bims-moremu Biomed News
on Molecular regulators of muscle mass
Issue of 2026–02–01
48 papers selected by
Anna Vainshtein, Craft Science Inc.
  1. The role of circular RNAs in mediating the protective effects of exercise against muscle degeneration and aging.
  2. Branched actin polymerization drives invasive protrusion formation to promote myoblast fusion during mouse skeletal muscle regeneration.
  3. Fiber-type vulnerability and proteostasis reprogramming in skeletal muscle during pancreatic cancer cachexia.
  4. MRG15 decline in aged/injured MuSCs hinders regeneration via differentiation defects.
  5. Inhibition of TRPC3-Nox2 Complex Formation Ameliorates Skeletal Muscle Atrophy.
  6. Mitophagic activity and protein levels differ across and within muscles: implications for future skeletal muscle mitophagy research.
  7. Cellular survivorship bias as a mechanistic driver of muscle stem cell aging.
  8. Effects of local skeletal muscle cooling prior to acute exercise and endurance training on mitochondrial adaptation in mice.
  9. Fibre Type-Specific Proteomics Reveals Shared and Distinct Skeletal Muscle Adaptations to Resistance Training and Beta2-Adrenergic Agonist.
  10. Twisting Paths: The Paradox of Fiber Branching in Muscle Regeneration.
  11. Resistance Exercise Counteracts Skeletal Muscle Atrophy in T2DM Mice by Upregulating FGF21 and Activating PI3K/Akt Pathway.
  12. Bioinformatic Analysis of Differentially Expressed Long Non-Coding RNAs in Skeletal Muscle Following Aerobic and Resistance Exercise.
  13. Reframing fibrosis as a barrier to regeneration and gene delivery in muscular diseases.
  14. Adamts5 deletion exacerbates inflammation and fibrosis resulting in compromised skeletal muscle regeneration.
  15. Myostatin in Obesity: A Molecular Link Between Metabolic Dysfunction and Musculotendinous Remodeling.
  16. EIF4A3-Induced Circular RNA circSnd1 Promotes Muscle Atrophy and Muscle Ageing by Stabilizing EEF1A1.
  17. Aberrant skeletal muscle morphogenesis and myofiber differentiation characterize equine myotonic dystrophy.
  18. Oculopharyngeal muscular dystrophy (OPMD) associated alanine expansion impairs the function of the nuclear polyadenosine RNA binding protein PABPN1 as revealed by proximity labeling and comparative proteomics.
  19. Selenoprotein N and SEPN1-Related Myopathies: Mechanisms, Models, and Therapeutic Perspectives.
  20. Muscle stem cells trade functionality for survival.
  21. Intricacies of PKB/Akt Activity after Sciatic Nerve Damage: A Comprehensive Review.
  22. Biallelic PAX7 variants cause a novel Satellite Cell-opathy with progressive muscle involvement resembling facioscapulohumeral muscular dystrophy.
  23. RGMa Nuclear Localization in Skeletal Muscle Cells Reveals a Novel Role in Cell Viability and Proliferation.
  24. Mitochondria transfer from myocytes to endothelial cells Promotes angiogenesis in skeletal muscle.
  25. Intramuscular collagen accumulation in different types of skeletal muscle fibers in middle-aged male rats.
  26. Automated Classification of Store-Operated Calcium Entry Activity and Disease Conditions in Murine Skeletal Muscle Images Using Machine Learning.
  27. Peptide OH-CATH30 Mitigates Cachexia-Induced Muscle Atrophy via Modulation of TLR4-Associated Inflammation.
  28. Impaired stem cell migration and divisions in Duchenne muscular dystrophy revealed by live imaging.
  29. Mitocytosis, mitophagy, and apoptosis coordinately drive mitochondrial clearance to regulate myogenic differentiation.
  30. Opposing effects of Gα12 and Gα13 loss on myotube size regulation via mTORC1 signaling.
  31. Enhancement of Hypoxia-Induced Autophagy via the HIF-1apha/BNIP3 Pathway Promotes Proliferation and Myogenic Differentiation of Aged Skeletal Muscle Satellite Cells.
  32. Hypobaric Hypoxia Ameliorates Impaired Regeneration After Diabetic Skeletal Muscle Injury by Promoting HIF-1α Signaling.
  33. Single-Cell Sequencing Reveals the Crosstalk Between MuSCs and FAPs in Ruminant Skeletal Muscle Development.
  34. Annexin A2 Causes Motor Incoordination via Muscle-Cerebellum Axis in Sarcopenia.
  35. Bridging skeletal stem cell diversity and human skeletal modeling.
  36. Leucine supplementation does not attenuate the decline in daily muscle protein synthesis rates or preserve leg muscle mass during leg immobilization in young or older adults: a double-blind randomized trial.
  37. Integrative Machine Learning and Network Analysis of Skeletal Muscle Transcriptomes Identifies Candidate Pioglitazone-Responsive Biomarkers in Polycystic Ovary Syndrome.
  38. Blood-flow restriction resistance training improves skeletal muscle mitochondrial capacity and cardiovascular risk factors in type 2 diabetes.
  39. An integrated drug repositioning analysis identifies rosiglitazone as a treatment for sarcopenia.
  40. How much exercise do you really need?
  41. The surprisingly big health benefits of just a little exercise.
  42. Muscle RING finger-1 facilitates skeletal muscle regeneration via regulating myoblast proliferation and differentiation.
  43. The Lactate Nexus: A Molecular Bridge Linking Physical Activity, Sleep, and Cognitive Enhancement.
  44. Gne-Depletion in C2C12 Myoblasts Leads to Alterations in Glycosylation and Myopathogene Expression.
  45. Direct Effects of Capsaicin on Voltage-Dependent Calcium Channels of Mammalian Skeletal Muscle.
  46. The Promise and Pitfalls of AAV-Mediated Gene Therapy for Duchenne Muscular Dystrophy.
  47. Genetic depletion of the early autophagy protein ATG13 impairs mitochondrial energy metabolism, augments oxidative stress, induces the polarization of macrophages to the M1 inflammatory mode, and compromises myelin integrity in skeletal muscle.
  48. The role of artificial intelligence in sarcopenia: Advances, applications, and future directions.
  1. Biogerontology. 2026 Jan 30. 27(1): 43
    The role of circular RNAs in mediating the protective effects of exercise against muscle degeneration and aging.
    Bo Li, Ling Chen, Yiping Su, Junyan Meng, Zhanguo Su.
      A newly identified specific category of non-coding RNA (ncRNA), circRNAs, is drawing interest for their role in controlling several biological processes including muscle regeneration, aging, and adaptation to physical activity. Unlike linear RNAs, circRNAs are very stable and can have long-lasting regulatory impact since they create a covalently closed loop structure. Emerging evidence indicates that circRNAs play a pivotal role in skeletal muscle biology by regulating myogenesis, satellite cell activation, protein synthesis, and cellular senescence-processes significantly influenced by aging. These molecules are crucial for muscle function and regeneration, acting as microRNA sponges, interacting with RNA-binding proteins, and modulating gene expression and translation. Exercise-especially resistance and endurance training-has been shown to change circRNA expression in skeletal muscle, therefore possibly reducing age-related muscle loss and improving regenerative capacity. Though encouraging, much of the circRNA in muscle biology research is still in its early stages, with few functional studies and varying outcomes across various species and exercise models. Moreover, the exact ways circRNAs affect muscular adaptation to exercise and stop aging-related degeneration are still not completely known. This review addresses the existing knowledge gaps regarding the potential therapeutic applications of circRNAs in combating muscle degeneration and sarcopenia, as well as their role in muscle health and aging.
    Keywords:  Aging; CircRNA; Exercise; Muscle
    DOI:  https://doi.org/10.1007/s10522-026-10390-8
  2. Elife. 2026 Jan 29. pii: RP103550. [Epub ahead of print]14
    Branched actin polymerization drives invasive protrusion formation to promote myoblast fusion during mouse skeletal muscle regeneration.
    Yue Lu, Tezin Walji, Pratima Pandey, Chuanli Zhou, Christa W Habela, Scott B Snapper, Rong Li, Elizabeth H Chen.
      Skeletal muscle regeneration is a multistep process involving the activation, proliferation, differentiation, and fusion of muscle stem cells, known as satellite cells. Fusion of satellite cell-derived myoblasts (SCMs) is indispensable for generating the multinucleated, contractile myofibers during muscle repair. However, the molecular and cellular mechanisms underlying SCM fusion during muscle regeneration remain incompletely understood. Here, we reveal a critical role for branched actin polymerization in SCM fusion during mouse skeletal muscle regeneration. Using conditional knockouts of the Arp2/3 complex and its actin nucleation-promoting factors N-WASP and WAVE, we demonstrate that branched actin polymerization is specifically required for SCM fusion but dispensable for satellite cell proliferation, differentiation, and migration. We show that the N-WASP and WAVE complexes have partially redundant functions in regulating SCM fusion and that branched actin polymerization is essential for generating invasive protrusions at fusogenic synapses in SCMs. Together, our study identifies branched-actin regulators as key components of the myoblast fusion machinery and establishes invasive protrusion formation as a critical mechanism enabling myoblast fusion during skeletal muscle regeneration.
    Keywords:  Arp2/3 complex; branched actin polymerization; developmental biology; invasive protrusions; mouse; myoblast fusion; regenerative medicine; satellite cells; skeletal muscle regeneration; stem cells
    DOI:  https://doi.org/10.7554/eLife.103550
  3. JCI Insight. 2026 Jan 27. pii: e200396. [Epub ahead of print]
    Fiber-type vulnerability and proteostasis reprogramming in skeletal muscle during pancreatic cancer cachexia.
    Bowen Xu, Aniket S Joshi, Meiricris Tomaz da Silva, Silin Liu, Ashok Kumar.
      Cachexia is a debilitating syndrome characterized by progressive skeletal muscle wasting, commonly affecting cancer patients, particularly those with pancreatic cancer. Despite its clinical significance, the molecular mechanisms underlying cancer cachexia remain poorly understood. In this study, we utilized single-nucleus RNA sequencing (snRNA-seq) and bulk RNA-seq, complemented by biochemical and histological analyses, to investigate molecular alterations in the skeletal muscle of the KPC mouse model of pancreatic cancer cachexia. Our findings demonstrated that KPC tumor growth induced myofiber-specific changes in the expression of genes involved in proteolytic pathways, mitochondrial biogenesis, and angiogenesis. Notably, tumor progression enhanced the activity of specific transcription factors that regulate the mTORC1 signaling pathway, along with genes involved in translational initiation and ribosome biogenesis. Skeletal muscle-specific, inducible inhibition of mTORC1 activity further exacerbated muscle loss in tumor-bearing mice, highlighting its protective role in maintaining muscle mass. Additionally, we uncovered new intercellular signaling networks within the skeletal muscle microenvironment during pancreatic cancer-induced cachexia. Together, our study revealed previously unrecognized molecular mechanisms that regulates skeletal muscle homeostasis and identified potential therapeutic targets for the treatment of pancreatic cancer-associated cachexia.
    Keywords:  Cancer; Cell biology; Expression profiling; Muscle; Muscle biology
    DOI:  https://doi.org/10.1172/jci.insight.200396
  4. Cell Regen. 2026 Jan 25. 15(1): 8
    MRG15 decline in aged/injured MuSCs hinders regeneration via differentiation defects.
    Zhuoyang Li, Mei Ma, Siyi Shen, Ruisen Ma, Wenqing Kong, Yuting Wu, Qiurong Ding, Hao Ying, Yuying Li.
      Skeletal muscle aging is characterized by a functional decline in muscle stem cells (MuSCs), yet the key regulatory mechanisms driving this deterioration remain poorly understood. By integrating transcriptomic profiles from aged MuSCs with data from C2C12 cells exposed to spaceflight conditions (which mimic an aging-like phenotype), we identified MORF4-related gene on chromosome 15 (MRG15) as a putative epigenetic regulator involved in age-related myogenic decline. Using a MuSC-specific inducible knockout (iKO) mouse model, we found that loss of MRG15 severely compromises myogenic differentiation and muscle regeneration. Subsequent RNA sequencing of iKO MuSCs, combined with ChIP-seq analysis of histone modifications, revealed that MRG15 modulates the chromatin landscape of myogenic genes through interaction with MyoD, thereby facilitating transcriptional activation and differentiation. Our findings establish MRG15 as a critical epigenetic regulator that cooperates with MyoD to orchestrate chromatin remodeling, thereby promoting transcriptional activation of the myogenic program. Dysregulation of MRG15 may underlie impaired muscle regeneration during aging.
