested the ability of the NAD+ precursor nicotinamide riboside (NR) to improve mitochondrial performance. We performed a natural history study in homozygous Kbtbd13R408C-knockin mice (NEM6 mouse model) to investigate the onset and progression of mitochondrial dysfunction in NEM6. We performed high-resolution respirometry, metabolic treadmill experiments and histoenzymatic NADH and SDH stainings on cryosections. Additionally, we used multi-omics analyses to investigate impacted pathways and metabolite dysregulation and performed NR supplementation for eight weeks to prevent the onset of mitochondrial dysfunction in NEM6 mice. Throughout disease progression, NEM6 mice display decreased mitochondrial respiration, impaired metabolic performance and the presence of cores with histoenzymatic reactions. Multi-omics studies revealed that the TCA cycle is heavily impacted and that NAD+ levels are decreased throughout disease progression. We aimed to restore NAD+ levels by supplementation of NR. Remarkably, NR treatment in 1-months-old NEM6 mice, prevented the onset of mitochondrial dysfunction. In conclusion, these results provide insight in the onset and progression of mitochondrial dysfunction in NEM6 and offer proof-of-concept for NR as a therapeutic strategy.
    Keywords:  Congenital myopathy; Mitochondria; NAD+ metabolism; Nemaline myopathy; Skeletal muscle
    DOI:  https://doi.org/10.1093/hmg/ddag023
  45. Microorganisms. 2026 Jun 19. pii: 1366. [Epub ahead of print]14(6):
    The Gut-Brain-Muscle Axis: Microbial Regulation of Neuromuscular Aging and Cognitive Frailty.
    Nurpudji Astuti Taslim, Jeremy Nicolas Sibarani, Ricky Indra Alfaray, Nelly Mayulu, Arifa Mustika, Dian Aruni Kumalawati, Happy Kurnia Permatasari, Raymond Rubianto Tjandrawinata, Fahrul Nurkolis.
      Cognitive frailty, characterized by the coexistence of physical frailty and cognitive impairment, has emerged as a major challenge in aging populations and is closely linked to sarcopenia, neurodegeneration, and chronic inflammation. Increasing evidence suggests that the gut microbiota acts as a central regulator of neuromuscular and neurocognitive aging through the integrated gut-brain-muscle axis. This review highlights how microbial dysbiosis, reduced short-chain fatty acid (SCFA) production, systemic endotoxemia, and altered microbial metabolites contribute to mitochondrial dysfunction, neuroinflammation, anabolic resistance, and impaired neuroplasticity. Key signaling mediators, including SCFAs, bile acids, tryptophan-derived metabolites, cytokines, and myokines such as irisin, brain-derived neurotrophic factor (BDNF), and cathepsin B, orchestrate bidirectional communication among the gut, skeletal muscle, and brain. We further discuss the role of exercise-induced microbiota remodeling and muscle endocrine signaling in promoting mitochondrial biogenesis and cognitive resilience. In addition, emerging translational strategies including probiotics, prebiotics, postbiotics, polyphenol-rich functional foods, marine bioactives, and precision nutrition are explored as potential interventions targeting this axis. Collectively, the gut-brain-muscle axis provides a novel systems biology framework for understanding cognitive frailty and developing integrated therapeutic strategies for healthy longevity.
    Keywords:  cognitive frailty; gut microbiota; gut–brain–muscle axis; microbial metabolites; mitochondria; myokines; neuroinflammation; neuromuscular aging; precision nutrition; sarcopenia
    DOI:  https://doi.org/10.3390/microorganisms14061366
  46. Mol Metab. 2026 Jun 20. pii: S2212-8778(26)00090-6. [Epub ahead of print] 102406
    Skeletal muscle-specific deficiency of Rab geranylgeranyl transferase beta subunit induces myopathy and exacerbates the symptoms caused by HMG-CoA reductase deficiency in mice.
    Yoshinori Osaki, Yuhei Mizunoe, Yoshimi Nakagawa, Takafumi Miyamoto, Ryo Fujita, Song-Iee Han, Masaya Araki, Masataka Tomoda, Kenta Kainoh, Hiroshi Ohno, Hitoshi Iwasaki, Takashi Matsuzaka, Hirohito Sone, Ken Ohashi, Shun Ishibashi, Motohiro Sekiya, Hitoshi Shimano.
       OBJECTIVES: Statins (HMG-CoA reductase inhibitors) are associated with myopathy, yet the precise in vivo mechanisms underlying this association remain unclear. Emerging evidence implicates a deficiency of geranylgeranyl pyrophosphate (GGPP), a key downstream isoprenoid metabolite of the mevalonate pathway. We employed novel muscle-specific genetic mouse models to elucidate the roles of GGPP and Rab geranylgeranyl transferase β (RabGGT-β) in the development of myopathy.
    METHODS: Using doxycycline-inducible Cre-LoxP technology, we generated three skeletal muscle-specific knockout (KO) models: Hmgcr-DimKO, Rabggtb-DimKO, and combined Hmgcr/Rabggtb-DimKO mice. The severity of myopathy was evaluated based on serum creatine kinase levels and histological examination. Mitochondrial mass and function were rigorously quantified. Prenylation deficit in Rabggtb-DimKO mice was confirmed via subcellular fractionation. To validate GGPP's involvement, rescue experiments were conducted using its precursor, geranylgeraniol (GGOH).
