bims-moremu Biomed News
on Molecular regulators of muscle mass
Issue of 2026–02–08
forty papers selected by
Anna Vainshtein, Craft Science Inc.
  1. Mechanisms of protein degradation in atrophying muscles: what have we learned during the past decade?
  2. Largely Distinct Post-Translational Modifications Differentiate Skeletal Muscle Wasting Caused by Cancer, Dexamethasone and Aging.
  3. Direct AMPK Activation Confers Mutation-Independent Therapeutic Benefit in Duchenne Muscular Dystrophy.
  4. Muscle-specific transcriptomic and metabolomic signatures reveal heterogeneous aging trajectories and altered intercellular communication in male murine skeletal muscle.
  5. Combined effects of high-intensity interval training in the form of swimming exercise and rapamycin-sensitive mTORC1 inhibition on mitochondrial adaptations in mouse skeletal muscles.
  6. Molecular Mechanisms and Therapeutic Potential of DJ-1 in Skeletal Muscle Homeostasis and Disease.
  7. A simulation approach to integrated metabolic regulation in working skeletal muscle.
  8. Effect of Denervation on Skeletal Muscle Mitochondria in Heterozygous mtDNA Mutator Mice.
  9. Mechanistic Insights Into NFIX-Mediated DNA Recognition and Transcriptional Regulation in Skeletal Muscle.
  10. Early-life NAD+ deficiency programs skeletal muscle aging by sustained suppression of hyaluronic acid synthesis beginning in childhood.
  11. Revitalizing Muscles: Harnessing Exercise to Modulate Inflammatory Cytokines and Conquer Sarcopenia in Aging.
  12. Nur77 Regulates the Phosphorylation of Smad3, Thereby Influencing Skeletal Muscle Fibrosis Caused by Obesity.
  13. Elevating Circulating L-Kynurenine Promotes Frailty in Aging Mice.
  14. Planar cell polarity protein Vangl2 interacts with M-cadherin and stabilizes its cell surface expression in mouse C2C12 myoblasts.
  15. Resistance exercise alleviates skeletal muscle atrophy through reduction of oxidative stress via Sestrin1 in C57BL/6J mice.
  16. Disruptions of Cell Signaling Pathways in Myotonic Dystrophy Type 1 (DM1) Skeletal Muscle, their Pathogenic Impact and Potential for Combinatorial Therapeutics.
  17. SMAD2 ubiquitination through PY motif regulates skeletal muscle mass and fibrotic degeneration.
  18. Targeted knockdown of Smn in muscle stem cells induces non-cell autonomous loss of motor neurons.
  19. Neuromuscular Junction as a Molecular Target in Sarcopenia: Mechanisms, Therapeutic Strategies, and Future Directions.
  20. Role of Septin7 in mitochondrial dynamics and oxidative metabolism in C2C12 skeletal muscle cells.
  21. TRPV1 manipulating polarization of M1/M2 macrophages to promote skeletal muscle regeneration.
  22. Myopathy With Exercise-Induced Intolerance due to Novel Biallelic Variants in OBSCN-A Clinical, Morphological and Molecular Analysis.
  23. Leveraging mitochondrial stress to improve healthy aging.
  24. Aged Small Intestine Derived Small Extracellular Vesicles miR-214-3p Leads to Intermuscular Fatty Infiltration Through Wnt/β-Catenin Mediated Fibro-Adipogenic Progenitors Adipogenesis.
  25. MicroRNA Regulatory Targets Related to VO 2 peak Decline in Older Adult Participants of the Study of Muscle, Mobility and Aging (SOMMA).
  26. Age-Dependent Effects of Losartan and Exercise on Skeletal Muscle Redox Balance and Protein Turnover in Mice.
  27. Tceal7 is a BRG1-regulated target of calcineurin signaling that promotes myoblast differentiation.
  28. Vitamin B12 Improves Skeletal Muscle Mitochondrial Biology in Aged Mice.
  29. Transcriptomic analysis reveals the impact of concurrent, resistance, and endurance training on skeletal muscle.
  30. The transcriptomic signature of age and sex is not conserved in human primary myotubes.
  31. Editorial: Advancements in therapeutic strategies for skeletal muscle and cardiovascular diseases: integrating innovative approaches for enhanced outcomes.
  32. The ARHGAP10-202aa protein encoded by circARHGAP10 promotes skeletal muscle development and regeneration.
  33. The Copper Chaperone ATOX1 Exhibits Differential Protein-Protein Interactions and Contributes to Skeletal Myoblast Differentiation.
  34. Dynamic Reorganization of Developmental to Adult Genome Topology Controls the Initiation and Stabilization of the Human Muscle Stem Cell State.
  35. In silico transcriptome-based drug screening identifies celastrol as a multi-species therapeutic agent against aging-related sarcopenia and mitochondrial dysfunction.
  36. Overexpression of Rtl1 via synonymous mutation silencing miRNA target site drives skeletal muscle hypertrophy and inflammation in mice.
  37. Comparative Analysis of Matrigel and Tunable Collagen-Fibrin Blends for in Vitro Skeletal Muscle Models.
  38. Dual AAV gene therapy using laminin-linking proteins ameliorates muscle and nerve defects in LAMA2-related muscular dystrophy.
  39. Muscle transcriptome profiling reveals novel molecular pathways and biomarkers in laminin-α2 deficient patients.
  40. Functional properties of skeletal myotube-derived extracellular vesicles based on microRNA profiles: a comparative analysis with mesenchymal stem cell-derived extracellular vesicles.
  1. J Biol Chem. 2026 Feb 03. pii: S0021-9258(26)00099-2. [Epub ahead of print] 111229
    Mechanisms of protein degradation in atrophying muscles: what have we learned during the past decade?
    Shenhav Shemer.
      Skeletal muscle atrophy occurs in diverse conditions, including aging, disuse, cancer cachexia, and chronic disease. It results from an imbalance between protein synthesis and degradation, where excessive proteolysis drives loss of contractile proteins, weakness, and metabolic decline. Recent advances in structural biology, multi-omics approaches, and high-resolution imaging have uncovered how sarcomeric and cytoskeletal components are gradually degraded by ubiquitin ligases, proteasomes, and autophagy. Mechanical loading and mechanotransduction emerge as key regulators of proteostasis, linking tension to anabolic signaling. Transcriptional and epigenetic control through IGF1-Akt-mTOR, TGF-β, inflammatory cytokines, and circadian rhythms as well as non-coding RNAs and miRNAs also contribute to wasting. This review summarizes these recent findings, and novel therapeutic strategies such as restoring mitochondrial function and modulating RNA networks and mechanosensitive signaling to preserve muscle mass and function.
    Keywords:  Ubiquitin proteasome system; autophagy; desmin; insulin signaling; lncRNA; mitochondria; muscular dystrophy; myofibrils; proteostasis; sarcomere; skeletal muscle atrophy
    DOI:  https://doi.org/10.1016/j.jbc.2026.111229
  2. J Cachexia Sarcopenia Muscle. 2026 Feb;17(1): e70220
    Largely Distinct Post-Translational Modifications Differentiate Skeletal Muscle Wasting Caused by Cancer, Dexamethasone and Aging.
    Anna Stephan, Flavia A Graca, Suresh Poudel, Yingxue Fu, Yong-Dong Wang, Myriam Labelle, Fabio Demontis.
       BACKGROUND: Skeletal muscle wasting and weakness are prominent disease features. Originally considered to arise from common transcriptional changes, recent analyses demonstrated that different stimuli induce muscle wasting via largely distinct mRNA and protein changes.
    METHODS: Here, we examined the post-translational modifications (PTMs) associated with muscle wasting induced by cancer (n = 15 078), dexamethasone (n = 15 078) and aging (n = 8777) in mice by utilising the JUMPptm pipeline to recover modified peptides from TMT (tandem mass tag) mass spectrometry analyses.
    RESULTS: We find that most PTMs that are significantly regulated are stimulus-specific and that only a few are cross-shared (n = 10; p < 0.05). These include P27 dihydroxylation of Lrpprc (leucine-rich pentatricopeptide repeat containing), an RNA binding protein and transcriptional co-activator mutated in Leigh syndrome, a mitochondrial disease. Contrary to the stimulus-specificity of other atrophy-associated PTMs, P27 dihydroxylation of Lrpprc declines (~20%; p < 0.05) with muscle wasting irrespective of the atrophic trigger. Electroporation of dihydroxylation-resistant LrpprcP27A (which mimics the reduction in Lrpprc dihydroxylation that occurs with atrophy) reduces muscle force in young (~23%-39%; p < 0.01) and old (~26%-36%; p < 0.01) male mice compared to the contralateral electroporation of LrpprcWT, indicating that a decline in Lrpprc P27 dihydroxylation contributes to muscle weakness in response to diverse catabolic stimuli. Comparison of LrpprcWT versus GFP electroporation indicates that there are mostly non-significant effects (p > 0.05) on muscle force in young and old mice. Mechanistically, LrpprcP27A does not affect proteostasis and mitochondrial function compared to control LrpprcWT but impairs (> 60% decline; p < 0.05) the expression of genes necessary for muscle strength, including the apelin receptor Aplnr and Col6a2/6 collagens. Moreover, LrpprcP27A reduces type 2b myofibre size (13% decline; p < 0.01) in old but not in young age.
    CONCLUSIONS: These analyses identify atrophy-associated PTMs that provide refined biomarkers for fingerprinting the atrophic stimulus. Although most PTMs are stimulus-specific, P27 dihydroxylation of Lrpprc declines during muscle wasting induced by cancer, dexamethasone and aging, suggesting that this is a general atrophy marker. Experimental up-regulation of the atrophy-mimicking variant LrpprcP27A reduces muscle force compared to wild-type Lrpprc in young and old mice, suggesting that atrophy-associated P27 dihydroxylation contributes to disease-associated muscle weakness.
    Keywords:  Leigh syndrome; Lrpprc; aging; atrophy; cancer cachexia; post‐translational modifications; sarcopenia; skeletal muscle weakness
    DOI:  https://doi.org/10.1002/jcsm.70220
  3. J Cachexia Sarcopenia Muscle. 2026 Feb;17(1): e70200
    Direct AMPK Activation Confers Mutation-Independent Therapeutic Benefit in Duchenne Muscular Dystrophy.