    Keywords:  Aging; Differentiation; MRG15; Muscle stem cell; Skeletal muscle regeneration
    DOI:  https://doi.org/10.1186/s13619-026-00279-9
  5. Antioxidants (Basel). 2025 Dec 26. pii: 38. [Epub ahead of print]15(1):
    Inhibition of TRPC3-Nox2 Complex Formation Ameliorates Skeletal Muscle Atrophy.
    Yuri Kato, Di Wu, Tomoya Ito, Yara Atef, Koichi Ayukawa, Xinya Mi, Kazuhiro Nishiyama, Akiyuki Nishimura, Motohiro Nishida.
      Skeletal muscle atrophy underlies sarcopenia, frailty, and muscular dystrophies, but the molecular mechanisms linking oxidative stress to muscle degeneration remain incompletely understood. We previously identified protein complex formation between transient receptor potential canonical 3 (TRPC3) and NADPH oxidase 2 (Nox2) as a key driver of anthracycline-induced myocardial atrophy. Here, we investigated whether this complex also contributes to skeletal muscle wasting. In skeletal muscle from sciatic nerve transection model mice and Duchenne muscular dystrophy (mdx) mice, TRPC3-Nox2 complex formation was enhanced. TRPC3 deletion significantly attenuated denervation-induced soleus atrophy and reduced reactive oxygen species (ROS) production. TRPC3-Nox2 complex formation was upregulated in the soleus muscle (SM) of mdx mice. Pharmacological disruption of the TRPC3-Nox2 interaction improved muscle size and strength and reduced plasma creatine kinase in mdx mice. A recombinant adeno-associated virus (AAV) encoding a TRPC3 C-terminal peptide was used to suppress TRPC3-Nox2 complex formation in vivo. AAV-mediated expression of TRPC3 C-terminal peptide mitigated muscle wasting (CSA) in mdx mice, while muscle strength and plasma CK were not significantly improved. Thus, TRPC3-Nox2 complex formation may be a pivotal driver of oxidative stress-mediated skeletal muscle atrophy. Targeting this protein-protein interaction represents a promising therapeutic strategy for Duchenne muscular dystrophy (DMD) and other intractable muscle-wasting disorders.
    Keywords:  Nox2; TRPC3; protein–protein interaction; skeletal muscle atrophy
    DOI:  https://doi.org/10.3390/antiox15010038
  6. Autophagy. 2026 Jan 28.
    Mitophagic activity and protein levels differ across and within muscles: implications for future skeletal muscle mitophagy research.
    Fasih A Rahman, Mackenzie Q Graham, Joe Quadrilatero.
      Skeletal muscle is a heterogeneous tissue consisting of fibers with distinct contractile speeds, metabolic profiles, and cellular signaling. This heterogeneity may extend to mitochondrial quality control processes such as mitophagy. Using mt-Keima mice, we found that mitophagic activity was greater in the fast-twitch, glycolytic extensor digitorum longus (EDL) compared to the slow-twitch, oxidative soleus (SOL) muscle. Live imaging of quadriceps (QUAD) muscle revealed two distinct fiber populations: those with high total mt-Keima signal but low mitophagic activity, and others with low signal but higher mitophagic activity. Additionally, we observed skeletal muscle type and regional differences in autophagic and mitophagic protein content. Further, select mitophagic proteins strongly correlated with mitochondrial proteins across different regions of the gastrocnemius, while others did not. These findings highlight the complexity of mitophagy regulation in skeletal muscle and emphasize the importance of considering muscle phenotype, including fiber type, region, and mitochondrial content when studying mitophagy.
    Keywords:  Fibers; metabolism; mitochondria; mitophagy; skeletal muscle
    DOI:  https://doi.org/10.1080/15548627.2026.2623988
  7. Science. 2026 Jan 29. 391(6784): 517-521
    Cellular survivorship bias as a mechanistic driver of muscle stem cell aging.
    Jengmin Kang, Daniel I Benjamin, Qiqi Guo, Chauncey Evangelista, Soochi Kim, Marina Arjona, Pieter Both, Mingyu Chung, Ananya K Krishnan, Gurkamal Dhaliwal, Richard Lam, Thomas A Rando.
      Aging is characterized by a decline in the ability of tissue repair and regeneration after injury. In skeletal muscle, this decline is largely driven by impaired function of muscle stem cells (MuSCs) to efficiently contribute to muscle regeneration. We uncovered a cause of this aging-associated dysfunction: a cellular survivorship bias that prioritizes stem cell persistence at the expense of functionality. With age, MuSCs increased expression of a tumor suppressor, N-myc down-regulated gene 1 (NDRG1), which, by suppressing the mammalian target of rapamycin (mTOR) pathway, increased their long-term survival potential but at the cost of their ability to promptly activate and contribute to muscle regeneration. This delayed muscle regeneration with age may result from a trade-off that favors long-term stem cell survival over immediate regenerative capacity.
    DOI:  https://doi.org/10.1126/science.ads9175
  8. J Physiol Sci. 2026 Jan 23. pii: S1880-6546(26)00005-3. [Epub ahead of print]76(1): 100059
    Effects of local skeletal muscle cooling prior to acute exercise and endurance training on mitochondrial adaptation in mice.
    Ryotaro Kano, Tatsuya Kusano, Taichi Ando, Reo Takeda, Ryui Natsuyama, Ryo Takagi, David C Poole, Yutaka Kano, Daisuke Hoshino.
      While post-exercise cooling is known to enhance skeletal muscle adaptations, the effects of pre-exercise cooling remain unclear. This study investigated whether local muscle cooling immediately before exercise augments training-induced mitochondrial biogenesis in male C57BL/6 mice. Pre-exercise cooling involved 6 cycles of 6 min at 13°C followed by 4 min at 35°C on one hindlimb for 60 min before treadmill running. Acutely, this pre-cooling protocol increased exercise-induced PGC-1α mRNA expression by ∼13 % (p < 0.05) compared to exercise alone; this effect was abolished when cooling and exercise were separated by 3 h. Chronically, over 4 weeks, combined pre-cooling and exercise training significantly enhanced mitochondrial enzyme activities: citrate synthase (both main effects) and β-hydroxyacyl-CoA dehydrogenase (+23.9 % compared with exercise alone). However, mitochondrial structural protein levels remained unchanged. These results indicate that pre-exercise cooling promotes mitochondrial enzymatic adaptations in skeletal muscle, potentially offering a practical strategy to optimize the outcomes of endurance training.
    Keywords:  Endurance training; Mitochondrial biogenesis; PGC-1α; Pre-exercise cooling
    DOI:  https://doi.org/10.1016/j.jphyss.2026.100059
  9. J Cachexia Sarcopenia Muscle. 2026 Feb;17(1): e70175
    Fibre Type-Specific Proteomics Reveals Shared and Distinct Skeletal Muscle Adaptations to Resistance Training and Beta2-Adrenergic Agonist.
    Søren Jessen, Andrea Di Credico, Roger Moreno-Justicia, Lukas Moesgaard, Anders Lemminger, Ben Stocks, Angela Di Baldassarre, Jens Bangsbo, Atul S Deshmukh, Morten Hostrup.
       BACKGROUND: Skeletal muscle is essential for metabolic health and physical function. While resistance training promotes muscle hypertrophy, alternative therapeutic strategies are needed for individuals unable to engage in physical activity. Because beta2-adrenergic stimulation induces muscle growth without mechanical load, we assessed muscle fibre type-specific proteomic adaptations to prolonged beta2-adrenergic stimulation and resistance training to decipher shared and distinct remodelling patterns.
    METHODS: We collected vastus lateralis biopsies from 21 moderately trained young males (mean ± SD, age: 24 ± 3) before and after 4-week whole-body resistance training (three sessions/week) or daily inhalation of beta2-adrenergic agonist terbutaline (4 mg/day). From each biopsy, we isolated 40 muscle fibres and typified them using myosin-heavy-chain markers. Fibre pools were analysed using LC-MS/MS-based proteomics.
    RESULTS: Beta2-adrenergic stimulation and resistance training both increased peak-power output during bike-ergometer sprinting (+36 W; 95% CI: 11 to 61, p = 0.007 and +27 W; 95% CI: -1 to 56, p = 0.062, respectively) with no between-treatments differences (treatment × time interaction: p = 0.644). Beta2-adrenergic stimulation regulated 15 and 23 proteins in Type I and Type II fibres, respectively, compared to 101 and 65 with resistance training. There was a remarkable fibre type-dependent response, with ~7% of regulated proteins shared between Type I and Type II fibres with resistance training and ~3% with beta2-adrenergic stimulation. Both interventions increased abundance of ribosomal proteins, in which resistance training induced a 25% increase in Type I fibres (p < 0.001) but only 3% in Type II (p = 0.374), while beta2-adrenergic stimulation increased ribosomal proteins in both fibre types (Type I: 6% increase, p = 0.008; Type II: 9% increase, p < 0.001). Mitochondrial electron-transport-chain protein abundances decreased with both interventions: resistance training reduced abundances mainly in Type I fibres (17% decrease, p < 0.001; Type II: 5% decrease, p = 0.147), while beta2-adrenergic stimulation caused uniform decreases (Type I: 7% decrease, p = 0.018; Type II: 9% decrease, p = 0.001). Resistance training uniquely increased contractile, cytoskeletal and extracellular matrix proteins, which was not mimicked by beta2-adrenergic stimulation. S100A13 was upregulated across both interventions and fibre types, whereas MUSTN1 was regulated exclusively with resistance training. Knock-down of S100a13 (-52%; p < 0.001) and Mustn1 (-96%; p < 0.001) in C2C12 myotubes impaired myotube formation (fusion index: S100a13: -5%; p = 0.002; Mustn1: -21%; p < 0.001).
    CONCLUSIONS: Beta2-adrenergic stimulation induces proteomic adaptations that partially mimic resistance training, particularly in ribosomal proteins. Shared regulation of S100A13 and unique regulation of MUSTN1 with resistance training suggest distinct and complementary roles in regulating muscle growth. These findings indicate that the beta2-adrenergic receptor is a potential target to counter muscle atrophic conditions, offering a pharmacological approach for individuals unable to engage in resistance training.
    Keywords:  beta2‐agonist; exercise mimetic; muscle growth; salbutamol
    DOI:  https://doi.org/10.1002/jcsm.70175
  10. Int J Mol Sci. 2026 Jan 09. pii: 684. [Epub ahead of print]27(2):
    Twisting Paths: The Paradox of Fiber Branching in Muscle Regeneration.
    Leonit Kiriaev, Kathryn N North, Stewart I Head, Peter J Houweling.
      Muscle regeneration following injury reveals a striking paradox: the same phenomenon, fiber branching, can serve as both a beneficial adaptation in healthy muscle and a pathological hallmark in disease. In healthy muscle, branched fibers emerge as an adaptive response to extreme mechanical loading, redistributing stress, enhancing hypertrophy, and protecting against injury. Conversely, in conditions such as Duchenne Muscular Dystrophy, excessive and complex branching contributes to mechanical weakness, increased susceptibility to damage, and progressive functional decline. This review explores the dichotomy of fiber branching in muscle physiology, synthesizing current research on its molecular and cellular mechanisms. By understanding the paradoxical nature of fiber branching, we aim to uncover new perspectives for therapeutic strategies that balance its adaptive and pathological roles to improve outcomes for muscle diseases.
    Keywords:  Duchenne muscular dystrophy; eccentric contractions; fiber branching; mdx mouse; muscle regeneration
    DOI:  https://doi.org/10.3390/ijms27020684
  11. Biomolecules. 2025 Dec 19. pii: 3. [Epub ahead of print]16(1):
    Resistance Exercise Counteracts Skeletal Muscle Atrophy in T2DM Mice by Upregulating FGF21 and Activating PI3K/Akt Pathway.
    Xiaojie Ma, Zhijian Rao, Zhihai Jin, Yibing Lu, Zhitong Sun, Lifang Zheng.
