bims-moremu 2025-12-21 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2025–12–21
24 papers selected by
Anna Vainshtein, Craft Science Inc.

The impact of cellular senescence on aging skeletal muscle.
Uncovering the muscle clock-mitochondria axis through exercise.
TRPV2 in muscle satellite cells is crucial for skeletal muscle remodelling.
Muscle satellite cell editing by LNP-CRISPR-Cas9 to resist muscle injury.
A novel role of Mef2a in mitochondrial homeostasis and muscle regeneration during sarcopenia.
Skeletal Muscle HSF1 Alleviates Age-Associated Sarcopenia and Mitochondrial Function Decline via SIRT3-PGC1α Axis.
Exercise attenuates stress-related signaling as sensed by higher phosphorylation of small heat shock proteins in skeletal muscle from older individuals.
Sarcopenia and body temperature-the significance of interorgan metabolic networks in skeletal muscle atrophy.
HDAC11 deficiency improves muscle phenotype in a Duchenne muscular dystrophy murine model by reducing inflammation and fibrosis.
Effect of Muscle Contraction Under Caloric Restriction on Irisin and FGF21 Secretion in Mice.
Myokines in Aging: A Multi-Organ Network Perspective.
Fhod3 in zebrafish supports myofibril stability during growth of embryonic skeletal muscle.
Gne deletion in adult mice can cause thrombocytopenia, anemia, myopathy, bleeding, and death.
RBFOX2-dependent alternative splicing of Numb regulates Notch signaling during muscle stem cell activation.
Targeting Skeletal Muscle in Duchenne Muscular Dystrophy: Integrating In-Silico and Experimental Approaches to SGLT2 Inhibition.
Glucagon Like Peptide-1 Receptor Agonists for Sarcopenia and Muscle Wasting Disorders: A Systematic Review of Efficacy and Mechanisms.
Long-term DNA methylation changes induced by age and elevated CO2 in skeletal muscle.
Preserving the Metabolic Engine: Muscle as the Therapeutic Target for Cardiovascular Prevention in Obesity Pharmacotherapy.
High-fat diet exacerbates skeletal muscle mass loss via Nrf2/Prdx6 pathway in sarcopenic obesity mice.
Myogenesis and Inflammatory Response of Fibro-Adipogenic Progenitors are Regulated by Hydrogel Biophysical Properties.
Effect of Exercise-Induced Hormonal Changes on Skeletal Muscle Physiology.
β-Catenin and AMPK/AKT/FOXO Signaling Mediate Doxorubicin-Induced Senescence and Lipid Accumulation in C2C12 Myoblasts.
CXCL5 neutralization mitigates cancer cachexia by disrupting CAF-cancer cell crosstalk.
Validation of an in vitro muscle platform to evaluate myogenesis and calcium handling in control and dystrophic human myotubes.

Front Cell Dev Biol. 2025 ;13 1719279

The impact of cellular senescence on aging skeletal muscle.

Michael Kamal, Ryan Bevington, Amanda Johnson, Gianni Parise.

  Skeletal muscle is a highly plastic tissue that relies on its resident muscle stem cell population, known as satellite cells (MuSC), for its timely repair and regeneration. During aging, there is a decline in muscle regenerative capacity that is largely attributed to the loss of MuSC content and function. These aberrations are thought to contribute to the aging-related decline in skeletal muscle mass and strength. Cellular senescence, which is characterized by a state of irreversible cell cycle arrest and the presence of a senescence-associated secretory phenotype (SASP), has emerged as a potential factor in the dysfunction of MuSCs with aging. Much effort has recently been made to examine the detrimental effects of senescence on skeletal muscle as well as identify therapeutic approaches to selectively eliminate these cells and improve the aging phenotype. Here, we discuss the current understanding of aging-related MuSC impairments and the underlying mechanisms that link cellular senescence to the decline in muscle regenerative capacity.

Keywords:  SASP; aging; cellular senescence; regeneration; satellite cells; senolytics; skeletal muscle

DOI:  https://doi.org/10.3389/fcell.2025.1719279
Trends Endocrinol Metab. 2025 Dec 17. pii: S1043-2760(25)00245-0. [Epub ahead of print]

Uncovering the muscle clock-mitochondria axis through exercise.

Mauricio Castro-Sepulveda.

  Emerging evidence suggests an interplay between the molecular clock and mitochondrial dynamics in skeletal muscle. In this Forum article, we hypothesize that exercise, as a metabolic challenge, provides a powerful physiological model to investigate the clock-mitochondria axis and its regulatory role in muscle function and metabolic health in humans.