    Sean Y Ng, Andrew I Mikhail, Stephanie R Mattina, Magda A Lesinski, Irena A Rebalka, Sophie I Hamstra, Donald Xhuti, Val A Fajardo, Mark A Tarnopolsky, Joshua P Nederveen, Gregory R Steinberg, Thomas J Hawke, Vladimir Ljubicic.
       BACKGROUND: Duchenne muscular dystrophy (DMD) is a severe, life-limiting neuromuscular disorder (NMD) characterized by progressive muscle wasting and mitochondrial dysfunction. Although gene therapies offer promise, even those already approved by regulatory agencies, their use remains constrained by mutation specificity, delivery challenges and durability. Pharmacologically targeting AMPK has shown potential to ameliorate dystrophic pathology, but prior strategies have been hindered by inadequate efficacy and off-target effects.
    METHODS: Comparative transcriptomic analyses were conducted to assess concordance between gene expression profiles induced by direct AMPK activation and those observed in DMD patient muscle. To evaluate the therapeutic potential of sustained AMPK activation, DBA/2J-mdx (D2.mdx; n = 8-10) mice were treated daily with MK-8722 (MK; 5 mg·kg-1) or vehicle for 7 weeks, with healthy DBA/2J mice serving as controls. Additionally, DMD patient-derived myotubes (n = 4) were treated with MK (1 μM, 24 h) to assess AMPK-mediated cellular adaptations in human cells.
    RESULTS: Transcriptomic profiling revealed that MK modulated 206 DMD-associated transcripts, reversing expression of 73 upregulated and 133 downregulated genes. In vivo, MK-treated D2.mdx mice showed enhanced AMPK signalling (ACC phosphorylation, +120%-150%; p < 0.05), increased Ppargc1a expression (+60%, p < 0.05) and reduced inflammation- and fibrosis-associated transcripts (-25%-50%; p < 0.05). Seven weeks of daily MK treatment enhanced (+95%; p < 0.05) whole-body lipid oxidation during active periods without affecting energy expenditure or activity. Notably, we observed that repeated MK dosing did not adversely impact cardiac morphology or function (p > 0.05). MK-treated D2.mdx mice demonstrated improved grip strength fatigability (-35%, p < 0.05), inverted hang performance (+100%, p < 0.05) and treadmill exercise capacity (+20%, p < 0.05). Additional ex vivo muscle assessments revealed (+30%; p < 0.05) greater peak isometric force and improved twitch contractile kinetics. These functional adaptations were coincident with reduced myofibre damage and fibrosis, with increased sarcolemmal expression of utrophin, γ-sarcoglycan and β-dystroglycan (+10%-70%; p < 0.05), despite no changes in fibre size or mass. Mitochondrial assessments showed increased State III respiration (+80%; p < 0.05), reduced reactive oxygen species production (-70%; p < 0.05) and elevated OXPHOS protein content (+25%-45%; p < 0.05). In patient-derived myotubes, MK similarly activated AMPK signalling, increased mitochondrial electron transport chain proteins (+25%-35%; p < 0.05) and enhanced maximal oxygen consumption (+50%-80%; p < 0.05) in DMDΔ44 and DMDΔ45 lines.
    CONCLUSIONS: These findings demonstrate that sustained, systemic activation of AMPK safely improves muscle function, metabolic health and dystrophic pathology in a mutation-independent manner. This supports the therapeutic potential of direct AMPK agonists as a disease-modifying strategy for DMD and other neuromuscular disorders.
    Keywords:  AMP‐activated protein kinase; Duchenne muscular dystrophy; heart; mitochondria; neuromuscular junction; skeletal muscle; utrophin
    DOI:  https://doi.org/10.1002/jcsm.70200
  4. Biogerontology. 2026 Feb 05. 27(2): 48
    Muscle-specific transcriptomic and metabolomic signatures reveal heterogeneous aging trajectories and altered intercellular communication in male murine skeletal muscle.
    Caifen Guo, Xinqiang Lan, Chunping Huang, Xiang Wang, Dongqin Zhang, Lin Zeng, Qiquan Wang, Yang Xiang, Jian Li.
      Skeletal muscle aging is characterized by progressive functional decline and molecular remodeling, yet how different muscle types respond to aging remains incompletely understood. Here, we performed integrated transcriptomic and metabolomic profiling of three functionally distinct muscles-gastrocnemius (GA), soleus (SOL), and tibialis anterior (TA)-from young (3-month) and aged (24-month) C57BL/6J male mice. Our multi-omics approach revealed both shared and muscle-specific molecular signatures of aging. While all three muscles exhibited a core set of 83 commonly altered genes enriched in circadian rhythm, xenobiotic metabolism, and immune signaling pathways, each muscle displayed unique aging trajectories. GA showed 881 differentially expressed genes with prominent alterations in PI3K-Akt and p53 signaling; SOL exhibited 1232 changes emphasizing oxidative phosphorylation and inflammatory responses; TA demonstrated the most extensive remodeling with 1492 altered genes, particularly in extracellular matrix organization and fatty acid metabolism. Metabolomic analysis revealed muscle-specific metabolic reprogramming: GA showed disrupted pentose phosphate and arginine pathways; SOL exhibited altered branched-chain amino acid metabolism; TA displayed TCA cycle perturbations. Notably, the coordination between transcriptomic and metabolomic changes varied by muscle type-GA showed decoupled responses, while SOL and TA demonstrated compensatory inverse relationships. Lipid metabolism emerged as a critical aging-associated process with distinct muscle-specific adaptations: SOL upregulated antioxidant defenses, TA activated compensatory PPAR and PI3K-Akt signaling, while GA showed intermediate responses. Furthermore, receptor-ligand correlation analysis revealed age-dependent reorganization of intermuscular communication networks, with enhanced chemokine signaling and altered growth factor crosstalk. These findings establish that skeletal muscle aging involves both systemic responses and highly muscle-specific molecular adaptations, providing insights for targeted therapeutic strategies against sarcopenia.
    Keywords:  Gastrocnemius; Lipid metabolism; Metabolomics; Oxidative stress; Sarcopenia; Skeletal muscle aging; Soleus; Tibialis anterior; Transcriptomics
    DOI:  https://doi.org/10.1007/s10522-026-10397-1
  5. Appl Physiol Nutr Metab. 2026 Jan 29.
    Combined effects of high-intensity interval training in the form of swimming exercise and rapamycin-sensitive mTORC1 inhibition on mitochondrial adaptations in mouse skeletal muscles.
    Kazuki Uemichi, Takanaga Shirai, Hayato Shinkai, Ryoto Iwai, Tomohiro Iwata, Shunsuke Sugiyama, Tohru Takemasa.
      High-intensity interval training (HIIT) is an effective strategy for enhancing exercise performance by stimulating skeletal muscle mitochondria and increasing their oxidative metabolic capacity. HIIT is also known to stimulate the mechanistic target of rapamycin complex 1 (mTORC1), a key regulatory factor in muscle protein anabolism; however, the role of mTORC1 in HIIT-induced mitochondrial adaptations remains unclear. We hypothesized that mTORC1 modulates mitochondrial adaptation induced by exercise training and investigated the effects of in vivo administration of rapamycin, a canonical inhibitor of mTOR, on skeletal muscle mitochondria after chronic HIIT. Male C57BL6/J mice (n = 21) were evenly assigned to three groups: one group served as the sedentary control (SED), another group performed 4 weeks of HIIT through loaded swimming five times per week (HIIT), and the third group underwent HIIT received intraperitoneal rapamycin administration (HIIT+RAPA). Twenty-four hours after completing the final training session, the animals were anesthetized and euthanized, following which the gastrocnemius, plantaris, and soleus muscles were collected, and their mitochondrial enzyme activities, content, morphology, and regulatory protein levels were evaluated. The combination of HIIT and rapamycin administration increased mitochondrial oxidative phosphorylation (OXPHOS) subunits (P = 0.0363 vs. HIIT, plantaris; P = 0.0176 vs. HIIT, soleus) and decreased the levels of proteins involved in mitochondrial fusion/fission (P = 0.0170 vs. HIIT, gastrocnemius OPA1; P = 0.0140 vs. HIIT, gastrocnemius DRP1 Ser616). Additionally, the number and circularity of mitochondria were increased only in the soleus muscle in the HIIT+RAPA group. These findings indicate that the regulatory role of rapamycin-sensitive mTORC1 on the mitochondrial molecular response and morphological changes in skeletal muscle induced by swimming-type HIIT varies across different skeletal muscles.
    DOI:  https://doi.org/10.1139/apnm-2025-0316
  6. Compr Physiol. 2026 Feb;16(1): e70091
    Molecular Mechanisms and Therapeutic Potential of DJ-1 in Skeletal Muscle Homeostasis and Disease.
    Yue Zhang, Menghuan Li, Xiaojing Xie, Baokai Tian, Zhenwei Bao, Xuejie Yi.
      The DJ-1 protein was initially identified as an oncogene, but subsequent studies revealed its crucial protective role in neurodegenerative diseases. Increasing evidence indicates that DJ-1 possesses critical physiological functions in skeletal muscle, but the underlying mechanisms remain to be systematically elucidated. Existing research has conclusively demonstrated that DJ-1 is widely expressed in skeletal muscle and functions as a central hub integrating multiple pathways to establish a multi-level cellular protection network: it safeguards energy metabolism by maintaining mitochondrial structure and function; enhances antioxidant capacity by directly scavenging ROS and regulating Nrf2/ARE signaling; and delays muscle aging by inhibiting protein aggregation and preserving protein homeostasis. Under pathological conditions, DJ-1 dysfunction is closely associated with muscular dystrophy, inflammatory myopathy, metabolic myopathy, and muscle atrophy. Its abnormalities lead to mitochondrial damage, exacerbated oxidative stress, and disrupted protein homeostasis, ultimately triggering muscle structural deterioration. Based on these insights, researchers have developed various DJ-1 regulatory strategies, including small-molecule activators, transcriptional modulators, and functional peptide compounds, which show promising therapeutic potential. This review represents the first systematic, cross-disease integration of DJ-1's role in aging-related sarcopenia, diabetic myopathy, inflammatory myopathies, and neuromuscular degenerative diseases. It elucidates DJ-1's core function as a central integrator coordinating antioxidant defense, mitochondrial homeostasis, metabolic regulation, and protein homeostasis. A deeper understanding of DJ-1's mechanisms will provide critical theoretical foundations for elucidating the common pathological basis of skeletal muscle diseases and developing novel therapeutic strategies.