      Decreased skeletal muscle mass and function are a serious complication of long-term diabetes, often leading to numerous adverse outcomes. The primary pathological features of diabetic sarcopenia include muscle fiber atrophy and interstitial fibrosis. Although resistance exercise (RE) has been reported to mitigate skeletal muscle atrophy in type 2 diabetes mellitus (T2DM), the underlying mechanisms remain unclear. Fibroblast growth factor 21 (FGF21), an exercise-induced cytokine, has been shown to protect against skeletal muscle atrophy at elevated levels. In this study, a T2DM mouse model was established through 12 weeks of high-fat diet feeding and intraperitoneal injection of streptozotocin (STZ) to investigate the effect and mechanism of RE on skeletal muscle atrophy in T2DM mice. Our results demonstrated that 8 weeks of RE significantly decreased body weight, fat mass, triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), fasting blood glucose (FBG), and serum insulin levels in T2DM mice. RE also improved lean mass, glucose tolerance (IPGTT), and insulin tolerance (ITT). Additionally, RE increased skeletal muscle mass cross-sectional area (CSA) while attenuating fibrosis and inflammatory responses in skeletal muscle. Notably, RE upregulated FGF21 expression and activated the PI3K/Akt signaling pathway in diabetic skeletal muscle. RE promoted the phosphorylation of mTOR, 4EBP1, and p70S6K while suppressing the expression of the atrophy-related E3 ubiquitin ligases MuRF1 and MAFbx/Atrogin-1. Furthermore, RE inhibited lipid synthesis and enhanced both lipid oxidation and glucose utilization in skeletal muscle of T2DM mice. RE also improved mitochondrial biogenesis and dynamics in skeletal muscle of T2DM mice. In summary, 8 weeks of RE alleviated skeletal muscle atrophy in T2DM mice via activation of the FGF21/PI3K/Akt signaling pathway, which enhanced protein synthesis, improved glycolipid metabolism and mitochondrial quality control, and attenuated fibrosis and inflammation.
    Keywords:  fibroblast growth factor 21; fibrosis; resistance exercise; skeletal muscle atrophy; type 2 diabetes mellitus
    DOI:  https://doi.org/10.3390/biom16010003
  12. Genes (Basel). 2026 Jan 20. pii: 110. [Epub ahead of print]17(1):
    Bioinformatic Analysis of Differentially Expressed Long Non-Coding RNAs in Skeletal Muscle Following Aerobic and Resistance Exercise.
    Kassia Régnier, Lucas P R Beaupre, Ian F Coccimiglio, Taylor J McColl, David C Clarke, Brendon J Gurd.
      Background/Objectives: Emerging evidence suggests that long non-coding RNA (lncRNA) molecules influence the adaptive response to exercise, but how lncRNA responses differ between endurance and resistance exercise (RE) modalities is poorly understood. The purpose of this study was to bioinformatically infer the expression of lncRNA in skeletal muscle following acute aerobic exercise (AE) and RE. Methods: We downloaded publicly available RNA-seq data, performed a differential expression (DE) analysis, and compared lncRNA expression profiles between different exercise types (AE vs. RE) at three timepoints: baseline, 1 h post-exercise, and 4 h post-exercise. Results: We observed distinct lncRNA profiles between acute AE and RE at different timepoints, suggesting that lncRNA perform distinct roles in controlling the response to different exercise modalities in skeletal muscle. Conclusions: Future studies should investigate the specific roles of these lncRNAs in the response to acute exercise in skeletal muscle.
    Keywords:  exercise; long non-coding RNA; skeletal muscle
    DOI:  https://doi.org/10.3390/genes17010110
  13. FEBS J. 2026 Jan 29.
    Reframing fibrosis as a barrier to regeneration and gene delivery in muscular diseases.
    Hasan Basri Kiliç, Y Çetin Kocaefe.
      Gene replacement therapies for muscular dystrophies show promise in preclinical models but often fail in clinical settings. A major difference between animal models and human pathology is the extent of fibrosis observed. Progressive and irreversible fibrosis needs to be targeted before or alongside genetic strategies. Fibrosis limits muscle function through a collagen-rich extracellular matrix (ECM) that forms a stiff barrier impeding penetration of gene therapy vectors, such as adeno-associated viruses (AAVs). It disrupts the satellite cell niche, compromising activation, proliferation, and differentiation. Even with successful gene delivery, regeneration in fibrotic muscle is severely impaired. Recent reports of acute liver toxicity leading to deaths in gene therapy trials using the AAVrh74 vector underscore the risks associated with high systemic AAV doses. If fibrosis can be alleviated, effective transduction might be achieved with lower vector quantities in a single therapeutic dose, reducing the systemic risks. Anti-fibrotic agents are being explored to counteract disease progression. Modulators of ECM maturation offer novel therapeutic targets. However, pleiotropic and context-dependent roles of these mediators complicate translation. Therapies must target pathological ECM remodeling without disrupting essential physiology elsewhere. In this Review, we examine therapeutic efforts targeting skeletal muscle dystrophies and emphasize fibrosis as a major barrier to gene and regenerative therapies. We highlight the need for a deeper investigation into fibrotic pathways, modulators, and extracellular maturation processes and propose that these underexplored areas may yield novel therapeutic targets for muscular dystrophies. A fibrosis-aware therapeutic framework that integrates insights across systems and pathologies is critical for improving treatment outcomes in skeletal muscle disorders.
    Keywords:  Duchenne Muscular Dystrophy (DMD); adeno‐associated virus (AAV); fibrosis; gene therapy; transforming growth factor‐beta (TGF‐β)
    DOI:  https://doi.org/10.1111/febs.70427
  14. Am J Physiol Cell Physiol. 2026 Jan 28.
    Adamts5 deletion exacerbates inflammation and fibrosis resulting in compromised skeletal muscle regeneration.
    John Dulos, Richard Sun, Valentina Jovanovska, Fabrice Kolb, Nicole Stupka.
      The extracellular matrix (ECM) protease Adamts5 and its ECM substrates are critical regulators of inflammation and fibrosis; whether Adamts5 also regulates muscle regeneration is not known. Right tibialis anterior (TA) muscles from adult Adamts5--/- mice or wild type mice were injected with glycerol to induce injury. In uninjured muscles and at 7- and 14-days post injury, TA contractile function was determined in situ, followed by an assessment of pathology using histology and immunohistochemistry. Immunoblotting was performed for the versikine fragment which is generated when Adamts5 cleaves its substrate versican. Versikine protein, which correlates with Adamts5 proteolytic activity, was lower in uninjured and injured TA muscles from Adamts5-/- mice versus wild type mice. In uninjured TA muscles, Adamts5 deletion of the catalytic and ancillary domains decreased the absolute (Po) and normalized to muscle size (sPo) force output, with no significant effect on muscle mass and myofiber size. Adamts5 deletion compromised regeneration with greater impairment evident at the later timepoint. Force output (Po and sPo) was lower in Adamts5-/- mice at 7- and 14-days post injury. TA mass and myofiber size were only decreased at 14-days post injury, while embryonic myosin heavy chain expression did not significantly differ between genotypes. Degeneration, mononuclear infiltrates, and ECM deposition including fibronectin protein were greater in injured TA muscles from Adamts5-/- mice. Resolution of inflammation was also delayed in Adamts5-/- mice, with more infiltrating macrophages observed at 14-days post injury. In conclusion, Adamts5 regulates the balance between muscle regeneration, fibrosis, and inflammation following glycerol injury.
    Keywords:  Adamts5; fibrosis; macrophage; regenerative myogenesis; versikine
    DOI:  https://doi.org/10.1152/ajpcell.00443.2025
  15. Int J Mol Sci. 2026 Jan 18. pii: 967. [Epub ahead of print]27(2):
    Myostatin in Obesity: A Molecular Link Between Metabolic Dysfunction and Musculotendinous Remodeling.
    Leonardo Cesanelli, Petras Minderis, Andrej Fokin, Aivaras Ratkevicius, Danguole Satkunskiene, Hans Degens.
      Obesity is increasingly recognized not only as a metabolic disorder but also as a condition marked by the structural and functional deterioration of skeletal muscle and tendon tissues. Central to this process is the dysregulation of the extracellular matrix (ECM) resulting in fibrosis and ectopic fat accumulation, factors that contribute to impaired tissue mechanics. Myostatin (GDF-8), a member of the TGF-β superfamily, is known as a negative regulator of muscle mass. It can also mediate interaction between adipose and other tissues including muscles and tendons. In obesity, elevated myostatin levels have been reported to be associated with insulin resistance, muscle atrophy, and activation of SMAD2/3 signaling, while experimental and preclinical studies indicate that myostatin inhibition can improve glucose homeostasis and increase lean mass. Emerging evidence suggests that myostatin also plays a critical role in muscle ECM and tendon remodeling. Restoring its physiological levels may help reverse ECM disorganization and reduce tissue fragility associated with musculotendinous dysfunction. This review highlights the multifaceted role of myostatin in obesity, beyond its role in muscle catabolism, to include modulation of structural integrity, metabolism, and mechanical adaptability of the musculotendinous system. Understanding how myostatin responds to metabolic stress and affects biomechanical remodeling offers novel insights into obesity-related muscle and tendon dysfunction.
    Keywords:  ECM; SMAD signaling; fibrosis; mechanotransduction; myostatin; obesity; skeletal muscle; tendon
    DOI:  https://doi.org/10.3390/ijms27020967
  16. J Cachexia Sarcopenia Muscle. 2026 Feb;17(1): e70210
    EIF4A3-Induced Circular RNA circSnd1 Promotes Muscle Atrophy and Muscle Ageing by Stabilizing EEF1A1.
    Jin Li, Bing Jin, Yuwei Yan, Yuying Chen, Xiaohang Yin, Xinyi Ren, Qian Li, Jingying Chen, Siqi Wang, Tingting Yang, Yanan Zhang, Qiumeng Nie, Dongchao Lu, Ming Wu, Yan Yu, Lei Chen, Tarun Keswani, Guoping Li, Dragos Cretoiu, T Scott Bowen, Junjie Xiao, Yongjun Zheng.
       BACKGROUND: Muscle atrophy is a common complication of ageing, and many chronic conditions, lacks defined therapeutic interventions. It is still mostly unknown how circular RNAs contribute to muscle atrophy.
    METHODS: circRNA sequencing and quantitative real-time PCR were performed to detect the changed circRNAs in muscle atrophy models and aged muscle. Then the gain-of-function and loss-of-function experiments were used to investigate the function of circSnd1 in muscle atrophy and muscle ageing. Furthermore, we used RIP-MS and RIP assay to determine the downstream and upstream mechanism of circSnd1 in muscle atrophy.
    RESULTS: Here, we characterized the function and mechanism of highly species-conserved circRNA derived from staphylococcal nuclease and Tudor domain containing 1 gene (named circSnd1) in muscle atrophy. CircSnd1 is upregulated in many types of muscle atrophy models in both in vivo and in vitro (all p < 0.01). Meanwhile, circSnd1 is also higher expressed in aged muscle in humans (+2.2-fold, n = 5, p < 0.05), mice (+43.96%, n = 6, p < 0.05) and myotubes (+42.21%, n = 6, p < 0.05). Functional analyses show that circSnd1 promotes muscle atrophy and muscle ageing at the cellular level and mouse level while repressing it ameliorates multiple types of muscle atrophy (all p < 0.05). Mechanistically, the RNA binding protein eukaryotic translation initiation factor 4A3 (EIF4A3) can bind to the intron flanking sequence of circSnd1 to induce circSnd1 cyclization and increase circSnd1 expression in muscle atrophy. In addition, circSnd1 promotes the binding between human HLA-F adjacent transcript 10 (FAT10) and eukaryotic translation elongation factor 1 alpha 1 (EEF1A1). FAT10 competes with ubiquitin for binding with EEF1A1, which decreases the ubiquitination of EEF1A1 and stabilizes the protein level of EEF1A1 in muscle cells to promote atrophy.
    CONCLUSIONS: We have identified circSnd1 as a novel circRNA that promotes muscle atrophy and highlighted its potential as a novel therapeutic target.
    Keywords:  EEF1A1 ubiquitination; EIF4A3; FAT10; circSnd1; muscle ageing; muscle atrophy
    DOI:  https://doi.org/10.1002/jcsm.70210
  17. PLoS One. 2026 ;21(1): e0341655
    Aberrant skeletal muscle morphogenesis and myofiber differentiation characterize equine myotonic dystrophy.
