bims-moremu Biomed News
on Molecular regulators of muscle mass
Issue of 2026–01–11
forty-one papers selected by
Anna Vainshtein, Craft Science Inc.
  1. Temporal Multi-Omic Analysis Uncovers Sex-Biased Molecular Programs Underlying Skeletal Muscle Adaptation to Endurance Training.
  2. Recent advances in the role of CARM1 in skeletal muscle development, metabolism, and homeostasis maintenance.
  3. FTO promotes skeletal muscle differentiation and regeneration by regulating m 6 A-modified c-Myc.
  4. Transient hypoxia followed by progressive reoxygenation is required for muscle repair.
  5. Targeting C1q signaling in fibro-adipogenic progenitors prevents regenerative fibrosis of aged muscle.
  6. Necessity of Notch3 signaling in myofiber maturation in a pluripotent stem cell transplant model.
  7. Age-Associated Dysregulation of Postsynaptic Mitochondria Perturbs Reinnervation Kinetics.
  8. CTRP1 regulates skeletal muscle differentiation through quality control of mitochondrial dynamics and function.
  9. Investigating the role of EGFR signalling in muscle dystrophies: implications for Duchenne muscular dystrophy.
  10. TAS1R3 Regulates GTPase Signaling in Human Skeletal Muscle Cells for Glucose Uptake.
  11. Intrinsic muscle stem cell dysfunction underlies functional deficits in models of type 1 diabetes.
  12. Non-regenerative myogenesis in adult skeletal muscles: myofiber death-independent muscle satellite cell expansion.
  13. The Liver Clock Tunes Transcriptional Rhythms in Skeletal Muscle to Regulate Mitochondrial Function.
  14. Aberrant mitochondrial hsp60 expression affects mitochondria homeostasis and results in muscle dystrophy and premature death.
  15. Epigenetics of sarcopenia: Insights into mechanisms and interventions for healthy muscle aging.
  16. Capillary differences with age and muscle fiber type are attenuated by accounting for fiber shape.
  17. Overactive PDGFRα and PDGFRβ promote distinct yet overlapping phenotypes of skeletal muscle fibrosis and stiffness, with PDGFRβ also driving drastic muscle growth.
  18. Skeletal Muscle as an Auto-, Para- and Endocrine Organ: The Role of Myokines in Muscle Metabolism and Other Metabolic Organs.
  19. IRP1 deficiency alters mitochondrial metabolism and protects against metabolic syndrome pathologies.
  20. Acute Cold Exposure Cell-Autonomously Reduces mTORC1 Signaling and Protein Synthesis Independent of AMPK.
  21. Zebrafish genetic model of neuromuscular degeneration associated with Atrogin-1 expression.
  22. Conserved differential expression of DDX helicase and CPEB genes in skeletal muscles potentially influences neuromuscular junctions during aging: a computational analysis.
  23. Cardiac and skeletal muscle delivery of biotherapeutics with a blood vessel epicardial substance-targeting peptide.
  24. Identification of KHDC1L, a DUX4-regulated protein, as a novel plasma biomarker in facioscapulohumeral muscular dystrophy.
  25. IGF-1 regulates PEAR1 through Egr1 to Promote Skeletal Muscle Post-injury Regeneration.
  26. mRNA transcription in skeletal muscle drives growth and determines nuclear accretion.
  27. A single S-ketamine injection enhances mTOR signaling in rat skeletal muscle.
  28. Myokines as mediators of muscle communication – does muscle fiber type matter?
  29. An Integrated Multi-Omics Study of Mammalian Skeletal, Cardiac, and Smooth Muscles.
  30. Mineralocorticoid receptor antagonists reduce inflammatory signaling independent of myofiber mineralocorticoid receptor.
  31. Disease exacerbation in human DMD MYOrganoids enables gene therapy evaluation and unveils persistence of fibrotic activity.
  32. Skeletal muscle metabolomic markers underlying the enhanced exercise-induced hypertrophy response to resistance training in older adults.
  33. Myoglobin Affects Tissue-Specific Transcriptome, Heart Regeneration and Whole Animal Metabolic Rates.
  34. A new dystrophin deficient rat model mirroring exon skipping in patients with DMD exon 45 deletions.
  35. ChREBP Deficiency Aggravates Diabetic Sarcopenia by Disrupting Glucose Signaling: A Novel Mouse Model of Muscle Atrophy.
  36. Low-dose lithium supplementation promotes musculoskeletal and metabolic health in ovariectomized female mice.
  37. PDMD: A Comprehensive Repository of Plants Reported for Skeletal Muscle-related Ailments.
  38. NUDT3 facilitates the formation of oxidative fibers and alleviates metabolic dysregulation by degrading TNNI2 mRNA in skeletal muscles.
  39. Revisiting noncoding RNAs: emerging coding functions and their impact on skeletal muscle development.
  40. Mechanism-based nutritional approaches in cancer cachexia.
  41. GABA induces myokine irisin release from skeletal muscle.
  1. bioRxiv. 2025 Dec 27. pii: 2025.12.26.696612. [Epub ahead of print]
    Temporal Multi-Omic Analysis Uncovers Sex-Biased Molecular Programs Underlying Skeletal Muscle Adaptation to Endurance Training.
    MoTrPAC study group
       Background: Exercise training is known to benefit health and reduce disease risk. While skeletal muscle adaptations are fundamental to many of the health benefits of exercise training, the common and sex-specific molecular regulators that mediate these adaptations remain to be fully elucidated.
    Methods: To this end, we leveraged skeletal muscle multi-omics data generated by the Molecular Transducers of Physical Activity Consortium (MoTrPAC), where 6 month-old male and female rats endurance trained for 1, 2, 4, or 8 weeks. Our objective was to identify shared and sex-specific multi-omic molecular responses to endurance training in skeletal muscle, and relate them to phenotypic adaptations.
    Results: We identified largely sexually-conserved transcriptomic and proteomic pathway enrichments in the gastrocnemius , which correlated with skeletal muscle responses from a published exercise study in humans. We uncovered sex-consistent post-translational modifications, including decreased oxidation of MYH2 and deacetylation of the β-oxidation enzyme HADHA. Pathway enrichment analyses revealed sex-specific remodeling across the acetylome, redox proteome, and phosphoproteome; females decreased mitochondrial protein cysteine oxidation and increased mitochondrial cristae proteins, indicative of enhanced redox buffering and mitochondrial efficiency. Despite decreases in cysteine oxidation of key mitochondrial proteins, females displayed increases in the cysteine oxidation of proteins involved in glucose catabolism relative to males after 8 weeks of training, suggestive of sex-biased subcellular reactive oxygen species generation. Males demonstrated earlier induction of mitochondrial transcripts and predicted activation of mTOR. Although the increase in mitochondrial protein abundance was more modest in males, there was greater oxidation of mitochondrial proteins in response to training compared to females.
    Conclusions: This work shows a large portion of the adaptive response to endurance training in skeletal muscle is shared between females and males, while there are distinct and nuanced sex-specific adaptations that are evident, particularly at the level of post-translational regulation.
    DOI:  https://doi.org/10.64898/2025.12.26.696612
  2. Front Cell Dev Biol. 2025 ;13 1709515
    Recent advances in the role of CARM1 in skeletal muscle development, metabolism, and homeostasis maintenance.
    Xiaojing Xie, Menghuan Li, Yue Zhang, Zhenwei Bao, Xuejie Yi.
      The development, metabolism, and functional maintenance of skeletal muscle is a complex dynamic balance process. Its imbalance may lead to muscular dystrophy, muscle atrophy, and other diseases, which seriously affect human health. Therefore, in-depth exploration of the regulatory mechanisms governing skeletal muscle homeostasis and the identification of effective therapeutic targets have garnered significant attention. Recent studies reveal that the protein arginine methyltransferase CARM1 plays a central regulatory role in skeletal muscle biology. Substantial evidence indicates that abnormal CARM1 expression and activity disrupt muscle regeneration, metabolic balance, and stress responses, leading to muscle functional decline. This highlights its indispensable role in maintaining skeletal muscle homeostasis. Furthermore, exercise-an effective intervention for improving muscle quality and function-may exert its beneficial effects through mechanisms closely linked to CARM1 function. Therefore, this review systematically summarizes the roles of CARM1 in skeletal muscle development, regeneration, material metabolism, and homeostasis based on its molecular structure and fundamental functions. It further explores CARM1's functional manifestations in muscle atrophy and exercise adaptation, providing a theoretical framework for comprehensively understanding its pivotal role in physiological adaptation and muscle diseases, while evaluating its potential value as a therapeutic target.
    Keywords:  CARM1; autophagy; exercise; metabolism; muscle atrophy; muscle development; oxidative stress; skeletal muscle
    DOI:  https://doi.org/10.3389/fcell.2025.1709515
  3. bioRxiv. 2025 Dec 30. pii: 2025.12.30.696954. [Epub ahead of print]
    FTO promotes skeletal muscle differentiation and regeneration by regulating m 6 A-modified c-Myc.
    Paromita Dey, Bijan K Dey.
      Recent studies have revealed the crucial role of m 6 A RNA methylation in various myogenic processes. However, the specific function and underlying molecular mechanisms of this modification in vivo during skeletal muscle differentiation and regeneration remain unclear. In this study, we examine the role and mechanism of the m 6 A RNA demethylase fat mass and obesity-associated protein (FTO) in skeletal muscle differentiation and regeneration in mice. Our findings demonstrate that FTO is upregulated during both skeletal muscle differentiation and regeneration and is essential for these key myogenic processes. We show that exogenous FTO expression in primary myoblasts enhances differentiation, whereas FTO knockdown inhibits it. Additionally, FTO knockout in mouse muscle stem cells impairs muscle regeneration. FTO promotes skeletal muscle differentiation and regeneration by directly targeting and regulating m 6 A-modified c-Myc, a well-known repressor of myogenesis. The IGF2BP2 reader protein recognizes m 6 A-modified c-Myc in undifferentiated myoblasts and stabilizes it. As FTO levels increase during myoblast differentiation, m 6 A levels on c-Myc decrease. This reduction prevents IGF2BP2 from binding to c-Myc, thereby destabilizing c-Myc levels and promoting differentiation. Overall, our findings underscore the significance of the novel FTO/c-Myc/IGF2BP2 axis in skeletal muscle differentiation and regeneration.