    Keywords:  DJ‐1; mitochondria; muscle diseases; oxidative stress; skeletal muscle
    DOI:  https://doi.org/10.1002/cph4.70091
  7. J Physiol. 2026 Feb 04.
    A simulation approach to integrated metabolic regulation in working skeletal muscle.
    Graham J Kemp.
      
    Keywords:  31P MRS; computational simulation; muscle energetics; muscle metabolism; nuclear magnetic resonance
    DOI:  https://doi.org/10.1113/JP290772
  8. FASEB Bioadv. 2026 Feb;8(2): e70088
    Effect of Denervation on Skeletal Muscle Mitochondria in Heterozygous mtDNA Mutator Mice.
    Takanaga Shirai, Hideto Hanakita, Kohei Takeda, Yu Kitaoka, Kaori Ishikawa, Kazuto Nakada, Tohru Takemasa.
      Mitochondrial function is essential for skeletal muscle health, and its disruption leads to atrophy and functional decline. This study examines the impact of denervation on skeletal muscle mitochondria in polymerase gamma (PolG)(+/mut) mice, which accumulate mitochondrial DNA (mtDNA) mutations due to a partial deficiency in polymerase gamma proofreading. Using a 14-day denervation protocol, we assessed muscle mass, mtDNA copy number, oxidative stress and mitochondrial dynamics in wild-type (WT) and PolG(+/mut) mice. Our findings reveal that while denervation significantly reduced muscle wet weight and mitochondrial enzyme activity, no genotype-specific differences in muscle atrophy were observed. However, PolG(+/mut) mice displayed more disorganized mitochondrial cristae and elevated oxidative stress markers, indicating greater mitochondrial vulnerability. Despite these changes, the lack of significant differences in mitochondrial proteins and gene expression between genotypes may reflect an adaptive antioxidant response, including increased catalase expression, although the compensatory nature of this response cannot be conclusively determined. These results suggest that oxidative stress-related responses are involved in mitochondrial adaptations during denervation-induced muscle atrophy. The increased expression of antioxidant enzymes, such as catalase, in PolG(+/mut) mice suggests that antioxidant mechanisms are activated in response to increased oxidative stress. These findings underscore the importance of controlling oxidative stress for maintaining muscle health.
    Keywords:  atrophy; mitochondria; mtDNA; oxidative stress; polymerase gamma; skeletal muscle
    DOI:  https://doi.org/10.1096/fba.2025-00072
  9. Smart Med. 2026 Feb;5(1): e70027
    Mechanistic Insights Into NFIX-Mediated DNA Recognition and Transcriptional Regulation in Skeletal Muscle.
    Ci Zhu, Shuang Liu, Xi Chen, Chengxiao Qin, Yueyu Wang, Chunchun Xue, Lingxing Li, Wenlan Du, Xin Chen, Xiaofeng Li, Jie Shen, He Song.
      Skeletal muscle is essential for voluntary movement and exhibits a remarkable capacity for regeneration following injury. NFIX, a member of the Nuclear Factor I (NFI) family of transcription factors, plays a critical role in both skeletal muscle development and regeneration. Despite its emerging importance, the molecular basis of NFIX-mediated DNA recognition and transcriptional regulation in skeletal muscle remains poorly defined. Here, we demonstrate that NFIX promotes key cellular processes in skeletal muscle cells, as siRNA-mediated knockdown of NFIX significantly reduces cell proliferation, increases apoptosis, and impairs differentiation. Transcriptomic analysis revealed that NFIX regulates a network of genes involved in muscle metabolism, stress responses, and immune inflammatory responses. Biophysical characterization showed that NFIX exists as a monomer in solution and binds palindromic DNA with a 1:1 stoichiometry. A high-resolution crystal structure of the NFIXDBD bound to palindromic DNA reveals a monomeric binding mode driven by base-specific recognition of the TGGCA motif. Mutations that disrupt key DNA-contacting residues abolished both DNA binding and transcriptional activation in luciferase reporter assays. Together, these findings define the molecular mechanism of NFIX-dependent gene regulation in skeletal muscle and establish a structural framework for its function, providing new insights into the potential therapeutic targeting of NFIX in muscle diseases.
    Keywords:  DNA recognition; NFIX; homeostasis; skeletal muscle development; transcriptional regulation
    DOI:  https://doi.org/10.1002/smmd.70027
  10. Cell Rep. 2026 Jan 28. pii: S2211-1247(25)01684-5. [Epub ahead of print]45(2): 116912
    Early-life NAD+ deficiency programs skeletal muscle aging by sustained suppression of hyaluronic acid synthesis beginning in childhood.
    Mariam Karim, Keisuke Yaku, Jun-Dal Kim, Akira Okekawa, Tsutomu Wada, Hitoshi Uchida, Amane Mizutani, Tran Canh Tung Nguyen, Yoshiharu Kawaguchi, Yoshimi Nakagawa, Toshiyasu Sasaoka, Yasuhito Yahara, Takashi Nakagawa.
      Nicotinamide adenine dinucleotide (NAD+) levels decline with age, which has been associated with the development of aging-associated diseases. However, it remains unknown whether low NAD+ levels in early life affect aging. This study demonstrates that deficiency of NAD synthetase (NADS), a critical enzyme of the deamidated NAD+ biosynthesis pathway, drastically reduced NAD+ levels in skeletal muscle and impaired muscle function at a young age. Intriguingly, NAD+ levels were restored to normal in middle-aged NADS-knockout mice, whereas muscle function remained compromised. Gene expression analysis showed that hyaluronic acid synthase 2 (Has2) was downregulated in both young NADS-knockout mice and aged wild-type mice. We also found that the α-ketoglutarate-JMJD3 axis downregulates Has2 expression. Then, impaired hyaluronic acid signaling dampened muscle stem cells, leading to decreased locomotor activity. These results suggest that maintaining NAD+ levels during early life is important for promoting healthy aging in skeletal muscle.
    Keywords:  CP: metabolism; DOHaD theory; NAD(+); aging; histone methylation; hyaluronic acid; skeletal muscle
    DOI:  https://doi.org/10.1016/j.celrep.2025.116912
  11. Cell Biochem Biophys. 2026 Feb 03.
    Revitalizing Muscles: Harnessing Exercise to Modulate Inflammatory Cytokines and Conquer Sarcopenia in Aging.
    Hongtao Li, Zhaosheng Chen, Xie Songlin.
      
    Keywords:  Exercise therapy; Inflammatory cytokines; Muscle aging; Sarcopenia; Satellite cells
    DOI:  https://doi.org/10.1007/s12013-026-02004-4
  12. FASEB J. 2026 Feb 15. 40(3): e71484
    Nur77 Regulates the Phosphorylation of Smad3, Thereby Influencing Skeletal Muscle Fibrosis Caused by Obesity.
    Na Li, Tingting Tian, Qihe Zhao, Difei Wang.
      Skeletal muscle fibrosis is caused by excessive production or reduced degradation of extracellular matrix, leading to excessive accumulation of collagen. Obesity can trigger physiological and pathological changes in skeletal muscle, such as fibrosis, muscle atrophy, and impaired muscle regeneration. Nerve growth factor-induced gene B (Nur77), a transcription factor encoded by orphan nuclear receptor 4A1 (NR4A1), a member of the immediate early gene nuclear receptor subfamily 4A group, participates in a variety of life activities. Here, we found that in the obese mouse model fed with a high-fat diet, mice with Nur77 gene knockout would exacerbate the skeletal muscle fibrosis phenotype caused by obesity. It is worth noting that Nur77 can bind to the central downstream molecules Smad3, which regulates the synthesis of fibrotic proteins COL1A1 and COL3A1. The activity of the Smad3 protein is crucial for obesity-related muscle fibrosis, suggesting that Nur77 may affect skeletal muscle fibrosis by regulating the activity of Smad3.
    Keywords:  Nur77; obesity; skeletal muscle fibrosis; smad3
    DOI:  https://doi.org/10.1096/fj.202502392RR
  13. J Cachexia Sarcopenia Muscle. 2026 Feb;17(1): e70214
    Elevating Circulating L-Kynurenine Promotes Frailty in Aging Mice.
    Mia Y Kawaida, Abigail L Tice, Samuel Alvarez, Jacob A Lackey, Benjamin Izaguirre, Qingping Yang, Lan Wei-LaPierre, Russell T Hepple, Terence E Ryan.
       BACKGROUND: L-Kynurenine (L-Kyn), a product of tryptophan catabolism, increases with age and has been associated with reduced physical function and increased frailty in humans. Robustly expressed in skeletal muscle, kynurenine aminotransferases (KATs) degrade L-Kyn into kynurenic acid and are regulated by the transcriptional co-regulator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α).
    METHODS: The study investigated (1) if elevating L-Kyn levels via a diet intervention exacerbates an age-related decline in physical, muscle and mitochondrial functions and (2) if transgenic expression of PGC1α in skeletal muscle (MCK-PGC1α) protects against age-dependent L-Kyn associated pathology in a cohort of aging MCK-PGC1α transgenic mice and their wildtype littermates of both sexes (n = 262). Physical function was assessed longitudinally from 16 to 24 months of age using treadmill endurance capacity, grip strength, walking speed and daily physical activity. Muscle function was assessed in situ using nerve-mediated contraction of the soleus muscle. Mitochondrial energetics were assessed using high resolution respirometry and fluorescence spectroscopy.
    RESULTS: MCK-PGC1α transgenic mice had significantly higher KAT expression ~2-5-fold compared with wildtype littermates (p < 0.0001 for all isoforms). A main effect of L-Kyn diet was observed for decreasing treadmill endurance capacity and daily physical activity in male mice (p ≦ 0.002). A main effect of L-Kyn diet for decreasing maximal walking speed only was found in female mice (p = 0.037). Correspondingly, L-Kyn increased frailty prevalence in male (+17%) and female (+26%) wildtype mice (p = 0.025 and 0.0001 respectively), which was mitigated by MCK-PGC1α in both sexes. Soleus muscle strength and power were not impacted by diet or genotype in either sex (p > 0.5). Mitochondrial oxidative phosphorylation function in male and female MCK-PGC1α mice was greater than wild type mice regardless of diet (p < 0.04), which is likely driven by upregulated expression of mitochondrial biogenesis related genes.