Keywords:  circadian clock; insulin resistance; mitochondrial dynamics; muscle atrophy

DOI:  https://doi.org/10.1016/j.tem.2025.11.001
Cell Death Dis. 2025 Dec 15. 16(1): 888

TRPV2 in muscle satellite cells is crucial for skeletal muscle remodelling.

Yanzhu Chen, Kimiaki Katanosaka, Makoto Shibuya, Yubing Dong, Lidan Zhang, Motoi Kanagawa, So-Ichiro Fukada, Keiji Naruse, Yuki Katanosaka.

Skeletal muscle remodelling relies on muscle stem cells (MuSCs) for regeneration after injury and hypertrophy in response to mechanical loading. However, the mechanisms that trigger MuSC activation and proliferation remain unclear. Transient receptor potential vanilloid 2 (TRPV2) ion channels respond to insulin-like growth factor-1 and mechanical stimuli to regulate the biological characteristics of various cells. Using a temporally inducible MuSC-specific conditional knockout (cKO) mouse, we show that TRPV2 regulates MuSC function and is essential for muscle remodelling. In cultured myofibre, MuSCs express TRPV2 and exhibit Ca2+ responses to the TRPV2 agonists 2-aminoethoxydiphenyl borate and probenecid, which are abolished upon TRPV2 deletion. TRPV2-deficient MuSCs exhibit reduced paired box 7 (Pax7) expression and impaired proliferation, suggesting TRPV2 is a factor that regulates the early stage of MuSC function. Myotube formation in MuSCs was enhanced by overexpression of TRPV2 and suppressed by TRPV2 deficiency, suggesting that TRPV2 is a factor that promotes myogenesis. Muscle-administered cardiotoxin promoted muscle regeneration and resulted in the appearance of numerous Pax7-positive MuSCs between myofibres. MuSC-specific TRPV2 cKO mice exhibit substantially impaired muscle regeneration after cardiotoxin-induced injury, drastically reducing Pax7-positive MuSCs between myofibres. In floxed mice, mechanical loading via synergist ablation induces hypertrophy and greatly increases the number of myonuclei per myofibre. In contrast, MuSC-specific TRPV2 cKO mice show no changes in myofibre thickness or nuclear number, either at baseline or after mechanical loading. Mechanical loading of floxed mice increased TRPV2+/Pax7+ double-positive MuSCs, but MuSC-specific TRPV2 cKO mice showed no change. Additionally, MuSCs exhibit Ca2+ responses to hypo-osmotic stimuli, which are suppressed by TRPV2 inhibitors and TRPV2 deletion, suggesting that MuSCs exhibit TRPV2-dependent mechanical responses. These results establish TRPV2 as a critical regulator of MuSC-mediated muscle remodelling, an important finding that may lead to therapeutic strategies for muscle repair and adaptation.

DOI: https://doi.org/10.1038/s41419-025-08242-3
Cell Rep. 2025 Dec 16. pii: S2211-1247(25)01467-6. [Epub ahead of print]45(1): 116695

Muscle satellite cell editing by LNP-CRISPR-Cas9 to resist muscle injury.

Taisuke Mochida, Naoko Fujimoto, Makoto Asahina, Shinya Asano, Shinsuke Araki, Naoto Inukai, Akitsu Hotta.

  Muscle satellite cells are essential for skeletal muscle regeneration and represent an attractive therapeutic target for gene delivery in Duchenne muscular dystrophy (DMD). However, efficient in vivo transduction of these cells has remained challenging. Here, we demonstrate that lipid nanoparticle (LNP)-mediated delivery of Streptococcus pyogenes CRISPR-Cas9 mRNA and guide RNA (LNP-CRISPR) induces exon skipping in Pax7-positive satellite cells more efficiently than adeno-associated virus (AAV) vectors following intramuscular or intravenous administration in a DMD mouse model. Furthermore, unlike AAV-CRISPR, LNP-CRISPR-mediated genome editing showed greater resistance to repeated muscle injuries, indicating successful editing of regenerative satellite cells. These results highlight the potential of LNPs as a non-viral platform for durable genome editing in skeletal muscle and lay the foundation for developing safe and sustainable genome-editing therapies for DMD.

Keywords:  AAV vector; CP: stem cell research; CRISPR-SpCas9; LNP; delivery; genome editing; muscle stem cell; muscular dystrophy; satellite cell

DOI:  https://doi.org/10.1016/j.celrep.2025.116695
Cells Dev. 2025 Dec 11. pii: S2667-2901(25)00070-1. [Epub ahead of print]185 204063

A novel role of Mef2a in mitochondrial homeostasis and muscle regeneration during sarcopenia.