    Stephanie J Valberg, Zoë J Williams, Elizabeth G Ames, James R Mickelson, Yvette S Nout-Lomas, Gabriele Landolt, Macarena Sanz, Keri Gardner.
      Equine myotonic dystrophy (eMD) is a rare neuromuscular disorder of undetermined origin marked by muscle hypertrophy and stiffness, dystrophic muscle histopathology, and myotonic discharges. In humans, myotonic dystrophy (DM) arises from trinucleotide repeat expansions in dystrophia myotonica protein kinase (DMPK) (DM1) or tetranucleotide expansions in cellular nucleic acid-binding protein (CNBP) (DM2), which disrupt mRNA processing and induce embryonic splicing patterns across multiple genes. In 6 eMD Quarter Horse types, (2-36 months-of-age) and 8 control Quarter Horses we determined: (1) fiber type composition of triceps, gluteal, and semimembranosus muscles; (2) differential gene (DEG) and protein (DEP) expression using transcriptomic and proteomic analyses; (3) presence of repeat expansions in transcripts of DMPK or CNBP and (4) exon 7 retention in CLCN1 or exon 22 splicing in ATP2A1. Predominance and clustering of type 1 fibers, expression of embryonic myosin, and upregulated mitochondrial and sarcomeric DEPs characterized eMD hindlimb musculature. Gene ontology (GO) analysis of 730 upregulated DEGs identified numerous GO terms related to morphogenesis of mesoderm-derived tissues and upregulated genes impacting myoD expression in eMD muscle. Top upregulated DEG involved myogenesis (MYOZ2, SBK2, SBK3, PAMR1), neurons, transcription/translation, cytoskeleton, basement/plasma membranes, and calcium binding/transport. Top upregulated proteins also impacted muscle morphogenesis (MUSTN1, CSRP3, TMSBX4, PDLIM, CALD1) as well as categories of mitochondria, sarcomere, extracellular matrix/ basement membrane, transcription, translation, cell cycle regulation, neurons amongst others. Downregulated DEP primarily impacted mitochondria, the sarcomere and glycogen metabolism. Notably, unlike human myotonic dystrophy, trinucleotide repeat expansions were not found in the DMPK 3'UTR (CTG)n nor tetranucleotide repeat expansions (CCTG)n in intron 1 of CNBP. Isoforms of CLCN1 containing fetal exon 7 were detected in equal frequency in eMD and control muscle and exon 22 was not alternatively spliced in ATP2A1 as has been found in DM1. Thus, distinct from DM1 and DM2, eMD is driven by unique molecular mechanisms impacting skeletal muscle morphogenesis, neurons and regulation of gene transcription/translation that alter fiber type composition, distribution and morphology. The origin of myotonia does not appear to be driven by a mutation in CLCN1 or retention of exon CLCN 7. Expanded splice site analysis and further research is warranted to elucidate the cause of myotonia and the distinct etiology of eMD.
    DOI:  https://doi.org/10.1371/journal.pone.0341655
  18. PLoS Genet. 2026 Jan 26. 22(1): e1011743
    Oculopharyngeal muscular dystrophy (OPMD) associated alanine expansion impairs the function of the nuclear polyadenosine RNA binding protein PABPN1 as revealed by proximity labeling and comparative proteomics.
    Allison T Mezzell, Yu Zhang, Alexandra M Perez, Katherine E Vest.
      Oculopharyngeal muscular dystrophy (OPMD) is a late-onset disease caused by modest alanine expansion at the amino terminus of the nuclear polyadenosine RNA binding protein PABPN1. PABPN1 is expressed ubiquitously and is involved in multiple steps in RNA processing including optimal cleavage and polyadenylation, polyadenylation signal selection, and export of polyadenylated RNAs from the nucleus. Expanded PABPN1 forms aggregates in a subset of muscle nuclei, but PABPN1 levels are paradoxically low in muscle compared to other tissues. Despite several studies in model systems and patient tissues, it remains unclear whether alanine expansion directly impairs PABPN1 function. The molecular mechanisms leading to OPMD pathology are poorly understood. Here we used a proximity labeling approach to better understand the effect of alanine expansion on PABPN1 function in a cell culture model of skeletal muscle. To avoid the confounding factor of overexpression, PABPN1 constructs containing a carboxy-terminal TurboID tag were expressed in skeletal myotubes at near native levels using an inducible promoter. Although non-expanded PABPN1-TurboID was able to complement RNA export and myoblast differentiation defects caused by deficiency of endogenous PABPN1, alanine expanded PABPN1-TurboID was not. Comparative proteomics revealed increased interaction between expanded PABPN1 and RNA splicing and polyadenylation machinery and follow-up studies identified a dominant negative effect of expanded PABPN1 on RNA export in differentiated myotubes. These data indicate that alanine expansion can impair PABPN1 function regardless of the presence of wild type PABPN1 and support a model wherein both loss function and dominant negative effects of expanded PABPN1 contribute to OPMD pathology.
    DOI:  https://doi.org/10.1371/journal.pgen.1011743
  19. Biomolecules. 2026 Jan 12. pii: 125. [Epub ahead of print]16(1):
    Selenoprotein N and SEPN1-Related Myopathies: Mechanisms, Models, and Therapeutic Perspectives.
    Martina Lanza, Ester Zito, Giorgia Dinoi, Antonio Vittorio Buono, Annamaria De Luca, Paola Imbrici, Antonella Liantonio, Elena Conte.
      Selenoprotein N (SelN or SELENON) is a selenium-containing protein of the endoplasmic/sarcoplasmic reticulum (ER/SR), encoded by the SEPN1 gene. In skeletal muscle, SelN is particularly important for regulating SR calcium homeostasis. It acts as a calcium sensor, modulating the activity of the sarcoplasmic reticulum calcium pump (SERCA) through a redox-dependent mechanism. Loss-of-function mutations in the SEPN1 gene give rise to a spectrum of skeletal muscle disorders collectively referred to as SEPN1-related myopathies (SEPN1-RM). Histopathologically, SEPN1-RM is characterized by the presence of minicores, which are localized regions within muscle fibers exhibiting mitochondrial depletion (i.e., cores) and sarcomeric disarray. As no effective therapy is currently available for SEPN1-RM, understanding SelN biology through loss-of-function models remains essential for elucidating disease mechanisms and identifying potential therapeutic targets. This review examines the current knowledge on SelN function and the pathological mechanisms underlying SEPN1 loss-of-function, with a particular focus on the connection between calcium handling, oxidative/ER stress, and muscle dysfunction. It also highlights emerging strategies aimed at restoring SelN activity or mitigating downstream defects, outlining potential therapeutic avenues for SEPN1-RM.
    Keywords:  ER stress; Selenoprotein N; myopathy; skeletal muscle
    DOI:  https://doi.org/10.3390/biom16010125
  20. Science. 2026 Jan 29. 391(6784): 444
    Muscle stem cells trade functionality for survival.
    Julia von Maltzahn.
      During aging, stem cell persistence is favored over functionality, resulting in delayed responses to injury.
    DOI:  https://doi.org/10.1126/science.aed3298
  21. Curr Protein Pept Sci. 2026 Jan 15.
    Intricacies of PKB/Akt Activity after Sciatic Nerve Damage: A Comprehensive Review.
    Rajesh Dabur.
      Sciatic nerve injury represents a prevalent and incapacitating condition characterized by denervation, muscular atrophy, and compromised functionality. The Protein Kinase B (PKB)/ Akt signaling cascade serves as a vital modulator of skeletal muscle hypertrophy, metabolic processes, and regenerative capabilities. Subsequent to sciatic nerve injury, the PI3K/Akt signaling pathway exhibits dysregulation, exacerbating muscle atrophy and hindering recovery processes due to feedback inhibition of PKB/Akt phosphorylation by mTORC1, which consequently increases the expression of E3 ubiquitin ligases and causes muscle atrophy. Additionally, a multitude of other variables, encompassing neurotrophic factors, intracellular calcium ion concentrations, carboxyl-terminal modulator proteins, connexins, and tumor necrosis factor-α, either exert regulatory influences on Akt or are subject to regulation by Akt in a multifaceted manner. Hence, this review discusses the complex role of the PI3K/Akt signaling pathway in skeletal muscle dynamics following sciatic nerve injury, emphasizing its regulatory mechanisms and downstream effectors, and highlights strategies to target this pathway to enhance muscle regeneration and restore functional capabilities.
    Keywords:  Brain-derived neurotrophic factor; TNFα.; carboxyl-terminal modulator protein; mTORC1; protein kinase B; skeletal muscle atrophy
    DOI:  https://doi.org/10.2174/0113892037393362251027073929
  22. Cell Death Dis. 2026 Jan 29.
    Biallelic PAX7 variants cause a novel Satellite Cell-opathy with progressive muscle involvement resembling facioscapulohumeral muscular dystrophy.
    Massimo Ganassi, Claudia Strafella, Marco Savarese, Philipp Heher, Elise N Engquist, Liam McGuire, Mridul Johari, Gian F De Nicola, Anne Bigot, Vincent Mouly, Sara Bortolani, Eleonora Torchia, Mauro Monforte, Domenica Megalizzi, Andrea Sabino, Enzo Ricci, Emiliano Giardina, Peter S Zammit, Giorgio Tasca.
      Inherited myopathies are genetic disorders characterised by declining motor function due to progressive muscle weakening and wasting. Recently, pathogenic variants in PAX7, the master transcriptional regulator of muscle stem cells, have been associated with myopathies of variable severity, arguing for impaired satellite cell function as the main pathogenic driver. Here, we report the characterisation of two missense PAX7 variants in a patient with asymmetric, progressive muscle weakness affecting facial, upper and lower body muscles, and myopathic changes on muscle pathology. Despite this disorder closely phenocopying the clinical presentation of Facioscapulohumeral muscular dystrophy (FSHD), genetic, epigenetic and transcriptomic profiling indicated that FSHD was unlikely. However, exome sequencing revealed two heterozygous variants in PAX7: c.335 C > T, (p.Pro112Leu) and c.1328 G > A (p.Cys443Tyr). Modelling these PAX7 variants in human myoblasts resembled the transcriptomic findings found in the muscle biopsy from the patient. Specifically, these PAX7 variants caused upregulation of splicing factors, an increase in mitochondrial reactive oxygen species levels and reduced cell proliferation. The phenotypic cell changes caused by the PAX7 variants support a pathomechanism whereby diminished satellite cell function impairs muscle homoeostasis. Together, multimodal investigation suggests that these variants in PAX7 are likely causative of an FSHD-like autosomal recessive myopathy and expand the spectrum of neuromuscular disorders originating from impaired satellite cell function.
    DOI:  https://doi.org/10.1038/s41419-025-08358-6
  23. Cells. 2026 Jan 15. pii: 161. [Epub ahead of print]15(2):
    RGMa Nuclear Localization in Skeletal Muscle Cells Reveals a Novel Role in Cell Viability and Proliferation.
    Cristhian David Andrade Alfaro, Julia Meireles Nogueira, Christhiam Douglas Caetano Ribeiro, Kirsty Ximena Noboa Carrasco, Ana Luísa Cremonese Lubiana, Ana Maria Alvarenga Fagundes, Natália Paloma Vieira de Souza, Victor Rodrigues Santos, Carolina Cattoni Koh, Walderez Ornelas Dutra, Erika Cristina Jorge.
      The Repulsive Guidance Molecule a (RGMa) is a multifunctional GPI-anchored protein localized in the sarcolemma and sarcoplasm of the adult skeletal muscle cell. Our research group showed that RGMa overexpression can promote myoblast fusion and induce hypertrophic muscle fibers during in vitro differentiation. Here, we report that RGMa is expressed in primary skeletal muscle cells cultured in vitro, showing a nuclear localization, revealed by immunostaining with an antibody targeting its C-terminal region (C-RGMa). While RGMa was detected in the nuclei, its canonical receptor, Neogenin, was predominantly found in the perinuclear region. Nuclear RGMa was absent in Neogenin-knockdown cells, suggesting that Neogenin mediates its nuclear transport. Functional assays suggested that RGMa promotes primary skeletal muscle cell viability and proliferation and supports their myogenic commitment. These findings reveal a previously unrecognized nuclear function of RGMa-Neogenin signaling and provide new insights into the regulation of skeletal muscle cell behavior in vitro.