    CONCLUSIONS: We conclude that PGC1α overexpression in skeletal muscle mitigates the exacerbation of physical frailty induced by elevated circulating L-Kyn in aging mice, in part through increased skeletal muscle capacity for L-Kyn metabolism due to PGC1α-induced increase in muscle KAT expression.
    Keywords:  aging; frailty; mitochondria; muscle; physical function
    DOI:  https://doi.org/10.1002/jcsm.70214
  14. Front Cell Dev Biol. 2026 ;14 1701716
    Planar cell polarity protein Vangl2 interacts with M-cadherin and stabilizes its cell surface expression in mouse C2C12 myoblasts.
    Tadahiro Nagaoka, Erina Sasaki, Sakiho Takagi, Masashi Kishi, Keisuke Hitachi, Kunihiro Tsuchida.
      Skeletal muscle regeneration depends on muscle stem cells (MuSCs), in which cadherin-mediated adhesion and planar cell polarity (PCP) signaling play critical roles. M-Cadherin is the major cadherin expressed in MuSCs; however, its functional link to PCP proteins remains unclear. In this study, we demonstrate that the PCP core component Vangl2 co-localizes with M-cadherin at the MuSC-myofiber boundary and directly interacts with it in C2C12 cells. Mutagenesis analyses revealed that the catenin-binding domain of M-cadherin and the C-terminal domain of Vangl2 are required for this interaction, which uniquely enables M-cadherin to form a ternary complex with Vangl2 and β-catenin. Knockdown of Vangl2 impaired myoblast fusion, reduced the expression of MyoD and Myomixer, and decreased the cell surface stability of M- and N-cadherins, while canonical Wnt/β-catenin and Akt signaling were unaffected. These findings demonstrate that Vangl2 stabilizes cadherins at the plasma membrane and promotes myogenic differentiation, suggesting a previously unrecognized role of PCP signaling in skeletal muscle maintenance and regeneration.
    Keywords:  M-cadherin; Vangl2; cell adhesion; myogenesis; planar cell polarity; skeletal muscle
    DOI:  https://doi.org/10.3389/fcell.2026.1701716
  15. Sports Med Health Sci. 2026 Jan;8(1): 50-60
    Resistance exercise alleviates skeletal muscle atrophy through reduction of oxidative stress via Sestrin1 in C57BL/6J mice.
    Xuege Yang, Jinglin Peng, Yating Huang, Sujuan Liu, Yanmei Niu, Li Fu.
      Resistance exercise has been confirmed to be important for maintaining muscle mass and function. However, despite considerable experimental studies, the underlying mechanisms still requires further investigation to be elucidated. Sestrin1 is a stress-inducible protein strongly associated with the occurrence and development of skeletal muscle dysfunction. Besides, oxidative stress is believed to be a major pathogenic mechanism in the development of skeletal muscle atrophy, whereas regular exercise training induces the endogenous antioxidative system and protects the body against adverse effects of oxidative stress. Nevertheless, whether Sestrin1 is involved in the amelioration of resistance exercise on muscle atrophy and the role of its antioxidant function in this process remains unknown. Here we show that six-week resistance exercise training significantly improved muscle function, muscle mass, and oxidative damage and maintained the level of Sestrin1 in dexamethasone-treated C57BL/6J mice. Mechanistically, Sestrin1 overexpression rescued protein degradation and oxidative stress in atrophied myotubes. Furthermore, an emerging regulator of cellular defense against toxic and oxidative insults, nuclear factor erythroid2-related factor 2 (Nrf2) controls the basal and induced expression of an array of antioxidant response element-dependent genes to regulate the pathophysiological outcomes of oxidant exposure. In this study, we found that Nrf2 is a target of Sestrin1, and Nrf2 nuclear translocation is facilitated by Sestrin1. ML385 (an Nrf2 inhibitor) treatment mitigated the regulatory effects of overexpression-Sestrin1. Therefore, Sestrin1 was involved in the process of resistance exercise against skeletal muscle atrophy, which may be closely related to its antioxidant capacity, revealing a potential therapeutic strategy for reducing the loss of skeletal muscle.
    Keywords:  Muscle atrophy; Nrf2; Oxidative stress; Resistance exercise; Sestrin1
    DOI:  https://doi.org/10.1016/j.smhs.2025.02.001
  16. J Biol Chem. 2026 Jan 30. pii: S0021-9258(26)00089-X. [Epub ahead of print] 111219
    Disruptions of Cell Signaling Pathways in Myotonic Dystrophy Type 1 (DM1) Skeletal Muscle, their Pathogenic Impact and Potential for Combinatorial Therapeutics.
    Aymeric Ravel-Chapuis, Shatha A Atieh, Chimène Fahmi, Bernard J Jasmin.
      Myotonic Dystrophy type 1 (DM1) is caused by a CUG expansion located in the 3' untranslated region (UTR) of dystrophia myotonica protein kinase (DMPK) mRNAs. The pathogenic model underlying DM1 implicates the accumulation of mutant DMPK transcripts in nuclei where they form toxic RNA foci. This, in turn, disrupts the functional availability of several RNA-binding proteins involved in pre-mRNA alternative splicing. Consequently, such dysregulations result in widespread missplicing of multiple mRNAs accounting for the plethora of DM1 symptoms. Accordingly, DM1 is referred to as a spliceopathy. Over the years, multiple signaling pathways have also been reported to be disrupted in DM1, especially in skeletal muscle. In this review, we focus on several of these pathways including protein kinase R (PKR), protein kinase C (PKC), glycogen synthase kinase 3β (GSK-3β), Akt-mTOR, AMP-activated protein kinase (AMPK), TWEAK-Fn14 and NF-kB, and calcineurin-NFAT. We describe the individual effects of these signaling disruptions on multiple skeletal muscle functions and characteristics, and we also present an overview of their cumulative impact. Based on the available literature, the dysregulation of signaling in skeletal muscle jointly results in global perturbations in protein synthesis and degradation, muscle repair, mitochondrial biogenesis, energy metabolism and inflammation. Despite these advances, the full spectrum of alterations in signaling pathways in DM1 muscle remains incomplete and a certain level of variability in the extent of signaling defects in DM1 muscles has been observed likely due to varied experimental approaches and designs. Additional key unanswered questions relate to how mechanistically the CUG expansion in DMPK mRNAs causes the dysregulation of multiple signaling cascades, and whether missplicing of pivotal signaling molecules within these various pathways further contributes to signaling defects. The fact that pharmacological, physiological, and transgenic approaches targeting these pathways have corrected defects observed in DM1 muscle provides a strong rationale for therapeutic intervention. These pathways can be targeted either individually or through combinatorial treatments involving two or more agents and/or strategies. Based on the importance and impact of these signaling pathways on multiple aspects of the DM1 muscle phenotype, therapeutically targeting these disruptions is becoming increasingly attractive and represents a critical area for additional research in the quest to slow or reverse muscle dysfunction in DM1.
    Keywords:  Cell Signaling; Myotonic Dystrophy; Skeletal Muscle; Therapeutics
    DOI:  https://doi.org/10.1016/j.jbc.2026.111219
  17. Sci Rep. 2026 Jan 30.
    SMAD2 ubiquitination through PY motif regulates skeletal muscle mass and fibrotic degeneration.
    Yuki Yamasaki, Keita Sakamoto, Shunki Yashiro, Yutaro Kawa, Akiko Kondow, Atsushi Kubo, Keisuke Hitachi, Masafumi Inui.
      Transforming growth factorβ (TGFβ) signaling regulates diverse aspects of vertebrate skeletal muscle tissue including differentiation, homeostasis, regeneration and pathogenic degeneration. Ubiquitination of SMAD2, an intracellular transducer of TGFβ signaling, is a well-studied negative feedback regulation of the signaling pathway in the field of cell biology, but it's relevance in skeletal muscle tissue has been elusive. In this study, to elucidate the in vivo role of SMAD2 ubiquitination, we generated Smad2dPY mutant mice in which a 15 bp sequence encoding the PY motif of SMAD2 protein is deleted from Smad2 gene. By removing this motif, the SMAD2 protein escapes from protein-protein interaction with NEDD4 family E3 ligases and thus is devoid of ubiquitination-dependent negative regulation. Smad2dPY mice showed no obvious abnormality in development, growth or fertility, indicating that SMAD2 ubiquitination through PY motif is dispensable for these processes. The skeletal muscle of Smad2dPY mice demonstrated reduced weight and myofiber size reduction at 12 months old. SMAD2 protein level was increased in the skeletal muscle of Smad2dPY mice while SMAD2 ubiquitination was reduced. Primary myoblasts of Smad2dPY mice displayed higher TGFβ responsiveness and suppressed terminal differentiation, which may explain the reduced muscle mass. The TGFβ responsiveness of the interstitial fibroblast population was also increased. Fibrotic tissue remodeling triggered by cardiotoxin injection was exacerbated in Smad2dPY mice. Altogether, our study identified SMAD2 ubiquitination through PY motif as an important regulatory mechanism operating in skeletal muscle tissue to maintain the TGFβ signaling pathway at the desired level in homeostasis and tissue remodeling.
    Keywords:  Fibrosis; Skeletal muscle; Smad2; TGF-beta; Ubiquitination
    DOI:  https://doi.org/10.1038/s41598-026-37582-z
  18. Brain. 2026 Feb 06. pii: awag045. [Epub ahead of print]
    Targeted knockdown of Smn in muscle stem cells induces non-cell autonomous loss of motor neurons.
    Jordan Mecca, Julien Mignot, Marianne Gervais, Teoman Ozturk, Stéphanie Astord, Juliette Berthier, Stéphanie Bauché, Julien Messéant, Maria G Biferi, Hélène Rouard, Martine Barkats, Frédéric Relaix, Nathalie Didier.