Xin Tao, Suhong Zhang, Yue Li, Gongbing Tu, Dianfu Zhang, Liping Yin.

  Sarcopenia, characterized by an age-related decline in skeletal muscle mass and function, is closely associated with mitochondrial dysfunction. This study aimed to explore the role of myocyte enhancer factor 2A (MEF2A) in alleviating sarcopenia, focusing on its regulatory effect on mitochondrial homeostasis. AAV9-MEF2A was administered to 24-month-old male SAMP8 mice, and their endurance capacity and muscle histology were assessed. In vitro, MEF2A was overexpressed in C2C12 cells to examine its impact on myoblast proliferation and differentiation. Chromatin immunoprecipitation (ChIP), luciferase assays, and rescue experiments were conducted to identify downstream targets and validate the MEF2A-regulated signaling pathway. MEF2A overexpression significantly enhanced endurance performance, with a 1.17-fold increase in muscle mass, a 2.4 to 4.9-fold decrease in muscle atrophy markers compared to the AAV9-NC group, and a nearly 2 to 3-fold increase in mitochondrial biogenesis and antioxidant enzyme expression in aged mice. In C2C12 cells, MEF2A stimulated proliferation (1.8 fold increase in EdU-positive cells vs vector group) and differentiation (2 to 3-fold increase in differentiation markers vs vector group) while improving mitochondrial function through 1.5 to 2-fold increases in both OxPhos complex proteins and mitochondrial biogenesis genes compared to vector control. Mechanistically, MEF2A directly activated the PGC-1α/NRF2 axis, as validated by ChIP and reporter assays. Rescue experiments further verified the critical role of this pathway in MEF2A-mediated effects. These findings demonstrate that MEF2A mitigates sarcopenia by improving mitochondrial function and promoting muscle regeneration via activation of the PGC-1α/NRF2 signaling axis. MEF2A represents a promising therapeutic target for combating age-related muscle degeneration.

Keywords:  MEF2A; Mitochondrial biogenesis; Myogenic differentiation; PGC-1α/NRF2; Sarcopenia

DOI:  https://doi.org/10.1016/j.cdev.2025.204063
Adv Sci (Weinh). 2025 Dec 16. e10368

Skeletal Muscle HSF1 Alleviates Age-Associated Sarcopenia and Mitochondrial Function Decline via SIRT3-PGC1α Axis.

Jun Zhang, Min Hu, Xia Wu, Mingwei Guo, Ying Ma, Jin Qiu, Siqi Wang, Yuxiang Cao, Yinzhao Zhong, Fangfang Chen, Yiwen Wang, Wei Wei, Yan Lu, Yong Zhang, Junjie Xiao, Zhenji Gan, Cheng Hu, Xinran Ma, Lingyan Xu.

  Age-related sarcopenia, characterized by progressive loss of skeletal muscle mass and strength, impacts metabolic health and quality of life in the elderly. Heat shock factor 1 (HSF1) is a transcription factor that orchestrates cellular responses to various stresses, while its role in sarcopenia remains unknown. Here, HSF1 mRNA expression was decreased in muscles of aged mice and humans, correlating negatively with the atrophic gene and positively with the mitochondrial gene. Aged HSF1 muscle-specific knockout mice exhibited severe muscle atrophy and reduced endurance capacity, partially due to smaller fast fibers and mitochondrial dysfunction in slow fibers, as well as impaired systemic metabolic performance. In contrast, HSF1 overexpression in skeletal muscle improved these functions. Mechanistically, via RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq), it is revealed that HSF1 transcriptionally activated Sirtuin3 (SIRT3) for the deacetylation of both PGC1α1 and PGC1α4 isoforms of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), in skeletal muscle, enhancing mitochondrial function and muscle hypertrophy in vivo and in vitro, and inducing fibronectin type III domain-containing protein 5 (FNDC5)/Irisin for tissue crosstalk. Thus, HSF1 regulates skeletal muscle functions and systemic energy homeostasis via the SIRT3-PGC1α axis, representing a potential therapeutic target for sarcopenia and metabolic disorders.

Keywords:  aging; mitochondria; muscle atrophy; oxidative function; sarcopenia

DOI:  https://doi.org/10.1002/advs.202510368
J Sport Health Sci. 2025 Dec 16. pii: S2095-2546(25)00119-X. [Epub ahead of print] 101111

Exercise attenuates stress-related signaling as sensed by higher phosphorylation of small heat shock proteins in skeletal muscle from older individuals.

Noni T Frankenberg, Victoria L Wyckelsma, Dion Ellul, Aaron C Petersen, Itamar Levinger, Michael J McKenna, Robyn M Murphy.