    DOI:  https://doi.org/10.64898/2025.12.30.696954
  4. EMBO Rep. 2026 Jan 07.
    Transient hypoxia followed by progressive reoxygenation is required for muscle repair.
    Marie Quétin, Audrey Der Vartanian, Christelle Dubois, Juliette Berthier, Marine Ledoux, Stéphanie Michineau, Bernadette Drayton-Libotte, Alexandre Prola, Athanassia Sotiropoulos, Frédéric Relaix, Marianne Gervais.
      Muscle stem cells (MuSCs) are essential for skeletal muscle repair. Following injury, MuSCs reside in low oxygen environments until muscle fibers and vascularization are restablished. The dynamics of oxygen levels during the regenerative process and its impact on muscle repair has been underappreciated. We confirm that muscle repair is initiated in a low oxygen environment followed by gradual reoxygenation. Strikingly, when muscle reoxygenation is limited by keeping mice under systemic hypoxia, muscle repair is impaired and leads to the formation of hypotrophic myofibers. Sustained hypoxia decreases the ability of MuSCs to differentiate and fuse independently of HIF-1α or HIF-2α. Prolonged hypoxia specifically affects the circadian clock by increasing Rev-erbα expression in MuSCs. Using pharmacological tools, we demonstrate that Rev-ERBα negatively regulates myogenesis by reducing late myogenic cell fusion under prolonged hypoxia. Our results underscore the critical role of progressive muscle reoxygenation after transient hypoxia in coordinating proper myogenesis through Rev-ERBα.
    Keywords:  Circadian Clock; Hypoxia; Muscle Stem Cell; Skeletal Muscle Regeneration
    DOI:  https://doi.org/10.1038/s44319-025-00679-z
  5. Proc Natl Acad Sci U S A. 2026 Jan 13. 123(2): e2423340122
    Targeting C1q signaling in fibro-adipogenic progenitors prevents regenerative fibrosis of aged muscle.
    Abhijnya Kanugovi, Paola Aguiari, Rachel Choi, Soochi Kim, Di Wu, Antoine De Morree, Summer Bui, Richard Lam, Stefano Biressi, Ling Liu, Thomas A Rando.
      Skeletal muscle fibrosis, as occurs with age, in response to injury, or in the setting of degenerative diseases, results in impairments of muscle regeneration and function. Fibro-adipogenic progenitors (FAPs), a distinct population of muscle-resident mesenchymal progenitor cells that reside in the muscle interstitium, play a crucial role in normal muscle regeneration by supporting muscle stem cell proliferation. However, in pathological conditions such as severe or recurrent muscle injury, FAPs can aberrantly differentiate into fibrogenic cells, resulting in excessive deposition of extracellular matrix and fibrosis. In this study, we explore the molecular regulation of FAP differentiation along the fibrogenic lineage to gain insights into the mechanisms of fibrosis in aged muscle in response to injury. Our findings reveal that aging is associated with an increased expression of the complement component 1q (C1q) in muscle-resident macrophages and elevated expression of the complement proteins C1r and C1s in FAPs. Exposure of proliferating FAPs to C1q results in the activation of the Wnt signaling pathway, elevated expression of collagen genes, and FAP fibrogenic differentiation, leading to increased tissue fibrosis. We demonstrate that either pharmacological inhibition of the complement pathway or genetic ablation of C1s in FAPs in aged mice reduces fibrogenic differentiation of FAPs by suppressing Wnt signaling. This reduction in FAP differentiation attenuates the fibrotic response to injury in aged animals as well as in a mouse model of muscular dystrophy. Our study supports the inhibition of complement signaling as a potential therapeutic strategy for mitigating fibrosis in skeletal muscle injury or degeneration.
    Keywords:  aging; complement, C1q; fibro-adipogenic progenitors; fibrosis; muscular dystrophy
    DOI:  https://doi.org/10.1073/pnas.2423340122
  6. Skelet Muscle. 2026 Jan 05. 16(1): 1
    Necessity of Notch3 signaling in myofiber maturation in a pluripotent stem cell transplant model.
    Aline M S Yamashita, Sarah B Crist, Bayardo I Garay, Hyunkee Kim, Karim Azzag, Darko Bosnakovski, Sergio H D M Faria, Juan E Abrahante, Phablo Abreu, Aaron Ahlquist, Rita C R Perlingeiro.
       BACKGROUND: Pluripotent stem cell-derived myogenic progenitors change from an embryonic to a postnatal molecular signature upon engrafting as satellite cells, which coincides with upregulation of Notch3. Since a role for Notch3 in skeletal muscle maturation is unknown, here we investigate whether Notch3 is required for this in vivo molecular maturation switch.
    RESULTS: Our results show that lack of Notch3 in transplanted progenitors (N3KO) does not impact degree of engraftment, but leads to increased numbers of embryonic myofibers. Conversely, transplantation of Notch3 overexpressing (N3OE) myogenic progenitors results in lower numbers of embryonic myofibers, but diminished muscle grafts when compared to empty vector (EV) controls. Secondary transplantation studies confirmed these effects, whereby Notch3 overexpression significantly reduced secondary engraftment. Further characterization of N3OE donor-derived satellite cells revealed reduced proliferation and downregulation of cell cycle genes. Importantly, secondary grafts from N3KO satellite cells had increased numbers of embryonic myofibers compared to N3OE and EV controls.
    CONCLUSIONS: Taken together, these findings demonstrate that Notch3 signaling is required for myofiber maturation, and that constant activation of Notch3 impairs proliferation and muscle regeneration. Transcriptional profiles of N3OE donor-derived satellite cells suggest that dampened regeneration may be driven by inhibitory alterations in cell cycle regulation.
    Keywords:  Muscle regeneration; Myofiber maturation; Myogenic progenitors; Notch3; Pluripotent stem cells; Satellite cells
    DOI:  https://doi.org/10.1186/s13395-025-00403-4
  7. Aging Cell. 2026 Jan;25(1): e70355
    Age-Associated Dysregulation of Postsynaptic Mitochondria Perturbs Reinnervation Kinetics.
    Steve D Guzman, Paula M Fraczek, Klimentini Itsani, Esraa K Furati, Devin Juros, Grace Kenney, Gregorio Valdez, Joe V Chakkalakal, Carlos A Aguilar.
      Age-associated degeneration of neuromuscular junctions (NMJs) contributes to sarcopenia and motor function decline, yet the mechanisms that drive this dysfunction in aging remain poorly defined. Here, we demonstrate that postsynaptic mitochondria are significantly diminished in quantity in old-aged skeletal muscle, correlating with increased denervation and delayed reinnervation following nerve injury. Single-nucleus RNA sequencing before and after sciatic nerve crush from young and old-aged muscles further revealed that sub-synaptic myonuclei in old-aged muscle exhibit attenuated expression of mitochondrial gene programs, including oxidative phosphorylation, biogenesis, and import. To test whether these deficits are causal, we developed a muscle-specific CRISPR genome editing approach and targeted CHCHD2 and CHCHD10-two nuclear-encoded mitochondrial proteins that localize to the intermembrane space and interact with the mitochondrial contact site and cristae organizing system. CRISPR knockout of CHCHD2 and CHCHD10 in young muscle recapitulated old-aged muscle phenotypes, including mitochondrial disorganization, reduced ATP production, NMJ fragmentation, and delayed reinnervation. Transcriptional profiling of sub-synaptic myonuclei using single-nuclei RNA sequencing from CHCHD2 and CHCHD10 knockout muscles revealed impairments in activation of mitochondrial remodeling programs and elevated stress signatures when compared with controls. These findings establish a critical role for postsynaptic mitochondrial integrity in sustaining NMJ stability and regenerative capacity and identify CHCH domain-containing proteins as key regulators of postsynaptic mitochondrial function during aging and injury.
    DOI:  https://doi.org/10.1111/acel.70355
  8. Mol Ther. 2026 Jan 02. pii: S1525-0016(25)01139-6. [Epub ahead of print]
    CTRP1 regulates skeletal muscle differentiation through quality control of mitochondrial dynamics and function.
    Sora Han, Youjeong Jang, Hyun Jeong Joo, Hye In Ka, Se Hwan Mun, Hai-Anh Nguyen, Doyeon Park, Yoohyun Jung, Doyeong Ko, Bo Ram Sohn, Seong Keun Sonn, Goo Taeg Oh, Young-Chul Choi, So-Young Park, Sung-Eun Kim, Young Yang.
      Mitochondrial dysfunction is a hallmark of myopathies and impaired skeletal muscle differentiation. Here, we demonstrate that C1q/TNF-related protein 1 (CTRP1) is essential for maintaining mitochondrial dynamics and supporting myogenic differentiation. Loss of CTRP1 in myoblasts and in skeletal muscle-specific knockout (CTRP1 KOΔACTA) mice led to impaired myotube formation, reduced muscle fiber cross-sectional area, and decreased muscle strength. CTRP1 deficiency also shifted the muscle fiber composition from oxidative Type IIA to glycolytic Type IIB fibers, indicating a compromised mitochondrial capacity. At the cellular level, CTRP1 loss resulted in elongated and disorganized mitochondria with diminished cristae density, membrane potential, and oxidative respiration. These mitochondrial abnormalities are associated with defective recruitment of dynamin-related protein 1 (DRP1), a central mediator of mitochondrial fission. Restoring CTRP1 expression or performing mitochondrial transplantation in CTRP1 KO myoblasts rescued mitochondrial function and re-established differentiation capacity. Furthermore, CTRP1 expression progressively decreased in accordance with disease severity in skeletal muscle biopsies from patients with polymyositis, dermatomyositis, and Duchenne muscular dystrophy, supporting its potential relevance to human myopathies. Together, these findings identify CTRP1 as a novel regulator of mitochondrial quality and myogenic differentiation, highlighting its potential as a therapeutic target for mitochondrial myopathies.