      Spinal Muscular Atrophy (SMA) is due to a deficit in SMN, a ubiquitously expressed protein encoded by the Survival of Motor Neuron 1 (SMN1) gene. Recently, SMN-targeted disease modifying treatments have greatly improved the clinical outcomes of this neuromuscular disease. However, uncertainties remain regarding their long-term efficacy and non-neuronal tissue involvement in disease progression. Skeletal muscle tissue and the Muscle Stem Cells (MuSC) that sustain its postnatal growth and regenerative capacity, are affected by SMN deficit. While a direct contribution of muscle tissue in the disease progression has been demonstrated, the extent to which MuSC are involved in this process remains to be established. Using SMA type II patient muscle biopsies and several mutant mouse models, we performed an accurate study of SMN role in MuSC function during postnatal growth and adulthood. We found that SMA type II patient muscles display a reduced number of quiescent PAX7+ MuSC. In SMA mice, we showed that SMN is an important regulator of myogenic progenitor fate during early postnatal growth, and that SMN deficit compromises MuSC reservoir establishment. In Pax7 Cre-driven conditional knockout mouse models, we demonstrated that deletion of a single Smn allele is sufficient to induce quiescent MuSC apoptosis in adult muscle, showing that high levels of SMN are required for the maintenance of the quiescent MuSC reservoir. We further established that depletion of MuSC yielded neuromuscular junctions remodeling followed by a non-cell autonomous loss of part of the alpha motor neurons (MN) in the long term. Overall, our findings demonstrate an interdependence between quiescent MuSC and the MN reservoirs, supporting that MuSC may be important therapeutic targets for the long-term treatment of SMA. Moreover, we provide important insights into the specific SMN requirements of MuSC, which could be valuable for to the development of next generation combinatorial therapies.
    Keywords:  motor neurons; muscle stem cells; neuromuscular junctions; spinal muscular atrophy
    DOI:  https://doi.org/10.1093/brain/awag045
  19. Mol Diagn Ther. 2026 Jan 31.
    Neuromuscular Junction as a Molecular Target in Sarcopenia: Mechanisms, Therapeutic Strategies, and Future Directions.
    Rizwan Qaisar, Firdos Ahmad, Asima Karim.
      Sarcopenia is a progressive loss of skeletal muscle mass and strength that significantly contributes to frailty and disability in older adults. Traditionally considered a consequence of myofiber atrophy and impaired protein turnover, recent evidence highlights neuromuscular junction (NMJ) degeneration as an early and critical event in the pathogenesis of this condition. Structural and functional changes at the NMJ, including fragmentation of acetylcholine receptor clusters, motor neuron loss, and disruption of agrin-muscle-specific kinase (MuSK) signaling, impair neuromuscular transmission and accelerate muscle decline. This review synthesizes current understanding of NMJ biology, its age-related deterioration, and emerging therapeutic strategies aimed at preserving synaptic integrity. We discuss pharmacological approaches that target presynaptic neurotransmitter synthesis, stabilize the synaptic cleft, and enhance postsynaptic receptor clustering, as well as interventions that activate Schwann and satellite cells to restore regenerative capacity. Adjunctive therapies such as antioxidants, mitochondrial protectants, and metabolic modulators complement NMJ-specific drugs by mitigating oxidative stress and inflammation. Translational insights underscore the importance of NMJ-specific biomarkers, such as circulating c-terminal agrin fragment-22 (CAF22), and advanced imaging modalities to facilitate early detection and personalized interventions. Future directions focus on multimodal regimens that combine NMJ-targeted agents with exercise, nutrition, and digital health tools, supported by computational analytics for precision care. By integrating molecular, systemic, and lifestyle strategies, NMJ-focused therapies offer a promising approach to delaying the progression of sarcopenia and improving functional independence in aging populations. Continued interdisciplinary research and mechanistically informed clinical trials are crucial for translating these advances into effective treatments.
    DOI:  https://doi.org/10.1007/s40291-026-00833-w
  20. J Physiol. 2026 Feb 03.
    Role of Septin7 in mitochondrial dynamics and oxidative metabolism in C2C12 skeletal muscle cells.
    Andrea Telek, Ivett Gabriella Szabó, Anikó Keller-Pintér, Mónika Gönczi, Eliza Guti, László Szabó, Brigitta Tillmann, Zoltán Márton Kohler, László Juhász, Péter Bai, Szilárd Póliska, Zsuzsanna Gaál, László Csernoch, János Fodor.
      Mitochondria are dynamic organelles that undergo fusion and fission. Key proteins are needed to create mitochondrial networks, as well as facilitate biogenesis, fragmentation or movement within the cell. Septins are considered as the fourth component of the cytoskeleton, providing attachment sites for proteins. Besides that, they have important roles in different cellular processes, including mitochondrial fission and fusion (remodelling). Septins form oligomeric complexes comprising various septin subgroups, which can create higher-order structures. Septin7 is the sole member of its subgroup. We aimed to examine how mitochondrial dynamics and oxidative phosphorylation (OXPHOS) are affected in Septin7 downregulated C2C12 (S7-KD) myoblasts and terminally differentiated myotubes compared to scrambled short hairpin RNA-transfected control cells. We detected altered expression of genes related to mitochondrial biogenesis (PGC1α), dynamics (DRP1, OPA1 and MFN2) and autophagy (PINK1 and BNIP3); furthermore, a significant decrease in differentiation-dependent mRNA expression of OXPHOS markers (ATP synthase, COX1 and SDH). Septin7 downregulation also affected the expression of post-translational modifications of MFN2 and DRP1. Functional measurements of OXPHOS revealed decreased O2 consumption (flux) and higher O2 concentration in Septin7 KD cultures following selective inhibition of electron transport complexes. We observed significant alterations in basal respiration and OXPHOS pathways in Septin7 KD cultures. Our results suggest that Septin7, as a cytoskeletal protein, could be a significant regulator of mitochondrial dynamics and oxidative metabolism. Therefore, these molecules, as mitochondrial dynamics modulators, can serve as potential therapeutic targets in diseases related to changes in mitochondrial function. KEY POINTS: Knockdown of Septin7 results in altered gene and protein expression of markers controlling mitochondrial dynamics. Diminished level of Septin7 causes decreased gene expression of members of oxidative phosphorylation. Knockdown of Septin7 has an impact on microRNAs involved in the regulation of mitochondrial markers. Septin7 has an impact on mitochondrial respiration.
    Keywords:  electron transport; mitochondria; remodelling; septin; skeletal muscle
    DOI:  https://doi.org/10.1113/JP288715
  21. Skelet Muscle. 2026 Feb 03.
    TRPV1 manipulating polarization of M1/M2 macrophages to promote skeletal muscle regeneration.
    Jinfang Liu, Na Li, Shuwei Jing, Fangyu Wu, Guoshuai An, Liangliang Wang, Jian Li, Ximei Cao, Junhong Sun.
      
    Keywords:  Inflammation; Macrophage polarization; Myoblasts differentiation; Skeletal muscle regeneration; TRPV1
    DOI:  https://doi.org/10.1186/s13395-026-00417-6
  22. Neuropathol Appl Neurobiol. 2026 Feb;52(1): e70065
    Myopathy With Exercise-Induced Intolerance due to Novel Biallelic Variants in OBSCN-A Clinical, Morphological and Molecular Analysis.
    Heidrun H Krämer-Best, Marlen C Reis, Andreas Hentschel, Michaela Weiß, Alexander Schaiter, Klaus-Dieter Böhm, Andreas Roos, Dagmar Nolte, Anne Schänzer.
      The phenotype of OBSCN variants consists of exercise intolerance ranging from myalgia and cramps to rhabdomyolysis. Symptoms are mainly induced by high-intensity sports. Molecular analysis showing a deregulation of muscle processes associated with Ca2+ regulation, extrasarcolemmal integrity and autophagy emphasised the critical role of obscurin in skeletal muscle function.
    Keywords:  Ca2+ regulation; autophagy; exercise intolerance; exercise‐induced myopathy; extrasarcomeric cytoskeleton; obscurin; sarcomere dysfunction; skeletal muscle
    DOI:  https://doi.org/10.1111/nan.70065
  23. Sports Med Health Sci. 2026 Jan;8(1): 23-33
    Leveraging mitochondrial stress to improve healthy aging.
    Abril Gorgori-Gonzalez, Silvana Soto-Rodriguez, Eva Tamayo-Torres, Esther Garcia-Dominguez, Vicente Sebastia, Juan Gambini, Gloria Olaso-Gonzalez, Maria Carmen Gomez-Cabrera.
      Aging is characterized by a progressive decline in physiological function, driven by intrinsic mechanisms (primary aging) and modifiable factors (secondary aging), ultimately leading to multimorbidity, disability, and mortality. Mitochondrial dysfunction, a major hallmark of aging, plays a central role in the loss of muscle mass and strength observed in frailty and sarcopenia. With age, mitochondrial quality control processes, including biogenesis, mitophagy, and dynamics, become dysregulated, impairing energy metabolism and muscle homeostasis. Mitochondrial dysfunction correlates with clinical biomarkers of sarcopenia and frailty, such as the decrease in walking speed and muscle strength, making it a therapeutic target for mitohormesis-based strategies aimed at preserving functional capacity. Mitohormetic agents induce reversible mitochondrial stress, triggering adaptive responses that enhance function. Among these interventions, physical exercise, particularly endurance and resistance training (RT), has been reported to be among the most effective, as it may modulate mitochondrial biogenesis, dynamics, and mitophagy through increases in proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and mitochondrial transcription factor A (TFAM) expression, mitochondrial deoxyribonucleic acid (mtDNA) copy number, and mitochondrial content. Chronic RT can also elevate fusion and fission markers, potentially as a compensatory mechanism to mitigate mitochondrial damage. Apart from exercise, mitohormetic compounds such as harmol and piceid are emerging as promising supplements in the aging field. By modulating mitochondrial bioenergetics and dynamics, they may complement lifestyle-based interventions to improve mitochondrial fitness and extend health span.
    Keywords:  Frailty; Mitochondrial dysfunction; Mitohormesis; Muscle homeostasis; Phytochemicals; Resistance training
    DOI:  https://doi.org/10.1016/j.smhs.2025.10.003
  24. FASEB J. 2026 Feb 15. 40(3): e71527
    Aged Small Intestine Derived Small Extracellular Vesicles miR-214-3p Leads to Intermuscular Fatty Infiltration Through Wnt/β-Catenin Mediated Fibro-Adipogenic Progenitors Adipogenesis.