    Keywords:  primary skeletal muscle cells; protein translocation; repulsive guidance molecule; subcellular compartment
    DOI:  https://doi.org/10.3390/cells15020161
  24. Mitochondrion. 2026 Jan 24. pii: S1567-7249(26)00006-1. [Epub ahead of print] 102116
    Mitochondria transfer from myocytes to endothelial cells Promotes angiogenesis in skeletal muscle.
    Yu-Feng Long, Ai-Jun Huang, Shuo Tang, Zhen Xu, Ming-Yue Wu, Kai Liu, Ze-Cai Chen, Lei Qin, Bing-Yang Dai, Cheng Dong, Wing-Hoi Cheung, Xin-Luan Wang, Da-Zhi Yang.
      Skeletal muscle and vascular health are closely interconnected, yet the mechanisms underlying their crosstalk remain poorly understood. This study investigates the role of mitochondria transfer from myocytes to endothelial cells. Using in vitro 2D and 3D coculture systems, combined with protein-level and functional analyses, we show that mitochondria are transferred via extracellular vesicles in a Rab7-dependent and cellular connection-independent manner. Connexin 43 (CX43) inhibition downregulating Growth-Associated Protein 43 (GAP43) but enhances mitochondria transfer, accompanied by increasing Rab7. Transferred mitochondria promote endothelial cells proliferation, migration, ATP production, and angiogenesis, which could be the key processes in preserving vascular integrity and muscle function. Our study indicated that the aging-associated decline in CX43 and mitochondrial quality exacerbates muscle atrophy by facilitating the transfer of dysfunctional mitochondria. These findings uncover a novel mechanism of muscle-vessel communication and highlight mitochondria transfer as a potential therapeutic target for aging-related muscular and vascular deterioration. New and Noteworthy. Mitochondria transfer is a way for cell communication. However, mitochondria transfer between myocyte and endothelial cell remains unknown. Here, we demonstrates that mitochondria transfer occurs between myocytes and endothelial cells. Interestingly, inhibition of CX43 leads to a decrease in GAP43 expression, while simultaneously upregulating Rab7 and enhancing mitochondria transfer from myocytes to endothelial cells. Furthermore, we reveal that Rab7-induced mechanism mediates the transfer of both functional and impaired mitochondria from myocytes to endothelial cells.
    Keywords:  Endothelial cells; Mitochondria transfer; Muscle; Myocytes; Vessel
    DOI:  https://doi.org/10.1016/j.mito.2026.102116
  25. J Toxicol Pathol. 2026 Jan;39(1): 45-50
    Intramuscular collagen accumulation in different types of skeletal muscle fibers in middle-aged male rats.
    Yoshikazu Taketa, Hideaki Takahashi.
      This study focused on the histological characterization of age-related intramuscular collagen accumulation in different skeletal muscle fiber types, specifically fast- and slow-twitch fibers, in young and middle-aged male rats, in relation to the number of nuclei between muscle fibers. The extensor digitorum longus (EDL) and soleus (SOL) muscles from male Sprague-Dawley (SD) rats were collected and sectioned. Hematoxylin and eosin staining was performed for histological examination, while Picrosirius Red and hematoxylin staining were used for morphometric analyses. The SOL, a slow-twitch dominant muscle, tended to have a more distinct and thicker interstitium, as well as more collagen fibers and nuclei between muscle fibers, than the EDL, a fast-twitch dominant muscle. The degree of collagen accumulation between muscle fibers was positively correlated with the number of nuclei. Intramuscular collagen fibers increased with age in both the EDL and SOL, particularly in the latter. The number of nuclei remained unchanged with age. These results suggest that the increase in intramuscular collagen fibers with age is due to increased collagen production by existing fibroblasts rather than fibroblast proliferation. Given that middle-aged male SD rats fed ad libitum were obese, their slow-twitch muscles may have become susceptible to sarcopenic obesity accompanied by intramuscular collagen accumulation.
    Keywords:  aging; collagen fiber; rats; skeletal muscle
    DOI:  https://doi.org/10.1293/tox.2025-0072
  26. Muscle Nerve. 2026 Jan 28.
    Automated Classification of Store-Operated Calcium Entry Activity and Disease Conditions in Murine Skeletal Muscle Images Using Machine Learning.
    Nasim Binesh, Kushi Vardhan Reddy Pasham, Katelyn R Villani, Urszula Krekora, Lan Wei-LaPierre, Elisabeth R Barton.
       INTRODUCTION/AIMS: Accurate detection of pathophysiology from tissue images is critical for appropriate diagnoses and treatments of muscular dystrophies. The application of machine learning (ML) models offers a promising approach for image assessment. We compared three ML models in their ability to classify mouse skeletal muscle images based on store-operated calcium entry (SOCE) activity, as an indicator of prolonged muscle activity and/or disease.
    METHODS: Immunofluorescent images were collected from muscle fibers obtained from calpain-3 null mice and wildtype mice at rest or following exercise. Images were categorized with respect to SOCE activity and disease status, then split into training, validation, and testing sets. Data were then utilized by three deep learning models: Convolutional Neural Networks (CNN), EfficientNet, and Support Vector Machines (SVM).
    RESULTS: CNN exhibited strongest performance in accuracy (0.91) and F1 score (0.88), and SVM exhibited the highest precision (0.92). Both models achieved similar area under the receiver operating characteristic curves (0.91). Performance differences between CNN and SVM yielded a p-value of 0.19, indicating no significant differences in their ability to classify SOCE activity in muscle images.
    DISCUSSION: This study demonstrated that CNN and SVM machine learning models provide a promising approach in classifying SOCE activity in muscle images. These models offer scalable solutions for automating tissue classification, with potential to transform clinical classification in muscle pathologies. Future research can explore using larger datasets and integration of other techniques, such as transformer-based models, to improve performance in more complex muscle conditions.
    Keywords:  artificial intelligence; calcium handling; calpain 3; image processing; muscular dystrophy
    DOI:  https://doi.org/10.1002/mus.70157
  27. J Cachexia Sarcopenia Muscle. 2026 Feb;17(1): e70195
    Peptide OH-CATH30 Mitigates Cachexia-Induced Muscle Atrophy via Modulation of TLR4-Associated Inflammation.
    Qiquan Wang, Jian Li, Mengqi Yang, Caifen Guo, Ming Zhang, Chunping Huang, Xiang Wang, Dongqin Zhang, Lin Zeng, Hao Ke, Yunling Wen, Shengan Li, Wenhui Lee, Limin Zhao, Xinqiang Lan, Yang Xiang.
       BACKGROUND: Cachexia, characterized by severe weight loss and muscle atrophy, frequently occurs in chronic conditions such as sepsis, cancer and chemotherapy, with limited effective treatments. Despite similar clinical manifestations, the underlying mechanisms across different disease contexts remain unclear. Identifying common pathways could lead to novel therapies. This study examines the role of Toll-like receptor 4 (TLR4), which is upregulated in various cachexia models, and assesses the therapeutic potential of the TLR4-inhibiting peptide OH-CATH30 in mitigating muscle atrophy.
    METHODS: In vivo models using 8-week-old mice treated with lipopolysaccharide (LPS), 4T1 tumour cells and cisplatin were used to investigate common pathways in cachexia. In vitro models were established by treating C2C12 myotubes with TNF-α, 4T1 culture supernatants and cisplatin. OH-CATH30's effects on muscle atrophy were assessed by measuring myotube diameter, grip strength, muscle weight and muscle fibre cross-sectional area (CSA) via H&E staining. RNA-seq, qPCR, ELISA and Western blotting were performed to explore pathways in cachexia-induced muscle atrophy and OH-CATH30's action mechanism.
    RESULTS: Transcriptomic analysis showed significant enrichment of inflammation and protein degradation pathways in skeletal muscle in LPS-induced sepsis, 4T1 tumour-induced cancer cachexia and cisplatin-induced cachexia models, with upregulated expression of TLR4 pathway genes such as Cd14, Tlr4 and Irak4 (p < 0.05). In myotube atrophy models induced by TNF-α, 4T1 and cisplatin, OH-CATH30 significantly increased MyHC protein levels (p < 0.05) and myotube diameter (p < 0.05). In mouse cachexia models induced by LPS, 4T1 and cisplatin, OH-CATH30 treatment significantly increased body weight (p < 0.05), muscle weight (p < 0.001), CSA (p < 0.05) and improved grip strength (p < 0.05). Transcriptomic analysis further revealed that OH-CATH30 treatment downregulated expression of inflammation and protein degradation-related genes across all cachexia models. In 4T1-treated mice, qPCR confirmed OH-CATH30 reduced mRNA levels of Il6 (p = 0.05), Mstn (p < 0.0001) and protein degradation genes such as Trim63, Fbxo32, Bnip3, Gabarapl1 and Ulk1 (p < 0.05). ELISA showed reduced serum IL-6 levels, and Western blot confirmed downregulation of atrogin1 (p < 0.05) and autophagy marker LC3II (p < 0.05) with OH-CATH30 treatment. Pharmacological inhibition of TLR4 using TAK-242 recapitulated the protective effects of OH-CATH30, with no additive benefit observed (p > 0.05).
    CONCLUSIONS: Our findings underscore the critical role of TLR4 signalling in cachexia-associated muscle wasting across different disease contexts and demonstrate the efficacy of OH-CATH30, a TLR4 inhibitor, in alleviating muscle atrophy in various cachexia models.
    Keywords:  OH‐CATCH30; TLR4; cachexia; inflammation; muscle atrophy; protein degradation
    DOI:  https://doi.org/10.1002/jcsm.70195
  28. Nat Commun. 2026 Jan 28.
    Impaired stem cell migration and divisions in Duchenne muscular dystrophy revealed by live imaging.
    Liza Sarde, Gaëlle Letort, Hugo Varet, Vincent Laville, Julien Fernandes, Shahragim Tajbakhsh, Brendan Evano.
      Dysregulation of stem cell properties is a hallmark of many pathologies, but the dynamic behaviour of stem cells in their microenvironment during disease progression remains poorly understood. Using the mdx mouse model of Duchenne Muscular Dystrophy, we developed innovative live imaging of muscle stem cells (MuSCs) in vivo, and ex vivo on isolated myofibres. We show that mdx MuSCs have impaired migration and precocious differentiation through unbalanced symmetric divisions, driven by p38 and PI3K signalling pathways, in contrast to the p38-only dependence of healthy MuSCs. Cross-grafting shows that MuSC fate decisions are governed by fibre-independent cues, whereas their migration behaviour is determined by the myofibre niche. This study provides the first dynamic analysis of dystrophic MuSC properties in vivo, reconciling conflicting reports on their function. Our findings establish DMD as a MuSC disease with niche dysfunctions, offering strategies to restore stem cell functions for improved muscle regeneration.
    DOI:  https://doi.org/10.1038/s41467-026-68474-5
  29. J Adv Res. 2026 Jan 26. pii: S2090-1232(26)00090-1. [Epub ahead of print]
    Mitocytosis, mitophagy, and apoptosis coordinately drive mitochondrial clearance to regulate myogenic differentiation.
    Dandan Wang, Mei Li, Jun Ma, Guocheng Du, Jingwen Zhou, Jian Chen, Xin Guan.
       INTRODUCTION: Skeletal muscle is a high-energy-consuming tissue whose development and function critically depend on mitochondrial homeostasis. Mitochondrial quality control involves multiple clearance mechanisms, including mitocytosis, mitophagy, and apoptosis. However, how these pathways are coordinated during myogenic differentiation remains systematically unexplained.
    OBJECTIVES: This study aimed to investigate the sequential activation and coordination of mitocytosis, mitophagy, and apoptosis inresponse to gradient mitochondrial damage, and to explore their impact on myogenesis.
    METHODS: We established a gradient mitochondrial damage model in myoblasts using different concentrations of CCCP. Through fluorescence imaging, western blotting, genetic interventions, and small-molecule inhibitors, we investigated the activation sequence and crosstalk among different clearance pathways, and explored their effects on myotube formation and function.