    DOI:  https://doi.org/10.1016/j.ymthe.2025.12.063
  9. Cell Death Dis. 2026 Jan 09. 17(1): 18
    Investigating the role of EGFR signalling in muscle dystrophies: implications for Duchenne muscular dystrophy.
    Esther Fernández-Simón, Ainoa Tejedera-Villafranca, Xiomara Fernández-Garabay, James Clark, Alexandra Monceau, Elisa Villalobos, Dan Cox, Javier Ramón Azcón, Juan M Fernández-Costa, Jordi Diaz Manera.
      The degeneration of the muscle in muscle dystrophies involves complex interactions among the different cell types. Here, we have used datasets from single-nuclei RNA sequencing (snRNAseq) of Duchenne Muscular Dystrophy (DMD) muscle samples to study the dysregulation of molecular pathways compared to healthy control muscle. We have observed that the epidermal growth factor (EGF) signaling is upregulated in DMD by an increase of the ligands EGF and EGF containing fibulin extracellular matrix protein 1 (EFEMP1). This study explores the role of EGF and EFEMP1 in FAPs and myoblasts in vitro. We provide evidence that EFEMP1 is secreted by FAPs in DMD and is mainly involved with increased myotube size but without enhancing muscle strength. Conversely, EGF enhances fibrotic differentiation in FAPs and promote smaller, proliferative myotubes in myoblasts, aligning with a fibrotic and dysfunctional muscle phenotype in DMD. The cellular differences from both ligands can be explained by the interactions with the receptor type, with EGF activating both EGFR and ErbB2, while EFEMP1 selectively maintained ErbB4 in an inactive state but promoting EGFR-ErbB2 and ErbB2-ErbB4 heterodimerization, potentially enhancing EGF signaling. Consequently, this study examinates the alteration of the EGF signalling in DMD and provides new molecular interactions in muscle that can be useful for targeted therapies of muscle degeneration.
    DOI:  https://doi.org/10.1038/s41419-025-08193-9
  10. Int J Mol Sci. 2025 Dec 22. pii: 103. [Epub ahead of print]27(1):
    TAS1R3 Regulates GTPase Signaling in Human Skeletal Muscle Cells for Glucose Uptake.
    Joseph M Hoolachan, Rekha Balakrishnan, Karla E Merz, Debbie C Thurmond, Rajakrishnan Veluthakal.
      Taste receptor type 1 member 3 (TAS1R3) is a class C G protein-coupled receptor (GPCR) traditionally associated with taste perception. While its role in insulin secretion is established, its contribution to skeletal muscle glucose uptake, a process responsible for 70-80% of postprandial glucose disposal, remains unclear. TAS1R3 expression was assessed in skeletal muscle biopsies from non-diabetic and type 2 diabetes (T2D) donors using qPCR and immunoblotting. Functional studies in human LHCN-M2 myotubes involved TAS1R3 inhibition with lactisole or siRNA-mediated knockdown, followed by the measurement of insulin-stimulated glucose uptake using radiolabeled glucose assays. Rac1 activation and phospho-cofilin were analyzed by G-LISA and Western blotting, and Gαq/11 involvement was tested using YM-254890. TAS1R3 mRNA and protein levels were significantly reduced in T2D skeletal muscle. Pharmacological inhibition or the knockdown of TAS1R3 impaired insulin-stimulated glucose uptake in myotubes. TAS1R3 regulates skeletal muscle glucose uptake through a non-canonical insulin signaling pathway involving Rac1 and phospho-cofilin, independent of IRS1-AKT and Gαq/11 signaling. These findings identify TAS1R3 as a key determinant of Rac1-mediated glucose uptake and a potential therapeutic target for improving insulin sensitivity in T2D.
    Keywords:  Rac1; TAS1R3 signaling; glucose uptake; insulin resistance; skeletal muscle; type 2 diabetes
    DOI:  https://doi.org/10.3390/ijms27010103
  11. NPJ Regen Med. 2026 Jan 06.
    Intrinsic muscle stem cell dysfunction underlies functional deficits in models of type 1 diabetes.
    Jin D Chung, Jennifer Trieu, Benjamin L Parker, John H Nguyen, Annabel Chee, Audrey S Chan, Abhirup Jayasimhan, Devy Deliyanti, Peter J Houweling, Holly K Voges, Karly C Sourris, Richard J Mills, Melinda T Coughlan, Jennifer L Wilkinson-Berka, Enzo R Porrello, Gordon S Lynch.
      Muscle function and regeneration are impaired in type 1 diabetes, but whether this arises directly from muscle stem cell (MuSC) dysfunction has not been addressed. Here, we utilized three-dimensional MuSC cultures (micromuscles) to demonstrate that hyperglycemia drives deficits in muscle stem cell function, leading to impaired force production in differentiated myotubes. The functional capacity of skeletal muscle was shown to decline after repeated bouts of injury in mouse models of type 1 diabetes, and this was replicated in micromuscles derived from MuSCs isolated from diabetic mice, indicating MuSC dysfunction was linked to poor muscle regeneration and function. The loss of force producing capacity was associated with impaired myotube hypertrophy in vitro and in vivo after injury. Furthermore, poor muscle regeneration was exacerbated by a loss of MuSC number due to aberrant activation, even in the absence of injury. Deficits in MuSC function and number could be rescued by early treatment with the glucose-lowering drug dapagliflozin, indicating that MuSC defects were driven by exposure to a hyperglycemic environment. The findings reveal that MuSC dysfunction contributes to muscle functional deficits in models of type 1 diabetes.
    DOI:  https://doi.org/10.1038/s41536-025-00452-9
  12. Skelet Muscle. 2026 Jan 08.
    Non-regenerative myogenesis in adult skeletal muscles: myofiber death-independent muscle satellite cell expansion.
    So-Ichiro Fukada, Atsushi Kubo, Takashi Yamada, Takayuki Akimoto.
      
    Keywords:  Exercise; Muscle satellite cell; Myogenesis; Proliferation; Quiescence; Regeneration
    DOI:  https://doi.org/10.1186/s13395-026-00412-x
  13. J Biol Rhythms. 2026 Jan 04. 7487304251386926
    The Liver Clock Tunes Transcriptional Rhythms in Skeletal Muscle to Regulate Mitochondrial Function.
    Valentina Sica, Tomoki Sato, Ioannis Tsialtas, Sophia Hernandez, Siwei Chen, Pierre Baldi, Pura Muñoz-Cánoves, Paolo Sassone-Corsi, Kevin B Koronowski, Jacob G Smith.
      Circadian clocks present throughout the brain and body coordinate diverse physiological processes to support daily homeostasis, yet the specific interorgan signaling axes involved are not well defined. We previously demonstrated that the skeletal muscle clock controls transcript oscillations of genes involved in fatty acid metabolism in the liver, yet the impact of the liver clock on the muscle remained unknown. Here, we use male hepatocyte-specific Bmal1 KO mice (Bmal1hep-/-) to reveal that approximately one-third of transcript rhythms in skeletal muscle are influenced by the liver clock in vivo. Treatment of myotubes with serum harvested from Bmal1hep-/- mice inhibits expression of genes involved in metabolic pathways, including oxidative phosphorylation. Only small transcriptional changes were induced by liver clock-driven endocrine communication in vitro, leading us to surmise that the liver clock acts to fine-tune metabolic gene expression in muscle. Consistent with functional tuning, treatment of myotubes with serum collected from Bmal1hep-/- mice during the dark phase lowers mitochondrial ATP production compared with serum from wild-type mice. Overall, our results reveal communication between the liver clock and skeletal muscle, uncovering a bidirectional endocrine communication pathway that may contribute to the metabolic phenotypes of circadian disruption.
    Keywords:  Bmal1; circadian clocks; circadian rhythms; clock communication; interorgan crosstalk; liver metabolism; mitochondria; muscle-liver axis; peripheral clocks; skeletal muscle
    DOI:  https://doi.org/10.1177/07487304251386926
  14. Cell Death Dis. 2026 Jan 08. 17(1): 9
    Aberrant mitochondrial hsp60 expression affects mitochondria homeostasis and results in muscle dystrophy and premature death.
    Tsung-Hsien Chen, Chu-Kuang Chou, Kurt Ming-Chao Lin.
      Heat shock protein 60 (HSP60) plays a vital role in maintaining mitochondrial homeostasis and essential functions and requires ATP for its assembly into chaperone complexes. This study aimed to investigate the long-term effects of HSP60 induction on mitochondrial homeostasis at varying doses and durations using HSP60 transgenic mice. In this study, we generated transgenic mice with elevated levels of native HSP60 using the LoxP-Cre system. These mice exhibited impaired postnatal development, skeletal muscle dystrophy, and increased mortality. Initially, excess HSP60 enhanced the mitochondrial oxidative respiratory capacity, which was later compensated for by increased glycolysis. Surplus HSP60 primarily accumulated in the mitochondria, likely due to insufficient ATP availability, leading to the buildup of HSP60 heptamers. Consequently, mitochondrial number and morphology were altered, protein levels in electron transport chain complexes were reduced, and oxidative phosphorylation was impaired. Additionally, reactive oxygen species accumulated, contributing to mitochondrial dysfunction in skeletal muscles. The upregulation of Pink-1/Parkin triggered enhanced autophagy, while increased Bax and poly (ADP-ribose) polymerase (PARP) cleavage mediated heightened apoptosis; both mechanisms aimed at eliminating damaged mitochondria. However, prolonged HSP60 accumulation overwhelmed these protective processes, ultimately leading to skeletal muscle dystrophy and premature death. Our findings demonstrated that excessive mitochondrial HSP60 initially boosts oxidative respiration; however, over time, it contributes to mitochondrial dysregulation and myopathy. This study provides novel insights into how excessive HSP60 affects mitochondrial oxidative respiration and glycolysis, with potential links to certain mitochondria-related diseases.