    Jing Liu, Fan Xia, Tingting Huang, Yunlu Sheng, Guoxian Ding, Yu Duan, Yifan Lyu.
      Age-related fat infiltration of skeletal muscle contributes to sarcopenia, declines in physical performance, and metabolic disorders such as insulin resistance in the elderly. However, the underlying mechanisms remain incompletely defined. Here, we investigated the effects of small extracellular vesicles (sEVs) derived from aged small-intestinal on intermuscular adipose tissue (IMAT) infiltration. In mouse models, systemic tail-vein administration of these sEVs in vivo, together with direct exposure of cultured cells to sEVs in vitro, promoted adipogenic differentiation of fibro-adipogenic progenitors (FAPs), thereby increasing IMAT infiltration and decreasing muscle strength in young recipient mice. High-throughput sequencing and functional analyses identified sEVs-derived miR-214-3p as a critical mediator of this phenotype; this microRNA suppresses the Wnt/β-catenin pathway by directly targeting the gene encoding β-catenin. Collectively, these findings reveal a mechanistic connection between intestinal signaling and muscle composition during aging, highlighting the gut-muscle axis as a promising therapeutic target for prevention or treatment of sarcopenia.
    Keywords:  Wnt/β‐catenin pathway; fibro‐adipogenic progenitors; intermuscular adipose tissue; senescence; small extracellular vesicles
    DOI:  https://doi.org/10.1096/fj.202503910R
  25. bioRxiv. 2026 Jan 22. pii: 2026.01.19.700188. [Epub ahead of print]
    MicroRNA Regulatory Targets Related to VO 2 peak Decline in Older Adult Participants of the Study of Muscle, Mobility and Aging (SOMMA).
    Genesio M Karere, Fang-Chi Hsu, Russell T Hepple, Paul M Coen, Steve R Cummings, Anne B Newman, Nancy W Glynn, Lauren M Sparks, Nancy E Lane, Albert G Hayward, Jianzhao Xu, Nathan Wagner, Ge Li, Jeanne Chan, Laura A Cox, Stephen B Kritchevsky.
      Skeletal muscle aging (sarcopenia) is associated with reduced peak oxygen consumption (VO peak) during exercise, a key determinant of physical function and overall health. However, the molecular mechanisms linking muscle aging to low VO peak remain poorly understood. We aimed to identify miRNA signatures and miRNA-gene regulatory networks associated with VO peak in older adults. Using small RNA and mRNA sequencing, we analyzed skeletal muscle from 72 SOMMA participants (70-79 years old) with low or high VO peak (n = 18/group) and from 36 participants spanning the full VO peak spectrum. Differential expression was assessed using LIMMA, with pathway and network analyses performed using Ingenuity Pathway Analysis (IPA) and Weighted Gene Co-expression Network Analysis (WGCNA). We detected 1,408 miRNAs and 16,210 genes; among these, 14 miRNAs and 2,018 genes were differentially expressed (FDR < 0.05). The 14 miRNAs regulated 142 genes, and expression of 10 miRNAs inversely correlated with 50 genes enriched in mitochondrial, sirtuin-1, and nitric oxide signaling pathways. Regression analyses identified 21 miRNAs and 1,744 genes significantly correlated with VO peak after adjusting for age and sex. WGCNA revealed 10 co-expression modules associated with VO peak, with the cyan module showing the strongest correlation and enrichment for nitric oxide signaling genes. These findings highlight novel miRNA-mediated molecular pathways potentially contributing to low VO peak and skeletal muscle aging in older adults. Future studies will further investigate these miRNA-gene interactions to uncover therapeutic targets for preserving muscle function with age.
    DOI:  https://doi.org/10.64898/2026.01.19.700188
  26. Biomed J. 2026 Feb 02. pii: S2319-4170(26)00007-7. [Epub ahead of print] 100951
    Age-Dependent Effects of Losartan and Exercise on Skeletal Muscle Redox Balance and Protein Turnover in Mice.
    Chung-Hao Lin, Po-Cheng Chang, Jyh-Jeen Yang, Gwo-Jyh Chang, Chiao-Nan Chen.
       BACKGROUND: Aging is associated with impaired muscle protein turnover, oxidative stress, and functional decline. Both renin-angiotensin system (RAS) inhibition and exercise modulate redox balance and anabolic-catabolic signaling; however, how aging influences their effects under physiological conditions remains unclear.
    METHODS: Middle-aged (50 weeks) and old (72 weeks) female C57BL/6 mice were randomly assigned to control (C), losartan (L; RAS inhibitor), exercise (E), or combined losartan plus exercise (LE) groups for a four-month intervention. Exercise capacity, cardiac function, oxidative stress markers [thiobarbituric acid reactive substances (TBARS) and total antioxidant capacity (TAC)] in skeletal muscles, and key regulators of muscle protein turnover (Akt, mTOR, ERK1/2, Smad2, FoxO3a, and p38 MAPK) were evaluated. Two-way analysis of variance was used to determine whether age influences the effects of interventions.
    RESULTS: Exercise training (E and LE) improved exercise capacity in both age groups. The combined LE intervention significantly enhanced cardiac systolic function compared to exercise alone. Losartan exerted age-dependent, opposite redox effects. In middle-aged mice, losartan increased TBARS and reduced TAC. Conversely, in old mice, losartan significantly reduced TBARS and increased TAC. Most protein turnover regulators (Akt, mTOR, ERK, FoxO3a, and p38 MAPK) remained unchanged by interventions, while Smad2 activation exhibited age-dependent patterns. Smad2 activation levels increased in middle-aged LE mice but were reduced by exercise in old mice.
    CONCLUSIONS: While exercise is a robust intervention, losartan's efficacy is critically dependent on the animal's baseline oxidative status. These findings highlight the importance of considering age as a critical factor when designing pharmacological interventions for age-related muscle atrophy.
    Keywords:  Exercise training; Losartan; Redox balance; Skeletal muscle; Smad2 signaling
    DOI:  https://doi.org/10.1016/j.bj.2026.100951
  27. bioRxiv. 2026 Jan 21. pii: 2026.01.20.700469. [Epub ahead of print]
    Tceal7 is a BRG1-regulated target of calcineurin signaling that promotes myoblast differentiation.
    Sandhya Yadav, Tapan Sharma, Teresita Padilla-Benavides, Anthony N Imbalzano.
      The transcriptional control of skeletal muscle differentiation requires the coordinated activity of lineage-defining transcription factors, signal-responsive regulators, chromatin modifiers, and ATP-dependent chromatin remodeling enzymes. Here, we identify TCEAL7, a member of the X-linked, poorly characterized TCEAL family of proteins, as a direct downstream target of BRG1-containing mammalian SWI/SNF (mSWI/SNF) complexes and calcineurin signaling during myoblast differentiation. Analyses of previously published datasets showed that pharmacological inhibition of mSWI/SNF bromodomains or knockdown of the BRG1 ATPase, but not knockdown of the homologue BRM ATPase, significantly reduced Tceal7 expression in differentiating C2C12 myoblasts. We demonstrate that BRG1 occupancy at the Tceal7 promoter increased during differentiation, paralleling the induction of Tceal7 expression and nuclear accumulation of TCEAL7 protein. BRG1 functions in part by integrating calcium-dependent cues via the phosphatase calcineurin (Cn); we also determined that Cn knockdown or pharmacological inhibition of Cn suppressed Tceal7 expression and impaired myoblast differentiation. The data suggest that both BRG1-driven chromatin remodeling and Cn signaling converge on Tceal7 regulation. Functionally, Tceal7 knockdown altered cell proliferation and disrupted myoblast differentiation, at least in part due to reduced expression of Myogenin , which encodes a transcription factor that is an essential differentiation determinant. RNA-seq analysis revealed broad dysregulation of myogenic, metabolic, and cell-cycle gene programs in Tceal7 -deficient cells, including changes in cyclin-dependent kinase-regulated pathways consistent with prior reports linking TCEAL7 to cell-cycle control. Together, these findings identify TCEAL7 as a necessary component of the myogenic regulatory network whose expression is controlled by BRG1-dependent chromatin remodeling and Cn activity.
    DOI:  https://doi.org/10.64898/2026.01.20.700469
  28. bioRxiv. 2026 Jan 14. pii: 2026.01.13.699119. [Epub ahead of print]
    Vitamin B12 Improves Skeletal Muscle Mitochondrial Biology in Aged Mice.
    Abigail R Williamson, Angad Yadav, Wenxia Ma, Susan Schmitt, Shelby Rorrer, Lauren E Odom, Luisa F Castillo, Chloe T Purello, Olga V Malysheva, James Mobley, Martha Field, Anna E Thalacker-Mercer.
      Age-related skeletal muscle deterioration is a commonly reported disability among older adults, attributed to several factors including mitochondrial dysfunction, a major hallmark of aging. Therapies to attenuate or reverse mitochondrial decline are limited. Despite identified positive relationships between vitamin B12 (B12) and mitochondrial biology, the impact of B12 supplementation on skeletal muscle mitochondria, in advanced aged, has not been examined. Thus, the impact of B12 supplementation on skeletal muscle mitochondrial biology was examined in (i) aged female mice, given 12 weeks of B12 supplementation (SUPP) or vehicle control, and (ii) in human primary myotubes. In the mouse model, mitochondrial DNA and content were measured with PCR and citrate synthase activity, respectively; mitochondrial morphology was examined using transmission electron microscopy; mitochondrial function was examined using extracellular metabolic flux analysis; and proteins and pathway enrichment was identified with proteomics. In the cell model, ROS and glutathione was measured using luminescent assays. The results demonstrated that SUPP in aged mice increased muscle mitochondrial content and improved morphology. Further, differentially expressed proteins were enriched in TCA cycle, OXPHOS, and oxidative stress pathways. In the cell model, B12 supplementation reduced ROS levels. This is the first study, to our knowledge, examining the impact of B12 supplementation on skeletal muscle mitochondrial biology in aged female mice. Results suggest that B12 supplementation improves mitochondrial biology in aged female mice.
    DOI:  https://doi.org/10.64898/2026.01.13.699119
  29. PLoS One. 2026 ;21(2): e0340309
    Transcriptomic analysis reveals the impact of concurrent, resistance, and endurance training on skeletal muscle.