   BACKGROUND: Heat shock proteins (HSPs) are key molecular chaperones that help maintain protein homeostasis by stabilising or removing damaged proteins during cellular stress. Aging weakens these stress-response systems, disrupting proteostasis and increasing vulnerability to sarcopenia. High-intensity training (HIT) can counteract these declines by activating protective pathways such as the HSP response. HSPs are highly responsive to stress, examining their regulation during aging is important, as altered HSP activity is linked to the progressive loss of muscle mass.
METHODS: This study investigated the abundance and phosphorylation of HSPs in skeletal muscle from healthy, active young and older adults (n = 7 per group), assessed at baseline and again in the older group following 12 weeks of HIT. Using calibrated Western blotting on both whole-muscle homogenates and pooled single muscle fibres, we quantified HSP content and phosphorylation to determine how aging and exercise influence stress-responsive protein regulation at both the tissue and cellular levels.
RESULTS: In whole muscle homogenates, HSPs (HSP72, HSP27, and αB-crystallin) did not differ between young and older adults, while higher phosphorylation of small HSPs (sHSPs): phospho-HSP27 at Serine15 (pHSP27 Ser15) and phospho-αB-crystallin at Serine59 (pαB-crystallin Ser59) (∼1.8-fold and ∼2.9-fold, respectively) were found in muscle from older adults, indicating higher cellular stress associated with aging. A 12-week HIT intervention in older adults reduced homogenate pHSP27 Ser15 and pαB-crystallin Ser59 abundances to similar levels found in young adults. Total HSPs typically displayed a distinct fiber-type profile in both age groups, with more in type I compared to type II fibers, distinguished by the presence of myosin heavy chain I (MHCI) or MHCII. Phosphorylation at pHSP27 Ser15 and pαB-crystallin Ser59 was not different between type I and type II fibers. The HIT in older adults decreased total and phosphorylated sHSPs in both type I and type II fibers but increased HSP72 in type I fibers.
CONCLUSION: HIT has the potential to mitigate age-related cellular stress and modulate protein expression patterns in aging skeletal muscle and, perhaps, has the potential to delay age-related muscle decline, thereby improving muscle health in older adults.

Keywords:  Aging; Fiber type; HSP; High-intensity training (HIT); Single muscle fibers

DOI:  https://doi.org/10.1016/j.jshs.2025.101111
Endocr J. 2025 Dec 17.

Sarcopenia and body temperature-the significance of interorgan metabolic networks in skeletal muscle atrophy.

Yuna Izumi-Mishima, Kazuhiro Nomura, Hiroshi Sakaue.

  The skeletal muscle plays a key role in thermogenesis and energy homeostasis in endotherms. Therefore, reduced skeletal muscle mass and function are closely associated with health disorders such as obesity and hypothermia. In humans, inactivity and nutritional deficiencies can lead to skeletal muscle atrophy. However, hibernating mammals, which can greatly suppress their metabolic rate, can maintain significant skeletal muscle mass even during prolonged periods of inactivity and nutritional restriction. This review focuses on how skeletal muscle contributes to maintaining body temperature as the organ that consumes the most energy, while also contributing to whole-organism homeostasis through its high metabolic flexibility in a self-sacrificing manner. Particularly, we reconceptualized muscle atrophy associated with the thermoregulatory process in terms of inter-organ metabolic interaction, proposing that sarcopenia is an integral component of systemic energy metabolism regulation. By deepening our understanding of the functional metabolic flexibility of skeletal muscle and its regulatory mechanisms, we can redefine sarcopenia as an adaptive response that contributes to maintaining metabolic homeostasis. This perspective could provide new insights into the pathophysiology of sarcopenia and metabolic disorders, and inform the development of more effective prevention and treatment strategies.

Keywords:  Amino acids; Interorgan metabolic network; Sarcopenia; Skeletal muscle; Thermogenesis

DOI:  https://doi.org/10.1507/endocrj.EJ25-0322
Life Sci. 2025 Dec 15. pii: S0024-3205(25)00786-6. [Epub ahead of print] 124150

HDAC11 deficiency improves muscle phenotype in a Duchenne muscular dystrophy murine model by reducing inflammation and fibrosis.

Renato Odria, Alexandra Mercado-Amarilla, Carolina Soler-Botija, Daniel M Borràs, Jessica Ohana, Pau Maestre, Anne Bigot, Xavier Suárez-Calvet, Eduard Gallardo, Gisela Nogales-Gadea, Mònica Suelves.