    DOI:  https://doi.org/10.1038/s41419-025-08260-1
  15. Biomed Pharmacother. 2026 Jan 06. pii: S0753-3322(25)01154-0. [Epub ahead of print]195 118960
    Epigenetics of sarcopenia: Insights into mechanisms and interventions for healthy muscle aging.
    Jida Wang, Ogbe Susan Enechojo, Yuexuan Shi, Dongdong Cao, Tianci Guo, Jiwei Zhong, Yang Lin, Yuhong Bian, Xiangling Wang, Aifeng Liu.
      Aging frequently correlates with the progressive decline in skeletal muscle mass and function, a condition termed sarcopenia. Epigenetic modifications, including DNA methylation, histone alterations, and microRNA regulation, critically influence gene expression changes throughout aging. This review elucidates molecular mechanisms underlying epigenetic alterations in aging skeletal muscle and their functional consequences. We elucidate how shifts in DNA methylation, histone modifications, and microRNA profiles contribute to muscle atrophy and dysfunction. Furthermore, we examine emerging therapeutic strategies targeting epigenetic pathways to mitigate age-related muscle deterioration. A deeper understanding of these epigenetic processes could facilitate the development of interventions to promote healthier aging and improve muscle function in older adults. A comprehensive understanding of these processes will guide therapeutic strategies aimed at improving elderly muscle health.
    DOI:  https://doi.org/10.1016/j.biopha.2025.118960
  16. FEBS J. 2026 Jan 10.
    Capillary differences with age and muscle fiber type are attenuated by accounting for fiber shape.
    Jonathan F Frydenholm, Cecilie J L Bechshøft, Michael Kjaer, Abigail L Mackey, Lasse Gliemann, Casper Soendenbroe.
      Age-related declines in skeletal muscle capillarization are well-documented, yet commonly used indices, such as the capillary-to-fiber perimeter exchange index (CFPE), assume uniform myofiber shape. Because fiber size and shape changes with age and fiber type, this assumption may lead to overestimation of true capillary rarefaction. This study aimed to refine capillarization metrics by accounting for fiber shape. Muscle biopsies from 12 young (23 ± 3 years) and 11 older (73 ± 2 years) women were analyzed for capillary-to-fiber ratio (C:F), capillary density (CD), and individual capillary-to-fiber ratio (C:Fi). Analyses were fiber type-specific and performed on both rested and previously exercised legs. C:Fi was normalized to fiber perimeter (CFPE), cross-sectional area (CFCE), and adjusted for the shape factor index (SFI: perimeter2/4π·CSA). Older participants exhibited smaller type II fibers (28%) and greater fiber shape irregularity (8% SFI) compared with young. C:Fi and CFPE showed consistent age-related (from 22% to 34%) and fiber type related (from 12% to 29%) reductions in capillarization. Adjusting CFPE for fiber shape (CFPESFIadjusted) reduced age-related differences from 22-25% down to 19-20% (~10-25% relative reduction) and fiber type differences from 12-15% down to 8-9% (~25-45% relative reduction). Normalizing C:Fi to fiber CSA (CFCE) further attenuated or eliminated most differences, with only an 18% difference remaining in type I fibers between age groups. These patterns were consistent in the exercised leg, supporting internal validity. Adjusting CFPE using SFI reduced apparent differences in capillarization between young and old muscle, as well as between fiber types. Shape-sensitive indices may provide a more physiologically accurate assessment of capillary supply in skeletal muscle.
    Keywords:  aging; capillarization; capillary supply; fiber morphology; skeletal muscle
    DOI:  https://doi.org/10.1111/febs.70401
  17. bioRxiv. 2026 Jan 02. pii: 2026.01.02.697406. [Epub ahead of print]
    Overactive PDGFRα and PDGFRβ promote distinct yet overlapping phenotypes of skeletal muscle fibrosis and stiffness, with PDGFRβ also driving drastic muscle growth.
    Mariola Gimla, Szczepan Olszewski, Jacob L Brown, Christiana Raymond-Pope, Sandra Rigsby, Frederick F Peelor, Hae Ryong Kwon, Longbiao Yao, Lorin E Olson, Jordan D Fuqua, Benjamin F Miller.
      Background: Fibrosis accumulates in skeletal muscle over time and leads to greater muscle rigidity, stiffness, and increased risk of injuries. However, investigations of experimental models to study the mechanisms through which muscle fibrosis occurs are often confounded by injury or disease. The contribution of platelet-derived growth factor receptors alpha and beta (PDGFRα or PDGFRβ) to muscle fibrosis is yet to be clarified. We hypothesized that both receptors would promote ECM deposition and fibrosis, causing muscle stiffening and weakness, with sex-specific differences arising due to hormonal influences on receptors. Methods: To test this hypothesis, we used a mouse model with inducible overactive PDGFRα or PDGFRβ signaling and assessed various indicators of muscle function, metabolism, motor coordination, exercise capacity, collagen deposition, and muscle stiffness. Results: Overactive PDGFRα led to more collagen deposition, increased collagen crosslinking, and higher AGE/LOX protein levels, all of which correlated with greater muscle stiffness compared to CON. Overactive PDGFRβ resulted in greater muscle mass and lower fat mass, and had higher collagen deposition in female mice compared to CON. There were also sex-specific differences with fibrotic remodeling, muscle stiffness, and muscle size in response to overactive PDGFRα and PDGFRβ signaling. Conclusion: These findings establish PDGFRα and PDGFRβ signaling as distinct regulators of muscle remodeling and establish overactive PDGFRα as a mouse model to study skeletal muscle fibrosis in the absence of other confounding variables.
    DOI:  https://doi.org/10.64898/2026.01.02.697406
  18. Physiol Res. 2025 Dec 31. 74(Suppl 1): S37-S56
    Skeletal Muscle as an Auto-, Para- and Endocrine Organ: The Role of Myokines in Muscle Metabolism and Other Metabolic Organs.
    L Horváth, M Pekař, Z Švagera, V Horká, M Mráz, M Bužga.
      Skeletal musculature represents the largest organ in the human body, playing a vital role in systemic metabolism, physiological functions, and glucose homeostasis. Skeletal muscles are also a significant source of multiple humoral factors, including myokines, which are, as part of the muscular secretome, involved in cellular signaling within and outside of the muscle. Myokines are a group of cytokines that exert a major influence on muscle metabolism through autocrine mechanisms and are involved in para- or endocrine regulation in organs outside of muscle tissue, such as the pancreas, adipose tissue, liver, heart, bone, gastrointestinal tract, and brain. In the future, these findings could be crucial for the identification of important biomarkers used for the monitoring of physical activity in the treatment of pathologies such as intensive care-associated muscle wasting, sarcopenia, diabetes, neurodegenerative diseases, etc. As skeletal muscle tissue is intrinsically linked to multiple types of tissues and organs metabolically, functionally, and most importantly, regionally, there can be a significant overlap between the auto- and paracrine effects of myokines, depending on the presence of that myokine. The following section will discuss the auto-, para-, and endocrine effects of some of the myo-inducible cytokines on skeletal muscles and adjacent tissue types. Key words Skeletal muscle cells " Myokines " Secretome " Autocrine effect " Paracrine effect.
  19. JCI Insight. 2026 Jan 06. pii: e183247. [Epub ahead of print]
    IRP1 deficiency alters mitochondrial metabolism and protects against metabolic syndrome pathologies.
    Wen Gu, Nicole Wilkinson, Carine Fillebeen, Darren Blackburn, Korin Sahinyan, Eric Bonneil, Tao Zhao, Zhi Luo, Vahab Soleimani, Vincent Richard, Christoph H Borchers, Albert Koulman, Benjamin Jenkins, Bernhard Michalke, Hans Zischka, Judith Sailer, Vivek Venkataramani, Othon Iliopoulos, Gary Sweeney, Kostas Pantopoulos.
      Iron regulatory protein 1 (IRP1) is a post-transcriptional regulator of cellular iron metabolism. In mice, loss of IRP1 causes polycythemia through translational de-repression of hypoxia-inducible factor 2α (HIF2α) mRNA, which increases renal erythropoietin production. Here we show that Irp1-/- mice develop fasting hypoglycemia and are protected against high-fat diet-induced hyperglycemia and hepatic steatosis. Discovery-based proteomics of Irp1-/- livers revealed a mitochondrial dysfunction signature. Seahorse flux analysis in primary hepatocytes and differentiated skeletal muscle myotubes confirmed impaired respiratory capacity, with a shift from oxidative phosphorylation to glycolytic ATP production. This metabolic rewiring was associated with enhanced insulin sensitivity and increased glucose uptake in skeletal muscle. Under metabolic stress, IRP1 deficiency altered the redox balance of mitochondrial iron, resulting in inefficient energy production and accumulation of amino acids and metabolites in skeletal muscle, rendering them unavailable for hepatic gluconeogenesis. These findings identify IRP1 as a critical regulator of systemic energy homeostasis.
    Keywords:  Diabetes; Glucose metabolism; Hepatology; Metabolism; Proteomics
    DOI:  https://doi.org/10.1172/jci.insight.183247
  20. Cells. 2025 Dec 30. pii: 65. [Epub ahead of print]15(1):
    Acute Cold Exposure Cell-Autonomously Reduces mTORC1 Signaling and Protein Synthesis Independent of AMPK.
    Benjamin Y Sung, Eliza J Ford, Daniel J Foster, Kyler J Fullmer, Cosette Cromwell, Benoit Viollet, David M Thomson.