    RESULTS: Escalating mitochondrial damage triggered a sequential activation of clearance mechanisms: KIF5B-mediated mitocytosis was first induced, followed by PINK1-dependent mitophagy, and ultimately Caspase 3-mediated apoptosis. When mitocytosis was inhibited, mitophagy dominated mitochondrial clearance, whereas enhanced mitocytosis suppressed both mitophagy and apoptosis. When mitophagy was impaired, cellular homeostasis could be maintained by upregulating mitocytosis under mild mitochondrial damage, but this led to premature apoptosis under severe mitochondrial damage. Myogenesis was significantly suppressed when either mitocytosis or mitophagy was impaired, whether through small-molecule inhibitors or the genetic knockdown of KIF5B or PINK1. Notably, low-dose CCCP treatment promoted myotube formation and mitochondrial function, and also attenuated the myogenic deficits resulting from KIF5B or PINK1 deficiency. Furthermore, KIF5B overexpression enhanced glycolytic metabolism and accelerated myoblast proliferation, highlighting its role beyond mitochondrial clearance.
    CONCLUSION: These findings provide new insights into the coordinated regulatory network among mitochondrial clearance mechanisms and their roles in myogenic differentiation. These insights advance the understanding of muscle biology and offer potential strategies for enhancing muscle regeneration in biomedical and cellular agriculture applications.
    Keywords:  Apoptosis; Mitochondrial clearance; Mitocytosis; Mitophagy; Myogenic differentiation
    DOI:  https://doi.org/10.1016/j.jare.2026.01.065
  30. Biochem Biophys Res Commun. 2026 Jan 21. pii: S0006-291X(26)00090-2. [Epub ahead of print]802 153326
    Opposing effects of Gα12 and Gα13 loss on myotube size regulation via mTORC1 signaling.
    Mai Kubota, Shuhei Fujita, Ryohei Kamata, Kazuma Tamura, Keiichiro Sugimoto, Tomoya Kitakaze, Naoki Harada, Ryoichi Yamaji.
      To reduce the risk of diseases caused by a reduction in skeletal muscle mass and quality, it is important to understand the molecular mechanisms underlying the maintenance and improvement of skeletal muscle mass and quality. Gα12 and/or Gα13 have been implicated in the regulation of myotube size through the mechanistic target of rapamycin complex 1 (mTORC1) signaling; however, their specific and potentially distinct molecular mechanisms remain unknown. Knockdown and rescue experiments revealed that the loss of Gα12 decreased myotube size, whereas the loss of Gα13 increased it. Gα12 knockdown reduced the phosphorylation levels of mTORC1 signaling components (Akt, mTOR, and p70S6K) and the levels of puromycin-labeled proteins, whereas Gα13 knockdown increased these levels. Loss of Gα12 or Gα13 suppressed SRF-RE-dependent transcriptional activity. While expression of a constitutively active form of RhoA (RhoA-CA) activated SRF-RE activity, notably, RhoA-CA expression did not affect myotube size, nor did it alter myotube atrophy induced by Gα12 knockdown or hypertrophy induced by Gα13 knockdown. Depletion of Gα12 increased the mRNA expression of oxidative myosin heavy chain (MyHC) isoforms Myh7 and Myh2 and decreased the mRNA expression of Myh1 and Myh4, whereas depletion of Gα13 increased the mRNA expression of Myh7, Myh2, Myh1, and Myh4. These results indicate that loss of Gα12 induces myotube atrophy by suppressing mTORC1 signaling and protein synthesis, whereas loss of Gα13 induces myotube hypertrophy by enhancing these processes, likely independent of SRF-RE-mediated transcription. Notably, Gα12 and Gα13 oppositely regulated the mRNA expression of MyHC isoforms, particularly Myh1 and Myh4.
    Keywords:  Atrophy; Gα12/13; Hypertrophy; Myosin heavy chain; Myotube; Serum response factor
    DOI:  https://doi.org/10.1016/j.bbrc.2026.153326
  31. Life (Basel). 2026 Jan 16. pii: 144. [Epub ahead of print]16(1):
    Enhancement of Hypoxia-Induced Autophagy via the HIF-1apha/BNIP3 Pathway Promotes Proliferation and Myogenic Differentiation of Aged Skeletal Muscle Satellite Cells.
    Li Zhou, Chenghao Feng, Jinrun Lin, Minghao Geng, Danni Qu, Jihao Xing, Hao Lin, Xiaoqi Ma, Ryosuke Nakanishi, Noriaki Maeshige, Hiroyo Kondo, Hidemi Fujino.
      Aged skeletal muscle satellite cells (MuSCs) exhibit impaired autophagy-related activity, reduced proliferative capacity, and compromised myogenic differentiation, which collectively contribute to defective muscle regeneration during aging. However, whether hypoxia-driven modulation of autophagy-related activity can improve aged MuSC function and the underlying molecular mechanisms remain incompletely understood. In this study, aged MuSCs were divided into three groups: normoxia, hypoxia, and hypoxia combined with an autophagy inhibitor. Aged MuSCs exhibited a decreased LC3B-II/LC3B-I ratio and Beclin-1 expression, together with elevated p62 levels, indicating altered autophagy-related activity. Hypoxic culture was associated with enhanced autophagy-related activity in aged MuSCs, accompanied by HIF-1α stabilization, BNIP3 upregulation, and reduced p62 accumulation. Functionally, hypoxia significantly promoted the proliferation and myogenic differentiation of aged MuSCs. Pharmacological inhibition of autophagy using 3-methyladenine, as well as BNIP3 suppression, markedly attenuated these hypoxia-induced functional improvements. Collectively, these findings suggest that hypoxia is associated with improved proliferative and myogenic capacities of aged MuSCs, potentially involving autophagy-related activity regulated by the HIF-1α/BNIP3 pathway. This study provides insight into the relationship between hypoxic signaling and autophagy in aged MuSCs and may inform future strategies aimed at improving muscle regeneration during aging.
    Keywords:  aging satellite cells; autophagy; hypoxia
    DOI:  https://doi.org/10.3390/life16010144
  32. Int J Mol Sci. 2026 Jan 08. pii: 648. [Epub ahead of print]27(2):
    Hypobaric Hypoxia Ameliorates Impaired Regeneration After Diabetic Skeletal Muscle Injury by Promoting HIF-1α Signaling.
    Jinrun Lin, Minghao Geng, Li Zhou, Danni Qu, Hao Lin, Jihao Xing, Ryosuke Nakanishi, Hiroyo Kondo, Noriaki Maeshige, Hidemi Fujino.
      Diabetes mellitus severely impairs skeletal muscle regeneration after injury, limiting satellite cell activation and angiogenesis and disrupting barrier integrity while increasing fibrosis. Hypobaric hypoxia has been proposed to improve the regenerative microenvironment through hypoxia-responsive signaling, but its temporal effects and the coordination between vascular and myogenic programs in diabetic muscle remain unclear. To clarify these processes, adult male mice were divided into five groups: diabetes mellitus control (DM), cardiotoxin-injured (CTX) diabetes assessed on days 7 and 14 (CTX7, CTX14), and hypobaric-hypoxia-treated diabetic injury assessed on days 7 and 14 (H+CTX7, H+CTX14). Animals in the hypoxia groups were exposed to a hypobaric hypoxia chamber for 8 h per day for 14 days. Fibrosis, angiogenic and myogenic markers, and endothelial junctional genes were examined using histology, immunofluorescence, immunoblotting, and qRT-PCR (Quantitative Real-Time PCR). Hypobaric hypoxia on day 7 enhanced HIF-1α (hypoxia-inducible factor 1 alpha), VEGF (vascular endothelial growth factor), eNOS (endothelial nitric oxide synthas), Kdr (kinase insert domain receptor, VEGFR-2), and Angpt2 (angiopoietin-2) expression, accompanied by simultaneous endothelial sprouting and early myogenic stimulation compared to CTX7. Improvements were observed in Angpt1 (angiopoietin-1), Cdh5 (cadherin-5, VE-cadherin), Emcn (endomucin), the Angpt1/Angpt2 ratio, and CD31 density. Myogenin and MyHC (myosin heavy chain) were induced with a reduction in eMyHC (embryonic myosin heavy chain) in accordance with stabilization of endothelium and maturation of fibers, which occurred by day 14. A decrease in fibrosis and an increase in the myofiber cross-sectional area occurred. These findings suggest that hypobaric hypoxia modulates HIF-1α signaling, which in turn induces the VEGF-Kdr-eNOS pathway and the angiopoietin-Tie2-VE-cadherin pathway. Together, these pathways coordinate vascular remodeling and myogenic regeneration, ultimately improving the structural and functional recovery of diabetic muscle.
    Keywords:  HIF-1α; angiogenesis; diabetes-induced muscle injury; hypobaric hypoxia; vascular remodeling
    DOI:  https://doi.org/10.3390/ijms27020648
  33. Cells. 2026 Jan 22. pii: 206. [Epub ahead of print]15(2):
    Single-Cell Sequencing Reveals the Crosstalk Between MuSCs and FAPs in Ruminant Skeletal Muscle Development.
    Yuan Chen, Yiming Gong, Xiaoli Xu, Meijun Song, Xueliang Sun, Jing Luo, Jiazhong Guo, Li Li, Hongping Zhang.
      Skeletal muscle orchestrates a remarkable journey from embryonic formation to age-related decline, yet its cellular intricacies in goats remain largely uncharted. We present the first single-cell RNA sequencing (scRNA-seq) atlas of the longissimus dorsi muscle from goats, profiling 120,944 cells across 14 developmental stages from embryonic day 30 (E30) to 11 years postnatal (Y11). We focused on skeletal muscle satellite cells (MuSCs) and fibro-adipogenic progenitors (FAPs), identifying a unique MuSCs_ACT1_high subpopulation in early embryogenesis and a senescence-associated MuSCs_CDKN1A_high subpopulation in later developmental stages. In FAPs, we characterized the early-stage FAPs_MDFI_high subpopulation with differentiation potential, which further exhibited the capacity to commit to both adipogenic and fibrogenic lineages. Transcription factor analysis revealed strikingly similar regulatory profiles between MuSCs and FAPs, suggesting that these two cell types are governed by shared signaling pathways during development. Cell-cell interaction analysis demonstrated that the DLK1-NOTCH3 ligand-receptor pair plays a critical role in enabling early embryonic FAPs to maintain the quiescent state of MuSCs. This dynamic single-cell transcriptomic atlas, spanning 14 developmental stages of skeletal muscle in ruminants for the first time, provides a valuable theoretical foundation for further elucidating the differentiation of skeletal muscle satellite cells and fibro-adipogenic progenitors in ruminants.
    Keywords:  FAPs; MuSCs; intercellular interaction; ruminants; single-cell RNA sequencing; skeletal muscle
    DOI:  https://doi.org/10.3390/cells15020206
  34. J Cachexia Sarcopenia Muscle. 2026 Feb;17(1): e70203
    Annexin A2 Causes Motor Incoordination via Muscle-Cerebellum Axis in Sarcopenia.
    Xin Jiao, Zengguang Wang, Hanwen Chang, Yongjin Li, Binbin Wang, Xinfa Shao, Yuxin Zhang, Yixuan Lin, Xinlin Jia, Xianhao Zhou, Wentao Li, Dinghao Luo, Tanjun Deng, Xingzuan Lin, Chen Xu, Yaokai Gan, Dongyun Gu.
       BACKGROUND: Sarcopenia is a prevalent age-related disorder characterized by progressive muscle atrophy. Impaired balance is one of its most critical clinical consequences, often leading to falling and even bone fractures. As the cerebellum plays a central role in regulating motor coordination, elucidating the molecular mechanisms underlying imbalance in sarcopenia, particularly those mediated by the muscle-cerebellum axis, remains an important yet unresolved question.
    METHODS: 4D label-free proteomics was employed to identify the key secretory protein mediating the interaction between muscles and cerebellums in young and aged mice. Annexin A2 (ANXA2), the candidate protein, was subsequently overexpressed using adeno-associated virus (AAV), and its effects on both muscle and cerebellum were systematically examined. RNA-sequencing was conducted to elucidate the molecular mechanisms underlying ANXA2 function in muscle, while stereotactic injection was performed to investigate its impact on cerebellum and related mechanisms. Finally, we evaluated the therapeutic potential of isoliquiritigenin, an inhibitor of ANXA2, in improving motor coordination and muscle function in aged mice.