    RESULTS: Hmgcr KO resulted in pronounced myopathy, marked by an early reduction in mitochondria-rich myosin heavy chain (MyHC) type I and IIa muscle fibers, followed by a later reduction in mitochondria-poor glycolytic MyHC type IIb muscle fibers, and these changes were reversed by GGOH administration. Rabggtb-DimKO mice developed myopathy later than Hmgcr-DimKO mice; however, in Hmgcr/Rabggtb-DimKO mice, myopathy was dramatically accelerated and more severe. Across all models, mitochondrial dysfunction emerged early-preceding clinical signs of myopathy-consistent with a causal relationship.
    CONCLUSIONS: Our findings demonstrate that myopathy induced by HMGCR deficiency is primarily driven by GGPP depletion in a mouse model. Furthermore, impaired RabGGT-β-mediated protein geranylgeranylation represents a critical downstream mechanism that aggravates the myopathic phenotype. Early mitochondrial abnormalities may contribute to the pathogenesis of myopathy due to disruption of the mevalonate pathway.
    Keywords:  Geranylgeranyl pyrophosphate; HMG-CoA reductase; Myopathy; Rab geranylgeranyl transferase; Skeletal muscle; Slow-twitch muscle
    DOI:  https://doi.org/10.1016/j.molmet.2026.102406
  47. Int J Mol Med. 2026 Sep;pii: 232. [Epub ahead of print]58(3):
    Skeletal muscle‑derived extracellular vesicles in multi‑organ degenerative disease: Mechanisms and therapeutic delivery perspectives (Review).
    Xianji Wei, Chengyan Guo, Wei Zhang, Guanyi Wang, Wenjing Li, Binghong Gao, Bo Gao, Lingli Zhang.
      Multi‑organ degenerative diseases are age-associated or chronic disorders marked by progressive tissue deterioration, impaired repair and functional decline, with representative conditions including sarcopenia, osteoporosis, osteoarthritis, neurodegenerative or ischemia‑associated neurological disorders, heart failure, chronic kidney disease and diabetes‑associated tissue dysfunction. Their frequent coexistence in aging populations limits the effectiveness of therapeutic strategies directed at a single organ or pathway. Extracellular vesicles (EVs) are lipid bilayer‑enclosed particles that shuttle proteins, lipids, metabolites and regulatory RNAs between cells and tissue. As a highly metabolic and secretory tissue, skeletal muscle releases skeletal muscle‑derived EVs (SkM‑EVs) that may carry muscle‑enriched microRNAs, together with other regulatory cargo molecules involved in local tissue remodeling and systemic signaling. SkM‑EVs have therefore been proposed as mediators of muscle‑centered cross‑organ communication and potential delivery vehicles for molecular intervention, although therapeutic evidence remains largely preclinical. The present review examines the biological functions of SkM‑EVs, their regulation by exercise, aging and metabolic stress and their potential involvement in multi‑organ degenerative diseases. The present study aimed to discuss engineering strategies for SkM‑EVs, including cargo loading, surface modification and targeted delivery, with particular attention to controversies, methodological limitations, quality control requirements and barriers to clinical translation.
    Keywords:  EV engineering; SkM‑EV; degenerative disease; extracellular vesicle; interorgan communication; myomiR; skeletal muscle; targeted delivery
    DOI:  https://doi.org/10.3892/ijmm.2026.5903
  48. Eur J Sport Sci. 2026 Jul;26(7): e70213
    The Effect of Strength Training During Chemotherapy in Women With Breast Cancer on Serum Cytokine Concentrations and Skeletal Muscle Autophagy-Related Proteins.
    Emelie Strandberg, Olav Vikmoen, Karianne Vassbakk Svindland, Atle Wendel Scheie, Hege Nymo Ødemark, Anna Henriksson, Sveinung Berntsen, Truls Raastad.
      To evaluate whether strength training during chemotherapy alters (1) serum cytokines and (2) skeletal muscle autophagy- and heat-shock-related proteins in women with breast cancer. Exploratory analyses assessed associations between changes in physiological outcomes (muscle strength, cardiorespiratory fitness, and capillary density) and biomarker responses, and among cytokine changes. Women with breast cancer were randomized to strength training (n = 23) or usual care (n = 17). The training group completed supervised strength training twice weekly during chemotherapy; usual care maintained habitual physical activity. Assessments were performed pre-chemotherapy (T0) and post-chemotherapy/intervention (T1). Serum cytokines (IFN-γ, IL-1RA, IL-6, IL-8, IL-10, IL-17, MCP-1, TNF-α) were quantified, and muscle biopsies were analyzed for autophagy- and heat-shock-related proteins. In the strength training group, mean ± SD IL-6 increased from 1.21 ± 0.47 to 1.69 ± 0.71 pg/mL and IL-17 from 1.24 ± 0.25 to 2.18 ± 0.87 pg/mL. IFN-γ also increased in the training group (14.4 ± 8.6 to 28.8 ± 17.3 pg/mL), however, the group×time interaction was not statistically significant. In the usual care group, IL-6 and IL-17 decreased. No changes were observed in other cytokines or in autophagy- or heat-shock-related proteins. Exploratory analyses showed no associations between changes in strength and autophagy proteins, cardiorespiratory fitness and cytokines, or capillary density and cytokines. Strength training during chemotherapy did not alter selected skeletal muscle autophagy- or heat-shock-related proteins, despite group differences in IL-6 and IL-17 over time. The clinical and mechanistic significance of these cytokine shifts remains uncertain and should be evaluated in larger studies with additional time points and complementary immune and muscle outcomes.
    Keywords:  anti‐cancer treatment; inflammation; interleukin 17; interleukin 6; muscle health
    DOI:  https://doi.org/10.1002/ejsc.70213
This page is being maintained by Thomas Krichel. It was last updated on 2026‒06‒28 at 0:38.