      Cryotherapy is a commonly used strategy for skeletal muscle recovery, although the efficacy of its use has been controversial. Therefore, more research is needed to understand under what circumstances it should be used. This study aimed to examine the cell-autonomous effects of acute cold exposure on primary mouse myoblasts, focusing on metabolic signaling through the AMPK/mTORC1 pathway. In it, we hypothesized that cold exposure (COLD) would impair myoblast proliferation, differentiation, and protein synthesis in an AMPK-dependent manner. Wild-type (WT) and AMPK double-knockout (dKO) myoblast cultures were treated at 37 °C or 26 °C to evaluate AMPK-dependent effects. As expected, 30 min of cold exposure activated AMPK and decreased mTORC1 activity and protein synthesis; however, mTORC1 and protein synthesis were downregulated independently of AMPK activation. Additionally, cold exposure suppressed proliferation 6 h post-treatment in WT, but not dKO, myoblasts. On the other hand, in differentiated WT and dKO cells, cold treatment did not influence myotube size, although dKO myotubes exhibited decreased fusion index and increased size compared to WT. These findings offer new insights into the cell-autonomous metabolic effects of cryotherapy in skeletal muscle and indicate that while COLD-induced AMPK activation contributes to impaired myoblast proliferation, AMPK is not necessary for the COLD-induced inhibition of the mTORC1 pathway and protein synthesis.
    Keywords:  AMPK; cryotherapy; injury recovery; mTORC1; protein synthesis; skeletal muscle
    DOI:  https://doi.org/10.3390/cells15010065
  21. PLoS Genet. 2026 Jan 09. 22(1): e1012019
    Zebrafish genetic model of neuromuscular degeneration associated with Atrogin-1 expression.
    Romain Menard, Elena Morin, Dexter Morse, Caroline Halluin, Marko Pende, Aissette Baanannou, Janelle Grendler, Heath Fuqua, Jijia Li, Laetitia Lancelot, Jessica Drent, Frédéric Bonnet, Joel H Graber, Prayag Murawala, Cédric Dray, Jean-Philippe Pradère, James A Coffman, Romain Madelaine.
      The degenerative loss of muscle associated with aging leading to muscular atrophy is called sarcopenia. Currently, practicing regular physical exercise is the only efficient way to delay sarcopenia onset. Identification of therapeutic targets to alleviate the symptoms of aging requires in vivo model organisms of accelerated muscle degeneration and atrophy. The zebrafish undergoes aging, with hallmarks including mitochondrial dysfunction, telomere shortening, and accumulation of senescent cells. However, zebrafish age slowly, and no specific zebrafish models of accelerated muscle atrophy associated with molecular events of aging are currently available. We have developed a new genetic tool to efficiently accelerate muscle-fiber degeneration and muscle-tissue atrophy in zebrafish larvae and adults. We used a gain-of-function strategy with a molecule that has been shown to be necessary and sufficient to induce muscle atrophy and a sarcopenia phenotype in mammals: Atrogin-1 (also named Fbxo32). We report the generation, validation, and characterization of a zebrafish genetic model of accelerated neuromuscular atrophy, the atrofish. We demonstrated that Atrogin-1 expression specifically in skeletal muscle tissue induces a muscle atrophic phenotype associated with locomotion dysfunction in both larvae and adult fish. We identified degradation of the myosin light chain as an event occurring prior to muscle-fiber degeneration. Biological processes associated with muscle aging such as proteolysis, inflammation, stress response, extracellular matrix (ECM) remodeling, and apoptosis are upregulated in the atrofish. Surprisingly, we observed a strong correlation between muscle-fiber degeneration and reduced numbers of neuromuscular junctions in the peripheral nervous system, as well as neuronal cell bodies in the spinal cord, suggesting that muscle atrophy could underly a neurodegenerative phenotype in the central nervous system. Finally, while atrofish larvae can recover locomotive functions, adult atrofish have impaired regenerative capacities, as is observed in mammals during muscle aging. In the future, the atrofish could serve as a platform for testing molecules aimed at treating or alleviating the symptoms of muscle aging, thereby opening new therapeutic avenues in the fight against sarcopenia.
    DOI:  https://doi.org/10.1371/journal.pgen.1012019
  22. Biogerontology. 2026 Jan 07. 27(1): 35
    Conserved differential expression of DDX helicase and CPEB genes in skeletal muscles potentially influences neuromuscular junctions during aging: a computational analysis.
    M J Nishanth, Shanker Jha.
      Locomotion in animals depends on muscle activity, controlled by the central nervous system. The neuromuscular junctions (NMJs) are specialized synapses pivotal in neural control of muscle function. Declining muscle function is a characteristic of aging (sarcopenia), and gradual loss of NMJ function could contribute to sarcopenia. The NMJs are cellular ensembles comprising presynaptic axon terminals, postsynaptic muscle cell, and the perisynaptic glial cells, and a coordination between these components is essential for NMJ development and functioning. At the molecular level, gene expression regulation is fundamental to drive these coordinated cellular processes. Though RNA-binding proteins (RBPs) have emerged as a major class of regulatory factors and are also implicated in several neuromuscular disorders, there is no comprehensive understanding of their potential involvement in aging-associated loss of muscular activity. The present study aimed at analysing the expression levels of RBP transcripts showing differential expression patterns during aging and are conserved in Caenorhabditis elegans, Drosophila melanogaster, Danio rerio, Mus musculus, and Homo sapiens. DDX helicases from D. melanogaster and humans were found to be downregulated in young muscles, while in young mouse muscle samples, they were upregulated. Also, CPEB transcripts showed differential expression in D. melanogaster, D. rerio, M. musculus, and humans. Further, these proteins interact with other major regulatory factors, and any variations in their levels within the cell can alter the stoichiometry of these interactions, affecting diverse regulatory pathways.
    Keywords:  Aging; CPEB; DEAD-box helicase; Neuromuscular junction; RNA-binding proteins; Skeletal muscle
    DOI:  https://doi.org/10.1007/s10522-025-10382-0
  23. Biomaterials. 2026 Jan 04. pii: S0142-9612(26)00010-4. [Epub ahead of print]329 123986
    Cardiac and skeletal muscle delivery of biotherapeutics with a blood vessel epicardial substance-targeting peptide.
    Biaobiao Wang, Jiahui Cao, Jingqiao Wu, Yiwen Zhao, Yao Zhang, Frank Abendroth, Caorui Lin, Li Zhong, Huanan Yu, Yiqi Seow, Meitong Ou, Olalla Vázquez, Lin Mei, HaiFang Yin, Gang Han.
      Although peptide-based delivery strategies show promise for muscle and heart diseases, delivery of biotherapeutics to both skeletal and cardiac muscles remains challenging. Here, we identified a muscle-homing peptide (BV2) against blood vessel epicardial substance (BVES) by phage display. BV2 shows high binding affinity to BVES and is internalized primarily via caveolae-mediated endocytosis. Importantly, BV2 enables efficient delivery of Duchenne Muscular Dystrophy (DMD) phosphorodiamidate morpholino oligomer (PMO), mCherry protein and exosomes to skeletal muscle and heart in vivo. BV2-mCherry protein and BV2-E31R anti-myostatin peptide were effectively delivered to muscle layers when microneedles loaded with these biotherapeutics were implanted on hindlimbs of mice. Muscle mass and myofiber size also significantly increased in muscle atrophy mice grafted with BV2-E31R microneedles. Moreover, significantly enhanced restoration of dystrophin protein was achieved in peripheral and cardiac muscles of dystrophin-deficient mdx and dystrophin/utrophin double-knockout mice when exosomes simultaneously modified with BV2 and PMO. These findings highlight the potency of BV2 in directing targeted delivery of diverse biotherapeutics to muscle and heart, thus providing an effective tool for DMD and other muscular and cardiac disorders.
    Keywords:  Blood vessel epicardial substance (BVES); Duchenne muscular dystrophy; Exon-skipping; Muscle-homing peptide (BV2); Muscle-targeted delivery
    DOI:  https://doi.org/10.1016/j.biomaterials.2026.123986
  24. Hum Mol Genet. 2025 Dec 12. pii: ddaf183. [Epub ahead of print]
    Identification of KHDC1L, a DUX4-regulated protein, as a novel plasma biomarker in facioscapulohumeral muscular dystrophy.
    Nicholas A Sutliff, Emily Chao, Sean R Bennett, Yee Nip, Omar Lakhdari, David A Canton, Yiming Zhu, Stephen J Tapscott.
      Facioscapulohumeral muscular dystrophy (FSHD) is caused by aberrant expression of the double homeobox transcription factor DUX4 in skeletal muscle. Because direct measurement of DUX4 in FSHD muscle is technically challenging, DUX4-regulated transcripts in muscle biopsies have been used as surrogates; however, this approach is invasive, limited to a single muscle, and less suitable for repeated monitoring. Thus, we sought to identify DUX4-regulated circulating biomarkers that could integrate DUX4 activity across all affected muscles and enable more frequent measurement. We performed mass spectrometry on conditioned media from DUX4-inducible immortalized human myoblasts (MB135iDUX4) and identified a top candidate-KHDC1L, the protein product of a DUX4-regulated mRNA previously shown to correlate with DUX4 expression in muscle. Western blotting confirmed KHDC1L release into the supernatant of DUX4-expressing cells. Plasma profiling demonstrated elevated KHDC1L levels in individuals with FSHD compared to healthy controls, supporting its role as a circulating readout of DUX4 activity. These findings suggest that plasma KHDC1L is a potential pharmacodynamic marker of DUX4 activity, providing a minimally invasive tool for disease monitoring and a potential response marker to evaluate emerging FSHD therapies.
    Keywords:  DUX4; KHDC1L; circulating biomarker; facioscapulohumeral dystrophy; plasma
    DOI:  https://doi.org/10.1093/hmg/ddaf183
  25. Dev Biol. 2026 Jan 06. pii: S0012-1606(26)00003-5. [Epub ahead of print]
    IGF-1 regulates PEAR1 through Egr1 to Promote Skeletal Muscle Post-injury Regeneration.
    Jinxia Wang, Yue Li, Yutong Zhang, Yu Zhao, Huili Tong, Shufeng Li.