    Longfei Zhao, Huangyan Li, Dongli Li, Li Luo, Shiliang Hu.
      The shared and divergent molecular mechanisms underlying skeletal muscle adaptation to different exercise modalities are not fully understood. This study aimed to compare the physiological and transcriptomic responses to 12 weeks of concurrent (CET), resistance (RES), or endurance (END) training in healthy males. While all groups exhibited similar increases in lean body mass, RES and END elicited distinct functional improvements in maximal strength and aerobic capacity, respectively. Notably, CET preserved strength gains comparable to RES but showed a blunted improvement in anaerobic power. Transcriptomic analyses revealed both common and modality-specific signatures. Although the number of differentially expressed genes varied across groups (CET: 392; RES: 17; END: 49), enrichment analyses consistently identified the engagement of extracellular matrix (ECM) organization pathways. Gene set enrichment analysis further demonstrated a universal activation of ECM remodeling and an inhibition of translation initiation processes post-training. Weighted gene co-expression and protein-protein interaction network analyses pinpointed core genes associated with each modality, including COL1A1/COL1A2 for CET and END, and SPARC/ASPN for RES. Regulatory network predictions implicated the miR-29 family and JUN as potential co-regulators of collagen-related genes. In conclusion, this integrated analysis establishes ECM remodeling as a fundamental transcriptional response supporting exercise-induced hypertrophy common to diverse training modalities, while simultaneously identifying distinct gene regulatory networks that underlie their divergent functional outcomes.
    DOI:  https://doi.org/10.1371/journal.pone.0340309
  30. Skelet Muscle. 2026 Feb 06.
    The transcriptomic signature of age and sex is not conserved in human primary myotubes.
    Séverine Lamon, Megan Soria, Ross Williams, Annabel Critchlow, Karel Van Belleghem, Andrew Garnham, Akriti Varshney, Traude Beillharz, Danielle Hiam, Mark Ziemann.
       BACKGROUND: Human primary muscle cell (HPMC) lines derived from skeletal muscle biopsies are potentially powerful tools to interrogate the molecular pathways underlying fundamental muscle mechanisms. HPMCs retain their genome in culture, but many endogenous circulating factors are not present in the in vitro environment, or at concentrations that do not mirror physiological levels. To address the assumption that HPMCs are valid models of age and sex-specificity in human muscle research, we examined to what extent differentiated HPMC lines retain their source phenotype in culture.
    METHODS: Biopsies from the vastus lateralis muscle were collected from ten males aged 18-30, ten females aged 18-30 and ten males aged 60-75 recruited from a healthy population. A portion of the muscle was used for the establishment of 30 individual HMPC lines. The remaining sample was immediately snap frozen and stored for further analysis. RNA was extracted from muscle tissue samples and their corresponding, fully differentiated HMPCs and analysed using RNA Sequencing. To compare their transcriptomic signature, principal component analysis (PCA), differential expression analysis, single-cell deconvolution and pathway enrichment analysis were conducted in R.
    RESULTS: A comparison of the transcriptomic signature of 30 human muscle biopsies and their corresponding differentiated HPMCs indicated a near-complete lack of retention of the genes and pathways differentially regulated in vivo when compared to their in vitro equivalent, with the exception of several genes encoded on the Y-chromosome.
    CONCLUSIONS: The diversity of resident cell populations in muscle tissue and the lack of sex- and age-dependent circulating factors in the cellular milieu likely contribute to these observations, which call for caution when using differentiated HPMCs as an experimental model of human muscle sex or age.
    Keywords:  Aging; Muscle cells; Primary cell culture; Sex; Transcriptome
    DOI:  https://doi.org/10.1186/s13395-026-00416-7
  31. Front Pharmacol. 2026 ;17 1779437
    Editorial: Advancements in therapeutic strategies for skeletal muscle and cardiovascular diseases: integrating innovative approaches for enhanced outcomes.
    Sara Carolina Vieira Terra, Leonardo Martin, Roberta Sessa Stilhano.
      
    Keywords:  cardiovascular diseases; cell therapy; gene therapy; skeletal muscle; stem cells
    DOI:  https://doi.org/10.3389/fphar.2026.1779437
  32. J Genet Genomics. 2026 Jan 28. pii: S1673-8527(26)00023-8. [Epub ahead of print]
    The ARHGAP10-202aa protein encoded by circARHGAP10 promotes skeletal muscle development and regeneration.
    Liyin Zhang, Yaoyao Ma, Dandan Zhong, Liangchen Gao, Ke Huang, Xinxin Li, Zhipeng Li, Jieping Huang, Hui Li, Ningbo Chen, Jian Wang.
      Muscle growth and development are fundamental biological processes with significant implications for both human health and livestock production. Although circular RNAs (circRNAs) have long been regarded as noncoding RNAs, recent studies suggest that some circRNAs possess protein-coding potential. However, the biological roles and mechanisms of circRNA-encoded proteins remain poorly understood. Here, we identify circARHGAP10 as a protein-coding circRNA in cattle skeletal muscle that encodes a 202-amino acid protein, ARHGAP10-202aa, through an internal ribosome entry site (IRES)-dependent mechanism. ARHGAP10-202aa expression is confirmed by in vitro translation, immunodetection with a specific antibody, and Western blotting analysis. Functional assays reveal that ARHGAP10-202aa interacts with myosin light chain 6 (MYL6) to promote myoblast differentiation. Moreover, in vivo overexpression of ARHGAP10-202aa significantly enhances MYL6 expression and accelerates the regeneration of injured tibialis anterior muscle in mice. These findings not only expand our understanding of the role of circRNAs in muscle biology but also underscore the functional significance of circRNA-encoded proteins in muscle recovery and regeneration.
    Keywords:  ARHGAP10-202aa; CircRNA; Muscle differentiation; Myogenesis; Translation
    DOI:  https://doi.org/10.1016/j.jgg.2026.01.008
  33. Mol Cell Biol. 2026 Feb 04. 1-20
    The Copper Chaperone ATOX1 Exhibits Differential Protein-Protein Interactions and Contributes to Skeletal Myoblast Differentiation.
    Nathan Ferguson, Yu Zhang, Alexandra M Perez, Allison T Mezzell, Jason D Fivush, Vinit C Shanbhag, Michael J Petris, Katherine E Vest.
      Copper is an essential but potentially toxic nutrient required for a variety of biological functions. Mammalian cells use a complex network of copper transporters and metallochaperones to maintain copper homeostasis. Previous work investigating the role of copper in various disease states has highlighted the importance of copper transporters and metallochaperones. However, questions remain about how copper distribution changes under dynamic conditions like tissue differentiation. We previously reported that the copper exporter ATP7A is required for skeletal myoblast differentiation and that its expression changes in a differentiation dependent manner. Here, we sought to further understand the ATP7A-mediated copper export pathway by examining ATOX1, the copper chaperone that delivers copper to ATP7A. To investigate the role of ATOX1 in a dynamic cellular context, we characterized its protein-protein interactions during myoblast differentiation using the proximity labeling protein APEX2 to biotinylate proteins near ATOX1. We discovered that the ATOX1 interactome undergoes dramatic changes as myoblasts differentiate. These dynamic interactions correlate with distinct phenotypes of ATOX1 deficiency in proliferating and differentiated cells. Together, our results highlight the dynamic interactome of ATOX1 and its contribution to myoblast differentiation.
    Keywords:  ATOX1; ATP7A; Copper homeostasis; copper distribution; metallochaperone; myoblast differentiation
    DOI:  https://doi.org/10.1080/10985549.2026.2621941
  34. bioRxiv. 2026 Jan 25. pii: 2026.01.23.701436. [Epub ahead of print]
    Dynamic Reorganization of Developmental to Adult Genome Topology Controls the Initiation and Stabilization of the Human Muscle Stem Cell State.
    Matthew A Romero, Peggie Chien, Chiara Nicoletti, Hanna L Liliom, Gabriella Cox, Emily Skuratovsky, Kholoud Saleh, Devin Gibbs, Lily Gane, Dieu-Huong Hoang, Luca Caputo, Jimmy Massenet, Débora R Sobreira, Pier Lorenzo Puri, April D Pyle.
      Developmental gene expression is under tight temporal and spatial control. This regulation is imparted by tissue specific enhancers that integrate developmental signals into transcriptional responses to allow for developmental progression. Often species specific, the enhancers that regulate human muscle progenitor and stem cell gene expression are currently unknown. Here, we define the 3D chromatin organization of human muscle development and reveal key changes across the human genome that are associated with multiple layers of 3D genome reorganization during the transition from a more progenitor-like to muscle stem cell state, including a reduction of TAD numbers and an increase in CTCF binding at TAD boundaries and chromatin loops throughout developmental progression. Specifically, we found that increased CTCF occupancy at human enhancers of PAX7 in stem cells holds enhancer-promoter (e-p) loops for timely activation of PAX7 enhancers during early human development. These findings demonstrate that stem cell state acquisition is stabilized earlier than previously known and provide unprecedented insights into the initiation and control of the muscle stem cell state in humans.
    DOI:  https://doi.org/10.64898/2026.01.23.701436
  35. J Adv Res. 2026 Feb 03. pii: S2090-1232(26)00107-4. [Epub ahead of print]
    In silico transcriptome-based drug screening identifies celastrol as a multi-species therapeutic agent against aging-related sarcopenia and mitochondrial dysfunction.
    Bangfu Wu, Jiaxin Liu, Zhaoyu Cui, Xingzhu Yin, Li Mo, Li Chen, Huimin Chen, Xuer Cheng, Yu Wang, Fangqu Liu, Chanhua Liang, Yuna Tian, Yuxia Chen, Xiaocui Liu, Yanyan Li, Ping Yao, Chao Gao, Yuhan Tang.
       INTRODUCTION: Sarcopenia, characterized by the progressive age-related loss of skeletal muscle mass and function, is a primary driver of ambulatory dysfunction in older adults and lacks approved therapeutics. Although exercise has been shown to mitigate muscle aging through activation of peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α)-dependent mitochondrial biogenesis and oxidative metabolism, the practical implementation of exercise regimens is often constrained by age-related physical frailty and declining mobility. This limitation underscores the need for pharmacological approaches to replicate these advantageous adaptations.