    RESULTS: Aged mice showed obviously impaired motor coordination in the accelerated rotarod (AR) test (p < 0.01) and reduced strength performance in the grip strength assay (p < 0.05) compared to young mice. Proteomic analysis identified ANXA2 as a secretory protein predominantly produced by aged skeletal muscles (p < 0.05 in tibialis anterior, gastrocnemius muscle and quadriceps femoris) but not by other aged organs such as heart, liver, kidney, spleen and lung (all p > 0.05). Functionally, ANXA2 exacerbated muscle atrophy by upregulating atrophy-related markers MuRF-1 and Atrogin-1 (both p < 0.05) and reducing the myotube diameter via regulation of Neuraminidase 2 (Neu2) (p < 0.05). Moreover, ANXA2 was transported into the cerebellum through the blood stream and targeted type 2 cannabinoid receptors (CB2R) in cerebellar Purkinje cells (PCs) of lobule IV/V, thereby contributing to motor incoordination as evidenced by impaired performance in AR tests (p < 0.05). Importantly, isoliquiritigenin, an extract from licorice, effectively inhibited ANXA2 expression in muscle (p < 0.05), alleviated muscle atrophy (p < 0.05) and motor incoordination (p < 0.05), while showing no adverse effects on anxiety-like behaviours associated with CB2R (p > 0.05).
    CONCLUSIONS: ANXA2 is a key mediator of the muscle-cerebellum axis in sarcopenia, contributing to muscle atrophy by downregulating Neu2 and motor incoordination by targeting CB2R. Isoliquiritigenin was identified as an effective compound targeting ANXA2 to improve motor deficits. These findings highlight ANXA2 as a potential therapeutic target and suggest isoliquiritigenin as a promising strategy for alleviating motor incoordination associated with sarcopenia.
    Keywords:  ANXA2; Purkinje cells; isoliquiritigenin; motor coordination; muscle–cerebellum axis; sarcopenia
    DOI:  https://doi.org/10.1002/jcsm.70203
  35. J Bone Miner Metab. 2026 Jan 28.
    Bridging skeletal stem cell diversity and human skeletal modeling.
    Shoichiro Tani.
       BACKGROUND: Skeletal stem cells (SSCs) underlie skeletal development, homeostasis, regeneration, and aging, yet their identities and functions are highly heterogeneous across anatomical sites and life stages. Mouse genetic studies have identified multiple SSC populations-each residing in distinct niches such as the growth plate, periosteum, and bone marrow-and revealed their dynamic regulation across developmental, homeostatic, regenerative, and aging contexts. However, translating these insights to humans remains challenging due to species differences and limited access to physiological human skeletal tissues. This review synthesizes current understanding of SSC diversity and how distinct compartments contribute to skeletal formation and maintenance throughout life. It also summarizes emerging human skeletal modeling strategies, including pluripotent stem cell differentiation, bioengineered in vitro systems, and in vivo transplantation, evaluating their ability to reconstruct skeletal components and SSC-bearing niches. Although recent models reproduce partial structures such as perichondrium-like layers or bone marrow-like microenvironments, most remain compartment-specific and lack integrated, stage-aware architectures that recapitulate physiological SSC behavior and skeletal functions in vivo. We propose an SSC-centric framework that incorporates spatiotemporal diversity, multi-compartment integration, physiological cues, and cross-validation with human tissues, providing predictive and translational platforms for skeletal biology, disease modeling, and regenerative medicine.
    Keywords:  Human skeletal modeling; Skeletal stem cells; Spatiotemporal diversity; Stem cell niche
    DOI:  https://doi.org/10.1007/s00774-025-01686-9
  36. Am J Clin Nutr. 2026 Jan 22. pii: S0002-9165(26)00014-6. [Epub ahead of print] 101205
    Leucine supplementation does not attenuate the decline in daily muscle protein synthesis rates or preserve leg muscle mass during leg immobilization in young or older adults: a double-blind randomized trial.
    Tyler A Churchward-Venne, Philippe J M Pinckaers, Joey S J Smeets, Gabriel Nasri Marzuca-Nassr, Stefan H M Gorissen, Cas J Fuchs, Joan M Senden, Joy P B Goessens, Annemie P Gijsen, Will K W H Wodzig, Luc J C van Loon.
       BACKGROUND: Muscle disuse leads to muscle atrophy that has been attributed to declines in basal and postprandial muscle protein synthesis (MPS) rates. Leucine regulates MPS and may attenuate disuse-induced declines in MPS rates and muscle mass.
    OBJECTIVE: The purpose of this study was to evaluate the capacity of leucine supplementation to attenuate disuse-induced declines in MPS rates and muscle mass in young and older adults.
    METHODS: In a randomized, double-blind, parallel-group design, 24 young (23±4y) and 24 older (69±4y) recreationally active adults (equal sex distribution) underwent 3 days of unilateral knee immobilization (leg casting) and received a leucine (LEU) or energy-matched carbohydrate (PLA) supplement (5g, 3×daily). Pre- and post-immobilization, quadriceps muscle cross-sectional area (CSA) was assessed in the immobilized (IM) and non-immobilized (NO-IM) leg by computed tomography. MPS rates were assessed in both legs during immobilization via 2H2O coupled with saliva, blood, and muscle biopsy sampling.
    RESULTS: In young and older adults, MPS rates were ∼15 and ∼23% lower in the IM versus NO-IM leg (1.28±0.29 versus 1.50±0.26 and 1.10±0.16 versus 1.46±0.28 %•day-1, respectively; leg: both P<0.001), with no differences between LEU versus PLA treatments (treatment: P=0.932 and P=0.742, respectively). CSA decreased by ∼1.2 and ∼1.1% in the IM leg in young and older adults (from 7162±1148 to 7076±1129 mm2 and from 5813±1092 to 5750±1096 mm2, respectively; leg × time interaction: both P<0.001), with no differences between LEU versus PLA (treatment: P=0.374 and P=0.998). IM leg MPS rates were lower in older versus young adults (difference: -0.18 (95% CI: -0.31, -0.04) %•day-1; P=0.013). No differences were observed in the absolute (mm2) or relative (%) decline in CSA between young and older adults (both P>0.05).
    CONCLUSIONS: Leucine supplementation does not attenuate the decline in daily MPS rates or muscle mass during short-term limb immobilization in young or older adults.
    CLINICAL TRIAL REGISTRY: This trial was prospectively registered at Netherlands Trial Register: https://onderzoekmetmensen.nl/en/trial/45771 as ID: NL-OMON45771.
    Keywords:  disuse muscle atrophy; leucine supplementation; limb immobilization; muscle protein synthesis; older adults; skeletal muscle; young adults
    DOI:  https://doi.org/10.1016/j.ajcnut.2026.101205
  37. Genes (Basel). 2025 Dec 29. pii: 28. [Epub ahead of print]17(1):
    Integrative Machine Learning and Network Analysis of Skeletal Muscle Transcriptomes Identifies Candidate Pioglitazone-Responsive Biomarkers in Polycystic Ovary Syndrome.
    Ahmad Al Athamneh, Mahmoud E Farfoura, Anas Khaleel, Tee Connie.
       BACKGROUND/OBJECTIVES: Polycystic ovary syndrome (PCOS) is a common endocrine-metabolic disorder in which skeletal muscle insulin resistance contributes substantially to cardiometabolic risk. Pioglitazone improves insulin sensitivity in women with PCOS, yet the underlying transcriptional changes and their potential as treatment-response biomarkers remain incompletely defined. We aimed to reanalyse skeletal muscle gene expression from pioglitazone-treated PCOS patients using modern machine learning and network approaches to identify candidate biomarkers and regulatory hubs that may support precision therapy.
    METHODS: Public microarray data (GSE8157) from skeletal muscle of obese women with PCOS and healthy controls were reprocessed. Differentially expressed genes (DEGs) were identified and submitted to Ingenuity Pathway Analysis to infer canonical pathways, upstream regulators, and disease functions. Four supervised machine learning algorithms (logistic regression, random forest, support vector machines, and gradient boosting) were trained using multi-step feature selection and 3-fold stratified cross-validation to provide superior Exploratory Gene Analysis. Gene co-expression networks were constructed from the most informative genes to characterize network topology and hub genes. A simulated multi-omics framework combined selected transcripts with representative clinical variables to explore the potential of integrated signatures.
    RESULTS: We identified 1459 DEGs in PCOS skeletal muscle following pioglitazone, highlighting immune and fibrotic signalling, interferon and epigenetic regulators (including IFNB1 and DNMT3A), and pathways linked to mitochondrial function and extracellular matrix remodelling. Within this dataset, all four machine learning models showed excellent cross-validated discrimination between PCOS and controls, based on a compact gene panel. Random forest feature importance scoring and network centrality consistently prioritized ITK, WT1, BRD1-linked loci and several long non-coding RNAs as key nodes in the co-expression network. Simulated integration of these transcripts with clinical features further stabilized discovery performance, supporting the feasibility of multi-omics biomarker signatures.
    CONCLUSIONS: Reanalysis of skeletal muscle transcriptomes from pioglitazone-treated women with PCOS using integrative machine learning and network methods revealed a focused set of candidate genes and regulatory hubs that robustly separate PCOS from controls in this dataset. These findings generate testable hypotheses about the immunometabolism and epigenetic mechanisms of pioglitazone action and nominate ITK, WT1, BRD1-associated loci and related network genes as promising biomarkers for future validation in larger, independent PCOS cohorts.
    Keywords:  biomarkers; co-expression networks; gene expression profiling; machine learning; pioglitazone; polycystic ovary syndrome; skeletal muscle
    DOI:  https://doi.org/10.3390/genes17010028
  38. Cell Metab. 2026 Jan 28. pii: S1550-4131(25)00547-9. [Epub ahead of print]
    Blood-flow restriction resistance training improves skeletal muscle mitochondrial capacity and cardiovascular risk factors in type 2 diabetes.
    Nina Trinks, Sofiya Gancheva, Jennifer Pützer, Martin Schön, Maximilian Huttasch, Kalliopi Pafili, Lucia Mastrototaro, Bedair Dewidar, Yuliya Kupriyanova, Christian Herder, Klaus Strassburger, Oana P Zaharia, Philip M M Ruppert, Sander Kersten, Joris Hoeks, Sandra Trenkamp, Vera Schrauwen-Hinderling, Patrick Schrauwen, Michael Roden, Dominik H Pesta.
      Impaired muscle strength and mitochondrial functionality are hallmarks of type 2 diabetes (T2D). Conventional combined resistance/endurance exercise training has limited efficacy to simultaneously improve muscle function and metabolism. We examined whether low-load blood-flow restriction training (BFRT) increases both muscle strength and mitochondrial oxidative capacity in T2D. Over 12 weeks, BFRT and conventional resistance training (CREST) similarly improved muscle strength despite lower workload in BFRT. Uniquely, BFRT enhanced muscle and adipose tissue oxidative capacity and increased muscle mitochondrial content. Transcriptomic profiling revealed more pronounced changes, particularly in angiogenesis-linked pathways, upon BFRT. BFRT also preferentially led to reductions in visceral adipose tissue volume and waist circumference, whereas CREST more effectively decreased subcutaneous adipose tissue volume. Both interventions lowered resting heart rate and diastolic blood pressure. These findings position BFRT as a promising low-load exercising strategy to simultaneously improve mitochondrial oxidative capacity, muscle strength, and body composition in individuals with T2D.
    Keywords:  adipose tissue distribution; angiogenesis; blood-flow restriction training; cardiovascular function; mitochondrial respiration; resistance training; skeletal muscle function; type 2 diabetes
    DOI:  https://doi.org/10.1016/j.cmet.2025.12.016
  39. Commun Biol. 2026 Jan 29.
    An integrated drug repositioning analysis identifies rosiglitazone as a treatment for sarcopenia.
    Liang Shuang, Yong Liu, Hong-Mei Xiao, Hong-Wen Deng.
      Age-related sarcopenia is a growing global health challenge with no approved pharmacotherapies. Here, we integrate network-based drug repurposing and Mendelian randomization to identify rosiglitazone, a PPARγ agonist used in diabetes, as a potential therapeutic candidate for sarcopenia. In aged male C57BL/6JRj murine models, rosiglitazone administration significantly improved muscle strength, mass, and endurance. Multi-omics profiling revealed its mechanism involves gut microbiota remodeling, activation of skeletal muscle Igf1 signaling, suppression of atrophy-related ubiquitin ligases (Atrogin-1/MuRF1), and modulation of protein metabolism, suggesting a coordinated "gut-muscle-metabolism" axis. Genetic analyses further support the causal role of Clostridiaceae/Clostridium in grip strength. Our findings nominate rosiglitazone as a promising intervention for sarcopenia, warranting further clinical investigation.