      Insulin-like growth factor 1 (IGF-1) is a key regulator of skeletal muscle growth and regeneration. In this study, we demonstrate that IGF-1 promotes C2C12 myoblast proliferation in a dose- and time-dependent manner. Mechanistically, IGF-1 induces the expression of early growth response 1 (Egr1), a transcription factor that directly binds to the promoter region of platelet endothelial aggregation receptor 1 (PEAR1) and enhances its transcription. Upregulation of PEAR1 subsequently facilitates myoblast proliferation by activating the Notch signaling pathway. Furthermore, IGF-1-induced activation of the Egr1-PEAR1 cascade enhances muscle stem cell (MuSC) proliferation and accelerates skeletal muscle regeneration following injury in vivo. Collectively, this study reveals the critical role of the IGF-1-Egr1-PEAR1 regulatory axis in skeletal muscle regeneration, providing novel mechanistic insight into IGF-1-mediated muscle repair.
    Keywords:  Egr1; IGF-1; MuSCs; PEAR1; Skeletal Muscle post-injury regeneration
    DOI:  https://doi.org/10.1016/j.ydbio.2026.01.003
  26. bioRxiv. 2025 Dec 29. pii: 2025.12.29.696842. [Epub ahead of print]
    mRNA transcription in skeletal muscle drives growth and determines nuclear accretion.
    Fabian Montecino-Morales, Cristofer Calvo, Casey O Swoboda, Alena Bruening, Alyssa A W Cramer, Xin Lin, Jennifer L Martin, Ramzi J Khairallah, Yarui Diao, Vikram Prasad, Douglas P Millay.
      Multinucleation of skeletal muscle cells (myofibers) is a determinant of size and fundamental for function. While it is established that myofibers need to accrue adequate numbers of nuclei for optimal growth, the molecular circuitry linking myonuclei to growth and why myofibers need additional nuclei remains unknown. We found that growth is still possible after restriction of nuclear content in myofibers and this was associated with increased levels of RNA Polymerase II ( Polr2a ) leading to elevated mRNA content. Through development of a genetic mouse model where endogenous Polr2a is upregulated in myofibers, we established that increased transcriptional output is sufficient to drive functional growth of myofibers. Notably, we discovered that Polr2a overexpression curtails the need for additional nuclei for myofiber growth. These data reveal a previously neglected driver of functional muscle growth and highlight that increasing Polr2a -mediated transcription from the vast numbers of nuclei within myofibers could be leveraged to combat muscle wasting conditions.
    DOI:  https://doi.org/10.64898/2025.12.29.696842
  27. J Muscle Res Cell Motil. 2026 Jan 06. 47(1): 1
    A single S-ketamine injection enhances mTOR signaling in rat skeletal muscle.
    Søren Andersen Skriver, Shokouh Arjmand, Andreas Breenfeldt Andersen, Gregers Wegener, Mette Hansen.
      S-ketamine is recognized as a rapid-acting antidepressant, exerting its effects primarily through activation of the mTOR signaling pathway in the brain, which plays a key role in neuroplasticity. Given the shared molecular mechanisms between brain and skeletal muscle, we investigated whether S-ketamine can also modulate regulatory proteins involved in muscle protein synthesis (MPS) and muscle protein breakdown (MPB) in skeletal muscle. Adult female Flinders Sensitive Line rats received a single intraperitoneal injection of S-ketamine (20 mg/kg) or saline, and soleus and extensor digitorum longus (EDL) muscles were collected two hours post-injection for protein analysis using Western blot. S-ketamine significantly increased phosphorylated mTOR (p-mTORSer2448) in both soleus and EDL, while total ULK1 protein expression was elevated in soleus. These findings suggest that S-ketamine can stimulate mTOR-related signaling in skeletal muscle, potentially enhancing MPS, although the activation was limited to specific signaling proteins. The results provide novel insights into the peripheral effects of S-ketamine beyond the central nervous system, highlighting the potential relevance for skeletal muscle physiology and anabolic regulation. Future studies are warranted to determine the temporal dynamics of these effects, the dose-dependence, and the impact of repeated administration on muscle hypertrophy. Overall, this study expands understanding of S-ketamine's systemic actions and raises new questions regarding its potential as a modulator of skeletal muscle protein metabolism.
    Keywords:  Animal data; Antidepressants; MTOR-signaling; Protein metabolism; Skeletal muscle.
    DOI:  https://doi.org/10.1007/s10974-025-09720-z
  28. Postepy Biochem. 2025 12 17. 71(4): 301-312
    Myokines as mediators of muscle communication – does muscle fiber type matter?
    Małgorzata Zimowska.
      Skeletal muscle is a dynamic tissue involved not only in mechanical functions but also in the regulation of metabolic and immune processes. It secretes signaling molecules known as myokines, which act in autocrine, paracrine, and endocrine ways- affecting both muscle function and other tissues and organs. Well-known myokines include myostatin, IL-6, IL-15, FGF21, and irisin. They regulate muscle mass and strength, promote angiogenesis, maintain glucose and lipid homeostasis, and contribute to immune and anti-cancer responses. Their activity depends on physiological and pathological conditions at both local and systemic levels. Notably, myokine secretion varies with muscle fiber type, influencing their specific biological effects. Understanding how myokines are regulated and function may support the development of new therapies in regenerative medicine, oncology, and metabolic disease treatment.
    DOI:  https://doi.org/10.18388/pb.2021_629
  29. Int J Mol Sci. 2025 Dec 25. pii: 242. [Epub ahead of print]27(1):
    An Integrated Multi-Omics Study of Mammalian Skeletal, Cardiac, and Smooth Muscles.
    Shengguo Tang, Kaiming Wang, Dongfang Li, Yanna Ma, Liangyuan Peng, Shuchao Liao, Haiming Ma, Hongjiang Wei.
      Muscle tissue, as a major tissue type, is classified by its structure and function into smooth, cardiac, and skeletal muscle. However, comprehensive studies on the evolutionary conservation of molecular differences among these three muscle tissues have been limited. In this study, we employed pigs and mice as models to perform multi-omics profiling (transcriptome, proteome, and metabolome) of these three muscle tissues in order to define their molecular landscapes. Furthermore, we characterized skeletal muscle metabolic heterogeneity. We identified 207 genes enriched in striated muscle, including poorly characterized genes such as LRRC2 and PPP1R14C. Distinct sets of genes and metabolites, conserved between the two species, were specifically enriched in each tissue: skeletal muscle (121 genes and 6 metabolites), cardiac muscle (57 genes and no specific metabolites), and smooth muscle (349 genes and 11 metabolites). Notably, the currently unannotated gene LRRC20 was most enriched in skeletal muscle, followed by cardiac muscle, and showed negligible expression in smooth muscle, suggesting its potential as a functional research target. Within skeletal muscle, 14 fast-twitch and 6 slow-twitch fiber-enriched metabolites were identified. In particular, 10-Deacetylbaccatin III was enriched in skeletal muscle and, more specifically, highly enriched in fast-twitch fibers, marking it as a promising and novel research target. These results provide a resource for research in both medicine and agricultural science.
    Keywords:  cardiac muscle; gene; metabolome; skeletal muscle; smooth muscle
    DOI:  https://doi.org/10.3390/ijms27010242
  30. Endocr Metab Sci. 2025 Dec;pii: 100266. [Epub ahead of print]19
    Mineralocorticoid receptor antagonists reduce inflammatory signaling independent of myofiber mineralocorticoid receptor.
    Jeovanna Lowe, Arden B Piepho, Chetan K Gomatam, Peyton Debell, Megan N Ballinger, Jill A Rafael-Fortney.
      Chronic inflammation is a feature of Duchenne muscular dystrophy (DMD), a degenerative striated muscle disease. Mineralocorticoid receptor (MR) antagonists (MRAs) have demonstrated clinical benefit on later onset DMD cardiomyopathy, and preclinical studies in mouse models have demonstrated efficacy on multiple steps of skeletal muscle pathology. MRA treatment of the mdx mouse model reduces pro-inflammatory gene expression from skeletal muscle myeloid immune cells and represses muscle cytokine signaling and fibrosis. Myofiber-specific knockout of MR in mdx mice improves muscle force and reduces fibrosis, but inflammation in this model had not been investigated. In this study we investigated muscle inflammation at the cellular level using flow cytometry and at the protein signaling level using an unbiased cytokine assay. Numbers and proportions of myeloid cells were the same in mdx mice and those lacking myofiber MR, similar to the absence of cell type differences previously observed with either MRA treatment or myeloid MR knockout. MRA treatment, but not myofiber MR deletion alone, led to reductions in numerous cytokines and chemokines also previously observed in mdx mice. These data suggest that the beneficial reduction of inflammatory signaling from MRAs is largely independent of myofiber MR and occurs through another mechanism.
    Keywords:  Inflammation; Mineralocorticoid receptor; Muscular dystrophy; Myeloid; mdx
    DOI:  https://doi.org/10.1016/j.endmts.2025.100266
  31. NPJ Regen Med. 2026 Jan 02.
    Disease exacerbation in human DMD MYOrganoids enables gene therapy evaluation and unveils persistence of fibrotic activity.
    Laura Palmieri, Giorgia Bimbi, Maxime Ferrand, Matteo Marcello, Louna Pili, Ai Vu Hong, Abbass Jaber, Riyad El-Khoury, Guy Brochier, Anne Bigot, David Israeli, Isabelle Richard, Sonia Albini.
      Leading gene therapy approaches for Duchenne muscular dystrophy (DMD) using AAV-mediated delivery of microdystrophin (µDys) have shown partial efficacy in patients, contrasting with the favorable outcomes observed in animal models. The identification of effective therapeutic strategies could be accelerated by using human high-throughput DMD models that replicate the molecular complexity driving pathology for accurate screening. To face this challenge, we develop MYOrganoids, an engineered muscle platform derived from patient-induced pluripotent stem cells (iPSC), recapitulating critical hallmarks of DMD, such as fibrosis and muscle dysfunction. We show that co-culture of fibroblasts with iPSC-derived muscle cells during organoid generation is pivotal for functional maturation and muscle force evaluation upon eccentric contractions. Notably, incorporation of DMD fibroblasts induced phenotypic exacerbation in DMD MYOrganoids by unraveling of fibrotic signature and fatiguability through cell-contact and paracrine mechanisms. We then exploited our system to interrogate gene therapy efficacy in this severe context. Although µDys gene transfer improves muscle resistance and partially restores membrane stability, it fails to reduce profibrotic signaling. These findings highlight the persistence of fibrotic activity post-gene therapy in our system, a limitedly explored aspect in DMD models, and provide the opportunity to study mechanisms of dysregulated cellular communication and empower gene therapy efficacy.