    OBJECTIVES: This study aimed to identify a potential therapeutic candidate that mimic the beneficial effects of PGC-1α overexpression and exercise intervention on aging-related sarcopenia and mitochondrial dysfunction.
    METHODS: We analyzed age-stratified muscle transcriptome datafrom various species and assessed the effects of muscle-specific PGC-1α overexpression on muscle aging. In silico transcriptome-based drug screening was conducted using the Connectivity Map (CMap). Subsequently, C2C12 myoblasts, young mice, aged Caenorhabditis elegans (C. elegans), and D-galactose (D-gal)-induced accelerated aging mice were administrated with celastrol to validate its therapeutic effect in counteracting aging-related muscle wasting and mitochondrial dysfunction. Celastrol's efficacy and mechanisms were assessed through histological analysis, molecular biology, and transcriptomics analysis.
    RESULTS: Celastrol, a bioactive triterpenoid from Tripterygium wilfordii Hook. F., was identified as a top candidate that mimicked the gene signature induced by PGC-1α overexpression or exercise. Celastrol potentiated myogenic differentiation and mitochondrial bioenergetic capacity in vitro and in vivo with no side effects. In C. elegans, celastrol extended lifespan by 27.6% at 10 μM, concurrently reducing aging markers while restoring muscle integrity and mitochondrial morphology. Administration of celastrol also ameliorated aging-related muscle decline through boosting myogenic differentiation and mitochondrial oxidative metabolism in accelerated aging mice.
    CONCLUSION: Collectively, these findings suggest celastrol as apharmacological mimetic of exercise-induced mitochondrial rejuvenation, offering a translatable strategy to combat age-related muscle decline.
    Keywords:  CMap; Celastrol; Mitochondria; Myogenic differentiation; PGC-1α; Sarcopenia
    DOI:  https://doi.org/10.1016/j.jare.2026.01.079
  36. BMC Biol. 2026 Feb 06.
    Overexpression of Rtl1 via synonymous mutation silencing miRNA target site drives skeletal muscle hypertrophy and inflammation in mice.
    Xianwei Song, Lizhu Niu, Xiaoxuan Fan, Xianghua Xu, Zihao Zhao, Zhixuan Zhang, Yingwei Tong, Hao Huang, Zhengmao Zhu, Huijun Cheng, Shengsong Xie, Xuewen Xu.
       BACKGROUND: The retrovirus-derived Rtl1 gene is integral to skeletal muscle development. However, the underlying mechanisms and functional roles of Rtl1 in skeletal muscle growth remain unclear.
    RESULTS: We generated conditional overexpression of Rtl1 in mice via synonymous mutations that silence seven miRNA target sites, thereby efficiently abolishing miRNA-mediated inhibition in vivo. This conditional, specific overexpression of synonymous mutated Rtl1 (mRtl1) in the diaphragm muscles of mice foetuses resulted in aberrant embryonic diaphragm muscle development, adversely affecting both diaphragmatic and pulmonary development. This modification ultimately culminated in severe respiratory distress, leading to postnatal mortality. Subsequently, the conditional overexpression of mRtl1 in the tibialis anterior muscle of adult mice resulted in inflammation and hypertrophy. Furthermore, the overexpression of mRtl1 in cultured myotubes activated the TLR7/8-NFκB and Jak-STAT3 signalling pathways, resulting in hypertrophy and inflammation.
    CONCLUSIONS: These findings suggest that the overexpression of Rtl1 may contribute to skeletal muscle hypertrophy and induce inflammation in murine models. Consequently, the precise regulation of Rtl1 expression is essential for maintaining skeletal muscle function.
    Keywords:  Conditional overexpression; Inflammation; Mice; Retrovirus-derived Rtl1 ; Skeletal muscle hypertrophy
    DOI:  https://doi.org/10.1186/s12915-026-02534-6
  37. J Biomed Mater Res A. 2026 Feb;114(2): e70039
    Comparative Analysis of Matrigel and Tunable Collagen-Fibrin Blends for in Vitro Skeletal Muscle Models.
    Jorge A Mojica-Santiago, Gopal Agarwal, Steven Robles-Blasini, Isabella C Young, Victor A Lopez, Shelby Giza, Aaron Choi, Siobhan Malany, Christine E Schmidt.
      In this study, we describe the gelation kinetics, cytocompatibility, and mechanical properties of interpenetrating networks of collagen (COL), fibrin (FIB), hyaluronan (HA), and laminin (LAM) to evaluate their potential to produce mature skeletal muscle tissue. Skeletal muscle is a dynamic tissue that relies on the fusion of myoblasts into multinucleated myofibers to maintain homeostasis. In progressively degenerative conditions, impaired myoblast fusion leads to skeletal muscle atrophy and significant mass loss. Three-dimensional (3D) in vitro models for skeletal muscle disease have been developed to better understand disease mechanisms and facilitate drug screening. However, most rely on Matrigel, a tumor-derived matrix that supports robust cell growth but has limited clinical relevance. To address this limitation, we focused on creating natural, multi-component scaffolds specifically tailored for muscle applications with clinically relevant drug testing use. Using spectrophotometry and rheology, we characterized the gelation kinetics and viscoelastic properties of interpenetrating networks with varying mass ratios of COL to FIB, supplemented with fixed proportions of HA and LAM. Tunable gelation was achieved within a range of 10 to 16 min. Cytocompatibility studies with C2C12 murine myoblasts demonstrated favorable cell viability in 1:1 and 1:2 (w/w) COL:FIB blends incorporating HA and LAM. Immunostaining of differentiated C2C12 cells confirmed Myosin 4 Monoclonal Antibody (MF-20) expression in these blends when seeded into polydimethylsiloxane (PDMS)-anchored bundles. Notably, in cell-laden 1:1 COL:FIB gels with a seeding density of 10 × 106 cells/mL, the compressive modulus increased three-fold between days 4 and 7 of differentiation. These findings highlight the potential of COL:FIB interpenetrating networks, enhanced with HA and LAM, as promising scaffolds for developing clinically relevant models of skeletal muscle tissue.
    Keywords:  3D in vitro scaffolds; C2C12; gelation kinetics; hyaluronan; indentation; laminin; rheology
    DOI:  https://doi.org/10.1002/jbma.70039
  38. Mol Ther. 2026 Feb 02. pii: S1525-0016(26)00084-5. [Epub ahead of print]
    Dual AAV gene therapy using laminin-linking proteins ameliorates muscle and nerve defects in LAMA2-related muscular dystrophy.
    Judith R Reinhard, Shuo Lin, Eleonora Maino, Daniel J Ham, Markus A Rüegg.
      Adeno-associated virus (AAV)-mediated gene replacement holds promise for treating genetic diseases but faces challenges due to AAV's limited packaging capacity and potential immune responses to transgene products, especially in patients lacking endogenous protein. LAMA2-related muscular dystrophy (LAMA2 MD), a severe congenital disorder caused by loss of laminin-α2, presents both hurdles: the LAMA2 gene exceeds AAV capacity, and severely affected patients do not produce the native protein. Here, we developed an AAV-based therapy using two engineered linker proteins derived from endogenously expressed components. These linker proteins restore laminin receptor binding and polymerization, enabling reassembly of a functional basement membrane. Dual AAV delivery of the linkers in a severe LAMA2 MD mouse model resulted in robust expression and significant improvements in muscle histology and function. Employing myotropic capsids enabled therapeutic efficacy at lower vector doses. However, muscle-specific targeting unmasked a LAMA2-related peripheral neuropathy. To address this, we expressed one linker under a muscle-specific promoter and the other under a ubiquitous promoter, delivered via AAV9 or AAV8. This approach achieved near-complete phenotypic restoration when administered neonatally and provided significant benefit when given at progressed disease stages. Our strategy offers a mutation-independent, size-compatible, and potentially immune-tolerable treatment for LAMA2 MD with broad clinical potential.
    DOI:  https://doi.org/10.1016/j.ymthe.2026.01.041
  39. Acta Neuropathol Commun. 2026 Feb 03.
    Muscle transcriptome profiling reveals novel molecular pathways and biomarkers in laminin-α2 deficient patients.
    Veronica Pini, Francesco Catapano, Rosa Bonaccorso, Ben Weisburd, Stefano C Previtali, Francesco Muntoni.
      
    Keywords:  Dystrophy; Laminin-211; Skeletal muscle pathology; Transcriptomic
    DOI:  https://doi.org/10.1186/s40478-026-02227-9
  40. Sci Rep. 2026 Feb 05.
    Functional properties of skeletal myotube-derived extracellular vesicles based on microRNA profiles: a comparative analysis with mesenchymal stem cell-derived extracellular vesicles.
    Yudai Kawamoto, Atomu Yamaguchi, Xiaoqi Ma, Yunfei Fu, Qingcheng Guo, Mikiko Uemura, Hidemi Fujino, Noriaki Maeshige.
      Skeletal muscle-derived extracellular vesicles (SkM-EVs) are promising candidates for non-invasive, systemically delivered therapies, but their functional specificity relative to clinically advanced mesenchymal stem cell-derived EVs (MSC-EVs) remains unclear. We reanalyzed public miRNA-seq datasets of SkM-EVs and MSC-EVs and integrated validated miRNA-mRNA interactions to infer pathway-level repression potential of EV miRNA cargo. Two complementary approaches were used: a differential-expression-based relative evaluation with RBiomirGS, and an abundance-weighted absolute evaluation that converts miRNA profiles into gene-level Impact Scores followed by preranked KEGG enrichment. Despite their different formulations, both approaches converged on a shared pattern. SkM-EV miRNAs showed a predicted repression bias in FoxO, TGF-β and ErbB signaling pathways linked to muscle atrophy, metabolic homeostasis and pro-proliferative signaling. By contrast, MSC-EV miRNAs showed a predicted repression bias in immune signaling pathways. These source-dependent pathway signatures provide hypothesis-generating evidence that SkM-EVs may be better suited for muscle-, metabolic-, and cancer-related indications, whereas MSC-EVs may be more appropriate for immunomodulatory indications, pending experimental validation. Our miRNA-target-based framework provides a general strategy to benchmark EV sources at the pathway level directly from miRNA profiles.
    Keywords:  Enrichment analysis; Extracellular vesicles; Mesenchymal stem cell; Skeletal muscle; microRNA profiling
    DOI:  https://doi.org/10.1038/s41598-026-38076-8
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