    DOI:  https://doi.org/10.1038/s42003-026-09595-x
  40. Nature. 2026 Jan 28.
    How much exercise do you really need?
    Nick Petrić Howe, Elizabeth Gibney.
      
    Keywords:  Cardiovascular biology; Health care; Physiology
    DOI:  https://doi.org/10.1038/d41586-026-00273-w
  41. Nature. 2026 Jan;649(8099): 1092-1094
    The surprisingly big health benefits of just a little exercise.
    Mariana Lenharo.
      
    Keywords:  Epidemiology; Public health
    DOI:  https://doi.org/10.1038/d41586-026-00237-0
  42. J Transl Med. 2026 Jan 29.
    Muscle RING finger-1 facilitates skeletal muscle regeneration via regulating myoblast proliferation and differentiation.
    Mengge Yang, Suqiong Ji, Huajie Gao, Huizhen Ge, Xingyu Han, Jiayang Zhan, Qing Zhang, Li Xu, Yue Li, Zhouping Tang, Bitao Bu.
      
    Keywords:  Differentiation; Immune-mediated necrotizing myopathy; MuRF-1; Muscle regeneration; Proliferation
    DOI:  https://doi.org/10.1186/s12967-025-07664-z
  43. Biomedicines. 2026 Jan 22. pii: 253. [Epub ahead of print]14(1):
    The Lactate Nexus: A Molecular Bridge Linking Physical Activity, Sleep, and Cognitive Enhancement.
    Alimjan Ablitip, Kefeng Zheng, Hao Ding, Yicong Cui, Xindong Ma, Yanwei You.
      Physical activity (PA) and quality sleep are essential for cognitive health, providing synergistic protection against age-related cognitive decline. However, the shared molecular pathways that explain their combined and interactive benefits remain poorly understood. This review suggests that lactate, long dismissed as a metabolic waste product, is a unifying mechanism. We introduce the "Lactate Nexus", a conceptual framework that proposes lactate functions as a key signalling molecule, mechanistically linking the pro-cognitive effects of both daytime exercise and nighttime sleep. We begin by outlining lactate's evolving role-from an energy substrate shuttled from astrocytes to neurons (the Astrocyte-Neuron Lactate Shuttle) to a pleiotropic signal. As a signal, lactate influences neuroplasticity via NMDA receptors, neuroinflammation via the HCAR1 receptor, and gene expression through the epigenetic modification of histone lactylation. We then compile evidence demonstrating how PA provides a substantial lactate signal that activates these pathways and primes the brain's metabolic infrastructure. Crucially, we integrate this with proof that lactate levels naturally increase during slow-wave sleep to support memory consolidation and glymphatic clearance. The "Lactate Nexus" framework offers a comprehensive molecular explanation for the synergy between PA and sleep, positioning lactate as a key signalling mediator and a promising biomarker and therapeutic target for fostering lifelong cognitive resilience.
    Keywords:  cognitive function; lactate; physical activity; sleep
    DOI:  https://doi.org/10.3390/biomedicines14010253
  44. Cells. 2026 Jan 20. pii: 199. [Epub ahead of print]15(2):
    Gne-Depletion in C2C12 Myoblasts Leads to Alterations in Glycosylation and Myopathogene Expression.
    Carolin T Neu, Aristotelis Antonopoulos, Anne Dell, Stuart M Haslam, Rüdiger Horstkorte.
      GNE myopathy is a rare genetic neuromuscular disorder caused by mutations in the GNE gene. The respective gene product, UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE), is a bifunctional enzyme that initiates endogenous sialic acid biosynthesis. Sialic acids are important building blocks for the glycosylation machinery of cells and are typically found at the terminal ends of glycoprotein N- and O-glycans. The exact pathomechanism of GNE myopathy remains elusive, and a better understanding of the disease is urgently needed for the development of therapeutic strategies. The purpose of this study was to examine the effects of hyposialylation on glycan structures and subsequent downstream effects in the C2C12 Gne knockout cell model. No overall remodeling of N-glycans was observed in the absence of Gne, but differences in glycosaminoglycan expression and O-GlcNAcylation were detected. Expression analysis of myopathogenes revealed concomitant down-regulation of muscle-specific genes. Among the top candidates were the sodium channel protein type 4 subunit α (Scn4a), voltage-dependent L-type calcium channel subunit α-1s (Cacna1s), ryanodine receptor 1 (Ryr1), and glycogen phosphorylase (Pygm), which are associated with excitation-contraction coupling and energy metabolism. The results suggest that remodeling of the glycome could have detrimental effects on intracellular signaling, excitability of skeletal muscle tissue, and glucose metabolism.
    Keywords:  GNE; GNE-myopathy; N-glycans; glycosylation; myopathogenes; sialic acids
    DOI:  https://doi.org/10.3390/cells15020199
  45. Biomolecules. 2026 Jan 13. pii: 135. [Epub ahead of print]16(1):
    Direct Effects of Capsaicin on Voltage-Dependent Calcium Channels of Mammalian Skeletal Muscle.
    Dmytro Isaev, Tatiana Prytkova, Badarunnisa Mohamed, Mohamed Omar Mahgoub, Keun-Hang Susan Yang, Murat Oz.
      Capsaicin, a naturally occurring polyphenol, is known to affect energy expenditure and muscle fatigue and modulate contractions in skeletal muscle. The L-type Ca2+ channels are known to be an important ion channel involved in the various muscle functions and the effect of capsaicin on the skeletal L-type Ca2+ channels is currently unknown. In this study, the effects of capsaicin and capsaicin analogs on depolarization-induced Ca2+ effluxes through L-type Ca2+ channels in transverse tubule membranes from rabbit skeletal muscle and L-type Ca2+ currents recorded using the whole-cell patch clamp technique in rat myotubes were examined. Capsaicin, in the concentration range of 3-100 µM, inhibited depolarization-induced Ca2+ effluxes. The effect of capsaicin was not reversed by TRPV1 antagonist SB-366791 (10 µM). While vanilloids (30 µM) including vanillin, vanillyl alcohol, and vanillylamine were ineffective, other capsaicinoids (30 µM) including dihydrocapsaicin, nonivamide, and nordihydrocapsaicin significantly inhibited Ca2+ effluxes, suggesting that hydrocarbon chains are required for inhibition. In rat myotubes, capsaicin inhibited L-type Ca2+ currents with an IC50 value of 27.2 μM in the presence of SB-366791. Furthermore, in docking studies and molecular dynamic simulations, capsaicinoids with an aliphatic tail showed stronger binding and stable bent conformations in CaV1.1, forming hydrogen bonds with Ser1011 and Thr935 and hydrophobic/π-alkyl contacts with Phe1008, Ile1052, Met1366, and Ala1369, resembling the binding mode of amlodipine. In conclusion, the results indicate that the function of L-type Ca2+ channels in mammalian skeletal muscle was inhibited by capsaicin and capsaicin analogs in a TRPV1-independent manner.
    Keywords:  T-tubule; calcium channels; capsaicin; skeletal muscle
    DOI:  https://doi.org/10.3390/biom16010135
  46. Curr Issues Mol Biol. 2025 Dec 17. pii: 1058. [Epub ahead of print]47(12):
    The Promise and Pitfalls of AAV-Mediated Gene Therapy for Duchenne Muscular Dystrophy.
    Elizaveta V Kurshakova, Olga A Levchenko, Svetlana A Smirnikhina, Alexander V Lavrov.
      Duchenne muscular dystrophy (DMD) is a severe X-linked hereditary disorder caused by pathogenic variants in the DMD gene encoding the dystrophin protein. The absence of functional dystrophin leads to destabilization of the dystrophin-associated glycoprotein complex (DAPC), sarcolemmal damage, and progressive degeneration of muscle fibers. Current therapeutic strategies focus on restoring dystrophin expression using genome editing approaches. Adeno-associated virus (AAV) vectors represent the primary delivery platform due to their strong tropism for muscle tissue, low immunogenicity, and ability to achieve long-term transgene expression. However, the limited packaging capacity of AAV (~4.7 kb) necessitates the use of truncated mini- and micro-dystrophin transgenes as well as compact genome editing systems (SaCas9, NmeCas9, Cas12f, TIGR-Tas, and others). Major challenges include immune responses against the viral capsid and transgene products, as well as the inability to perform repeated administrations. Moreover, the duration of expression is limited by the episomal nature of AAV genomes and their loss during muscle fiber regeneration. Despite substantial progress, unresolved issues concerning safety, immunogenicity, and stability of genetic correction remain, defining the key directions for future research in DMD therapy.
    Keywords:  AAV; CRISPR/Cas9; DMD; gene therapy
    DOI:  https://doi.org/10.3390/cimb47121058
  47. Inflamm Res. 2026 Jan 27. 75(1): 26
    Genetic depletion of the early autophagy protein ATG13 impairs mitochondrial energy metabolism, augments oxidative stress, induces the polarization of macrophages to the M1 inflammatory mode, and compromises myelin integrity in skeletal muscle.
    Mubaraq A Toriola, Emma Timlin, Sarojini Bulbule, Amy Reyes, Omolola Mary Adedeji, C Gunnar Gottschalk, Animesh Barua, Leggy A Arnold, Avik Roy.
       OBJECTIVE: M1 macrophage activation is crucial in chronic inflammatory diseases, yet its molecular mechanism is unclear.
    RESULTS: Our study showed that hemizygous deletion of the early autophagy gene atg13 (Tg+/-ATG13) disrupts cellular autophagy, hinders mitochondrial oxidative metabolism, and increases reactive oxygen species (ROS) levels in splenic macrophages, leading to M1 polarization. After reducing the expression of the autophagy markers WDFY3 and LC3, flow cytometric analysis of M1/M2 markers (CD40, CD86, CD115, CD163, and CD206), decreasing oxygen metabolism, as evaluated by the ROS-sensor dye DCFDA, and Seahorse oxygen consumption studies revealed that ablation of the atg13 gene impairs mitochondrial function, triggering M1 polarization. Additionally, redox imbalance may impair Sirtuin-1 activity via nitrosylation, increasing the level of acetylated p65 in macrophages and contributing to the inflammatory response in M1Mφs. Additionally, ablation of the atg13 gene resulted in increased infiltration of M1Mφs into the muscle vasculature, deterioration of myelin integrity in nerve bundles, and a reduction in muscle strength following treadmill exercise.
    CONCLUSIONS: Our study shows that impaired ATG13-driven autophagy increases inflammation through sirtuin-1 inactivation and NF-κB activation, suggesting a role for ATG13 in post-exertional malaise (PEM).
    DOI:  https://doi.org/10.1007/s00011-025-02158-6
  48. Comput Biol Chem. 2026 Jan 27. pii: S1476-9271(26)00055-1. [Epub ahead of print]122 108930
    The role of artificial intelligence in sarcopenia: Advances, applications, and future directions.
    Muhammad Waleed Yousaf, Ahmad Hassan Nadeem, M Faisal Nadeem, Rizwan Qaisar.
      Sarcopenia, the gradual loss of skeletal muscle mass, strength, and function, is a growing concern in aging populations. Early detection is vital to reduce the risk of frailty, disability, and mortality, yet traditional diagnostic methods such as imaging and physical performance tests are often costly, inconsistent, or difficult to implement in routine care. Artificial intelligence (AI), including machine learning (ML) and deep learning (DL), is emerging as a powerful tool in sarcopenia research and clinical practice. This review explores how AI is being applied to early detection, imaging-based diagnosis, prediction of functional outcomes, and personalized monitoring. Models trained on large datasets, such as NHANES, have demonstrated strong predictive performance using standard clinical variables. DL has enabled automated analysis of CT scans for muscle segmentation, reducing the need for manual interpretation. At the same time, ML systems integrated with wearable devices allow real-time tracking of physical function. Emerging approaches such as explainable AI, federated learning, and the integration of diverse data sources, including omics and microbiome profiles, are expanding opportunities for individualized care. Despite these advances, significant challenges remain, including variability in data quality, limited model transparency, algorithmic bias, and ethical concerns. Regulatory oversight and clinician engagement will be key to successful implementation. AI offers a promising path toward proactive, scalable, and personalized management of sarcopenia.
    Keywords:  Artificial intelligence; Deep learning; Machine learning; Medical imaging; Sarcopenia
    DOI:  https://doi.org/10.1016/j.compbiolchem.2026.108930
This page is being maintained by Thomas Krichel. It was last updated on 2026‒02‒01 at 1:28.