    DOI:  https://doi.org/10.1038/s41536-025-00445-8
  32. Geroscience. 2026 Jan 05.
    Skeletal muscle metabolomic markers underlying the enhanced exercise-induced hypertrophy response to resistance training in older adults.
    Changhyun Lim, Manoel Lixandrão, Dakshat Trivedi, Yun Xu, Konstantinos Prokopidis, Hamilton Roschel, Stuart M Phillips, Howbeer Muhamadali, Masoud Isanejad.
      Resistance training (RT) is an effective intervention for improving muscle health and metabolism in ageing, but the degree of responsiveness (hypertrophy) to RT varies substantially. We examined muscle metabolomic profiles before and after 10-weeks RT in older adults classified into upper (UPPER) and lower (LOWER) tertiles of hypertrophy to identify key metabolic adaptation differences. Fifty older adults (23 males, 27 females, mean 68.2 years old) completed 10 weeks of RT combined with whey protein supplementation. Quadriceps cross-sectional area (CSA) was assessed via magnetic resonance imaging before and after RT. Participants were grouped into UPPER (n = 25, 10.3 ± 2% CSA increase) or LOWER (n = 25, 3.3 ± 2% CSA increase) based on ranked CSA changes. We profiled skeletal muscle tissues from the UPPER and LOWER groups using a metabolomics platform. Over 2,500 metabolites were mapped to 104 metabolic pathways. In the UPPER group, upregulation of tryptophan-indole metabolites and the kynurenine pathway suggests a potential role of gut function and anti-inflammatory effect on RT-induced hypertrophy. Also, leucine, isoleucine and valine were significantly upregulated in the absence of their catabolites. Enrichment of urea cycle/amino group metabolism alongside mitochondria-matrix metabolites in the UPPER group indicates improved amino acids and energy homeostasis. Our findings highlight distinct RT-induced skeletal muscle metabolic profiles between UPPER and LOWER in older adults, underscoring the value of metabolic data. These metabolic pathways are important for understanding what contributes to the heterogeneity of hypertrophic response to RT in older adults.
    Keywords:  Ageing muscle metabolism; Muscle hypertrophy; Resistance training
    DOI:  https://doi.org/10.1007/s11357-025-02074-x
  33. FASEB J. 2026 Jan 15. 40(1): e71424
    Myoglobin Affects Tissue-Specific Transcriptome, Heart Regeneration and Whole Animal Metabolic Rates.
    Rasmus Hejlesen, Ciska Bakkeren, Christian Damsgaard, Lisbeth S Laursen, Kasper Kjær-Sørensen, Paola Corti, Hans Malte, Claus Oxvig, Angela Fago.
      Myoglobin (Mb) is a small haem-containing protein traditionally associated with oxygen carrier functions in cardiac and skeletal muscle. However, studies using Mb knockout mice have yielded conflicting results regarding its functional roles in vivo. Here, we used a CRISPR-Cas-generated zebrafish Mb knockout model to investigate the consequences of Mb loss across skeletal muscle types, transcriptomics profiles, and whole-animal metabolic rates under both resting and maximal exercise conditions. Mb deficiency did not alter skeletal muscle fiber composition or overall mitochondrial respiratory capacity but induced multiple tissue-specific transcriptomic changes, including downregulation of gene sets involved in respiration and differentiation pathways in the heart, while upregulating those associated with respiration and glycogen metabolism in the skeletal muscle. During cardiac regeneration following ventricle amputation in wild-type zebrafish, Mb expression was transiently suppressed, consistent with a role in maintaining the cardiomyocytes in a differentiated state. Physiologically, Mb knockout zebrafish displayed a reduced standard metabolic rate at rest, enhanced hypoxia tolerance (i.e., a lower critical oxygen tension), and increased maximal swimming speed, while maintaining unchanged maximal metabolic rate and aerobic scope relative to wild-type counterparts. Collectively, these findings show that loss of Mb in zebrafish elicits coordinated tissue-specific transcriptional changes, potentially facilitates cardiac regeneration, lowers standard metabolic rate, and enhances maximal swimming speed and hypoxia tolerance, thereby providing new insights into the multifaceted in vivo functions of Mb.
    Keywords:  heart; metabolic rate; myoglobin; respirometry; skeletal muscle; swimming performance; transcriptomics; zebrafish
    DOI:  https://doi.org/10.1096/fj.202503482RR
  34. Dis Model Mech. 2026 Jan 08. pii: dmm.052578. [Epub ahead of print]
    A new dystrophin deficient rat model mirroring exon skipping in patients with DMD exon 45 deletions.
    Tao Wang, Cynthia Daoud, Auriane Dubois, Guillaume Corre, Jessica Bellec, Matteo Bovolenta, Louise Philidet, Alan Dorval, Nathalie Bourg, Carinne Roudaut, Sonia Albini, Ganesh Warthi, Abbass Jaber, Isabelle Richard.
      Pathogenic variants in the dystrophin (DMD) gene cause muscle-wasting disorders ranging from the milder Becker muscular dystrophy (BMD) to the more severe Duchenne muscular dystrophy (DMD). Exon 45 deletion is the most frequent single-exon deletion in DMD patients. Here, we generated a novel rat model with an exon 45 deletion using CRISPR/Cas9. The DmdΔ45 rat recapitulate key features of DMD, including progressive skeletal muscle degeneration, impaired muscle and cardiac function and cognitive deficits. Transcriptomics analyses revealed gene expression patterns consistent with dystrophin deficiency. In skeletal muscle, we observed a transition from early stress responses and regeneration to chronic inflammation, fibrosis and metabolic dysfunction. Cardiac profiles similarly progressed from early inflammatory responses to fibrotic remodelling and metabolic impairment. Notably, DmdΔ45 rats displayed a milder phenotype than other DMD rat models. This attenuation is likely due to spontaneous exon skipping, particularly exon 44, which partially restores the reading frame and increases revertant dystrophin-positive fibres with age. Downregulation of spliceosome-related genes suggests a potential mechanism for this exon skipping. Overall, this model provides valuable insights into phenotypic variability and therapeutic exon-skipping strategies.
    Keywords:  Cardiomyopathy; Duchenne Muscular Dystrophy; Exon Skipping; Rat
    DOI:  https://doi.org/10.1242/dmm.052578
  35. J Endocrinol. 2026 Jan 09. pii: JOE-25-0257. [Epub ahead of print]
    ChREBP Deficiency Aggravates Diabetic Sarcopenia by Disrupting Glucose Signaling: A Novel Mouse Model of Muscle Atrophy.
    Toshinori Imaizumi, Katsumi Iizuka, Hiromi Tsuchida, Mayu Sakai, Sodai Kubota, Saki Kubota-Okamoto, Yoshihiro Takahashi, Ken Takao, Takehiro Kato, Masami Mizuno, Takuo Hirota, Yukio Horikawa, Shin Tsunekawa, Takaaki Murakami, Daisuke Yabe.
       Aims/Introduction: Diabetes is an increasingly prevalent global disease and often accompanied by sarcopenia, particularly in older adults. While insulin resistance is a well-known contributor to muscle loss in diabetes, the role of glucose signaling in diabetic skeletal muscle atrophy, particularly under insulin-deficient conditions, remains poorly understood. This study aimed to elucidate the pathophysiological role of the carbohydrate response element-binding protein (ChREBP), a glucose-sensing transcription factor encoded by the Chrebp gene in mice, in diabetic sarcopenia by generating Chrebp-deficient, insulin-deficient Ins2Akita/+ mice.
    Materials and Methods: We evaluated Chrebp+/+, Chrebp-/-, Ins2Akita/+; Chrebp+/+, and Ins2Akita/+; Chrebp-/- mice for muscle strength, endurance, survival, body composition, and muscle histology. Skeletal muscles were analyzed for gene expressions related to anabolic and catabolic pathways. Results: Ins2Akita/+; Chrebp-/- mice exhibited significant reductions in body weight, grip strength, survival, and skeletal muscle mass-particularly in the tibialis anterior, soleus, gastrocnemius, and quadriceps-compared to Ins2Akita/+ controls, despite similar hyperglycemia. Histological analysis revealed smaller mean muscle fiber size and reduced cross-sectional area of type 2A and 2B fibers, without changes in fiber-type composition. Furthermore, Igf-1 expression were suppressed, while the atrophy marker Fbxo32/Atrogin-1 was upregulated.
    Conclusions: These findings demonstrate that Chrebp deletion exacerbates muscle atrophy and frailty in insulin-deficient mice, underscoring a key role for ChREBP-mediated glucose signaling in maintaining muscle mass under diabetic conditions. The Ins2Akita/+; Chrebp-/- model provides a valuable platform for exploring diabetic sarcopenia mechanisms and potential therapeutic targets.
    Keywords:  Carbohydrate binding protein; diabetes; muscle mass; muscle strength; sarcopenia
    DOI:  https://doi.org/10.1530/JOE-25-0257
  36. J Physiol. 2026 Jan 08.
    Low-dose lithium supplementation promotes musculoskeletal and metabolic health in ovariectomized female mice.
    Bianca M Marcella, Jessica L Braun, Amélie A T Marais, Briana L Hockey, Mia S Geromella, Ryan W Baranowski, Rene Vandenboom, Rebecca E K MacPherson, Val A Fajardo.
      Postmenopausal women have an increased risk for age-related conditions like sarcopenia, osteoporosis and type 2 diabetes. Here we examined the effects of low-dose lithium (Li) supplementation, a well-known glycogen synthase kinase 3 (GSK3) inhibitor, on ovariectomized (OVX) mice, focusing on muscle strength and endurance, bone mineral density (BMD) and insulin sensitivity. 28-week-old female sham and OVX C57BL/6J mice were divided into three groups: sham, OVX and OVX-Li, with the latter receiving 50 mg/kg/day of Li in their drinking water for 8 weeks. Li supplementation enhanced isometric specific force and fatigue resistance of the soleus and extensor digitorum longus (EDL) muscles. Potential cellular mechanisms underlying these benefits include enhanced Ca2+ uptake, lowered oxidative stress, increased expression of select mitochondrial markers and a blunted muscle transcriptomic response to OVX surgery with Li supplementation. OVX mice exhibited lower BMD than sham controls; however Li supplementation restored BMD levels. Finally Li supplementation yielded modest improvements in insulin tolerance. In conclusion our findings highlight the advantages of low-dose Li for musculoskeletal and metabolic health in OVX female mice. KEY POINTS: Ovariectomy surgery compromises musculoskeletal and metabolic health in female mice. Here, we explored the potential benefits of low-dose lithium (Li) treatment. Li improved muscle isometric force production and fatigue resistance. RNA-Seq demonstrated that Li blunted the effects of OVX surgery. Li supplementation increased bone mineral density and insulin tolerance.
    Keywords:  GSK3; SERCA; fatigue; force production; insulin resistance; oestrogen; osteoporosis; skeletal muscle
    DOI:  https://doi.org/10.1113/JP289990
  37. Curr Drug Targets. 2026 Jan 06.
    PDMD: A Comprehensive Repository of Plants Reported for Skeletal Muscle-related Ailments.
    Aaysha Gupta, Sonam Chawla.
       INTRODUCTION: Medicinal plants and phytocompounds targeting skeletal muscle wasting in humans are under-represented in the majority of databases reporting plant/herb-diseases association. However, a large body of literature exists wherein plant extracts or active pharmaceutical ingredients thereof demonstrate potential benefit in skeletal muscle wasting diseases across model organisms. Underscoring the relevance of a repertoire documenting such medicinal plants, we introduce PDMD (Plants Database for Muscle Wasting Diseases), a manually curated plants database reported for muscle wasting diseases such as cachexia, sarcopenia, muscle atrophy, muscle frailty, impaired muscle regeneration, and muscle fatigue.
    METHODOLOGY: PDMD was developed through systematic manual collection and curation of published studies from PubMed, Science Direct, etc, retrieving literature on plants conferring pharmacological efficacy against muscle wasting across experimental model organisms. Phytochemical and taxonomic information were extracted via tools like ClassyFire, PubChem. To handle the storage of an annotated listing of plants, MS-Excel and MySQL were used. Frontend was designed in Visual Studio Code and HTML/CSS. An Apache/PHP server was used to integrate MS-Excel data and charts.
    RESULT AND DISCUSSION: PDMD encompasses 206 medicinal plants, 230 API reported across 18 model organisms, offering taxonomical information, phytochemical classes, SMILES structure, geographical distribution, and other bioactivity indications. PDMD is cross-referenced with standard databases such as PubChem and PubMed for enhanced functionality. PDMD highlights overlooked plant-muscle links, bridging ethnopharmacology and botany gaps, and can aid hypothesis generation for novel therapies.
    CONCLUSION: PDMD highlights overlooked plant-muscle links, bridging ethnopharmacology and botany gaps, and can aid hypothesis generation. PDMD is freely available at https://www.jiit.ac.in/biotechhighlightes/Research-Databases/PDMD/index.html, and was last updated in September 2025.
    Keywords:  Medicinal plants; active principal ingredients; cheminformatics.; database; skeletal muscle wasting pathologies
    DOI:  https://doi.org/10.2174/0113894501435270251129220150
  38. Int J Biol Macromol. 2026 Jan 07. pii: S0141-8130(26)00066-8. [Epub ahead of print] 150140
    NUDT3 facilitates the formation of oxidative fibers and alleviates metabolic dysregulation by degrading TNNI2 mRNA in skeletal muscles.
    Yongqi Yue, Xinyue Liang, Zihao Ge, Yang Li, Tengfei Zheng, Yanru Yue, Xiao Li.
      Genome-wide association studies (GWAS) across multiple human populations have identified NUDT3 as a leading obesity-associated candidate gene. Data from the human GTEx database indicate that NUDT3 is highly expressed in skeletal muscle; however, its physiological function in this tissue has remained largely unclear. In this study, NUDT3 overexpression significantly promoted the formation of slow/oxidative muscle fibers, as evidenced by increased expression of MyHC I, enhanced mitochondrial biogenesis, and improved mitochondrial function, whereas NUDT3 knockdown produced the opposite effects. Notably, NUDT3 overexpression in ob/ob mice significantly enhanced endurance exercise, improved glucose tolerance, oxygen consumption, and energy expenditure, thereby ameliorating metabolic dysfunction-associated hepatic steatosis. Mechanistically, NUDT3 directly bound to TNNI2 mRNA and reduced its stability, promoting a switch from fast/glycolytic to slow/oxidative myofibers, whereas TNNI2 overexpression counteracted the NUDT3-mediated promotion of slow/oxidative myofiber formation. Collectively, these findings elucidated a critical role of NUDT3 in regulating skeletal muscle fiber type switching and systemic energy expenditure, highlighting the pivotal contribution of dynamic skeletal myofiber composition to whole-body metabolic homeostasis.
    Keywords:  Metabolic homeostasis; Myofiber type; NUDT3; Obesity; TNNI2
    DOI:  https://doi.org/10.1016/j.ijbiomac.2026.150140
  39. Exp Mol Med. 2026 Jan 08.
    Revisiting noncoding RNAs: emerging coding functions and their impact on skeletal muscle development.
    Dandan Zhong, Jian Wang, Qi Li, Chuang Wang, Yuanyuan Huang, Yanhong Cao, Hui Li.
      Accumulating evidence has revealed noncoding RNAs (ncRNAs) as versatile regulators in skeletal muscle development, extending beyond their canonical roles as nontranslating transcripts. Recent advancements in proteomics and translatomics have demonstrated that ncRNAs containing cryptic open reading frames can encode peptides/proteins. Here we systematically evaluate computational tools and databases for predicting ncRNA-encoded products, dissect the molecular mechanisms underlying their translation and synthesize the current landscape of ncRNA-derived peptides/proteins identified in skeletal muscle across species. We further discuss their emerging roles in myogenesis and potential clinical implications for muscle-related disorders. By highlighting the dual functionality of ncRNAs as both regulatory RNAs and peptide/protein precursors, this work provides a comprehensive resource for understanding the expanding complexity of skeletal muscle development and proposes novel therapeutic targets for muscle diseases.
    DOI:  https://doi.org/10.1038/s12276-025-01610-1
  40. Curr Opin Clin Nutr Metab Care. 2026 Jan 07.
    Mechanism-based nutritional approaches in cancer cachexia.
    Emma Elisabeth Cappellato, Paola Costelli, Fabio Penna.
       PURPOSE OF REVIEW: Cancer cachexia is a complex multiorgan wasting syndrome that negatively impacts on cancer patient's survival and quality of life. Standard nutritional support is considered insufficient to counteract cachexia, and no approved nutritional approach or standard of care for cachexia exists so far. This review highlights recent reports focused on nutrition, aimed at sparing skeletal muscle and targeting molecular pathways underlying cachexia with specific supplements.
    RECENT FINDINGS: In animal models of cancer cachexia, branched-chain amino acids (BCAAs) help restore skeletal muscle proteostasis. In combination with the alanine dipeptide, with strong proteinogenic potential, BCAAs enhance anabolic signaling and suppress proteolysis via mTOR. α-ketoisocaproate exerts additional protective effects against muscle loss by targeting the Akt/FoxO3a and myostatin signaling. Methionine and the derivative SAM improve muscle status via epigenetic control and REDD1 suppression. L-carnitine shows multitarget functions, including muscle proteostasis control, inflammation attenuation, and reduced muscle fibrosis. Omega-3 polyunsaturated fatty acids show anti-inflammatory properties, improve the nutritional status, and prevent adipose tissue browning.
    SUMMARY: Overall, recent findings in preclinical and partly in clinical studies indicate that nutrient-based interventions target complementary cancer cachexia alterations. It is likely that combinatorial approaches, integrating several specific nutrients, will provide an effective base for managing cancer patients during the long journey of the disease, building future interventions against cancer cachexia.
    Keywords:  cancer cachexia; mechanisms; muscle wasting; nutritional support
    DOI:  https://doi.org/10.1097/MCO.0000000000001207
  41. Life Sci. 2026 Jan 03. pii: S0024-3205(25)00817-3. [Epub ahead of print]387 124181
    GABA induces myokine irisin release from skeletal muscle.
    Linling Fan, Yijing Liao, Zhihong Wang, Yunzhi Ni, Qiaoli Cui, Yahao Wang, Li Zhang, Hongying Ye, Xiaodong Sun, Yiming Li, Qinghua Wang.
       INTRODUCTION: γ-Aminobutyric acid (GABA), a classical neurotransmitter, also regulates skeletal muscle-an endocrine organ secreting irisin. This FNDC5-derived myokine induces white adipose tissue browning, augmenting thermogenesis and metabolic function.
    OBJECTIVES: This study investigated the effects of GABA on irisin secretion and its molecular mechanisms.
    METHODS: In L6 myotubes, GABA activated GABAAR, causing membrane depolarization and calcium influx, which upregulated CREB phosphorylation and increased PGC-1α and FNDC5 expression, significantly elevating irisin secretion. In vivo, GABA treatment increased PGC-1α/FNDC5 expression in mouse skeletal muscle and raised serum irisin levels. Additionally, GABA-induced irisin promoted the browning of white adipose tissue by upregulating thermogenic genes and remodeling fat metabolism.
    CONCLUSION: These findings reveal a novel role for GABA in regulating myokine secretion and suggest its potential as a therapeutic target for metabolic diseases such as obesity and type 2 diabetes.
    Keywords:  Adipose tissue; Irisin; Skeletal muscle; Γ-Aminobutyric acid
    DOI:  https://doi.org/10.1016/j.lfs.2025.124181
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