  Duchenne muscular dystrophy (DMD) is a devastating genetic disorder caused by mutations in the dystrophin gene, which encodes for an essential protein to maintain muscle integrity. Loss of dystrophin leads to progressive muscle degeneration, chronic inflammation and replacement of muscle by fibroadipose tissue. To date there is no cure for DMD and the identification of novel molecular targets involved in disease progression is needed to design new therapies to slow DMD progression and prolong survival. Here, we show for the first time that genetic deficiency of HDAC11 in a mouse model of DMD has a positive impact in dystrophic phenotype by reducing muscle damage and fibrosis, which results in improved muscle function. In addition, HDAC11-/- dystrophic muscles show diminished inflammation and changes in the inflammatory environment that positively affect regeneration. Importantly, a partial reduction in HDAC11 levels also improved the dystrophic phenotype, and this therapeutic impact was also observed in old mice. Dystrophic FAPs deficient for HDAC11 underwent more apoptosis, limiting their expansion, and produced less collagen. Single cell RNA sequencing data identified distinct FAP subpopulations, which differ between genotypes. These results were in agreement with the reduced inflammation observed in dKO mice, and suggest changes in the FAPs plasticity. Overall, our results show unequivocally that the total or partial reduction of HDAC11 levels improves the dystrophic phenotype, both histologically and functionally, in young and old mice, therefore HDAC11 could be envisioned as a new potential therapeutic target to ameliorate DMD pathology.

Keywords:  Duchenne muscular dystrophy; FAPs; Fibrosis; HDAC11; Inflammation; Skeletal muscle de/regeneration

DOI:  https://doi.org/10.1016/j.lfs.2025.124150
Physiol Res. 2025 Dec 15. 74(6): 969-980

Effect of Muscle Contraction Under Caloric Restriction on Irisin and FGF21 Secretion in Mice.

R Tanimura, H Watanabe, T Shirai, K Uemichi, T Iwata, T Takemasa.

Combining diet and physical activity is known to be more effective for health than either intervention alone. Recent research has shown that skeletal muscle secretes myokines in response to exercise, which contribute to the adaptation of other organs to exercise. Therefore, we hypothesized that muscle adaptation by calorie restriction (CR) might enhance myokine responses to exercise. It is known that the myokine fibroblast growth factor-21 (FGF-21) secreted by skeletal muscle during exercise activates adipose tissue browning. We have already reported that irisin, a myokine that contributes to the metabolic activation of adipose tissue and weight loss, is secreted in response to muscle contraction by electrical stimulation (ES). Thus, we investigated the secretion of FGF21 and irisin upon the combination of ES with CR in this study. Mice were divided into four groups: control mice (Con), calorie restriction mice (CR), acute muscle contraction mice (ES), and acute muscle contraction after calorie restriction mice (CRES). After 1 week of acclimation, we subjected the mice to 60 % calorie restriction. After 2 weeks of CR, we performed ES. The results showed that the irisin expression level in serum was significantly increased by the combination of ES and CR, and an interaction between CR and ES was confirmed. FGF21 expression in serum was significantly decreased by CR. In conclusion, we confirm that irisin is a myokine whose secretion is increased synergistically by CR and muscle contraction. Keywords Muscle " Calorie restriction " Myokine " Irisin " FGF21.
Aging Dis. 2025 Dec 11.

Myokines in Aging: A Multi-Organ Network Perspective.

Mei Xue, Chengcheng Liao, Yige Liu, Weidong Tian, Li Liao.

Exercise training represents a well-established anti-aging intervention that counteracts the multisystem functional decline. Skeletal muscle, the primary effector of physical activity, functions as a potent secretory organ, releasing myokines and extracellular vesicles into circulation. These muscle-derived factors mediate extensive crosstalk between muscle and distant organs, thereby coordinating the multi-tissue adaptations that underline the systemic benefits of exercise. This review synthesizes current knowledge on how myokine networks counteract aging across key physiological systems-including the metabolic, cardiovascular, musculoskeletal, nervous, and immune systems-by modulating core aging-related processes such as chronic inflammation, metabolic dysregulation, and loss of tissue homeostasis. We highlight how diverse myokines converge on conserved signaling hubs to exert integrated protective effects and discuss the profound influence of sex and age on myokine action. Finally, we outline the translational potential of, and challenges to, harnessing this myokine network in clinical practice, proposing personalized exercise regimens and engineered myokine-based therapies as promising strategies for promoting healthy aging.

DOI: https://doi.org/10.14336/AD.2025.1040
Dev Dyn. 2025 Dec 19.

Fhod3 in zebrafish supports myofibril stability during growth of embryonic skeletal muscle.

Aubrie Russell, Tracy Eng, Jeffrey D Amack, David Pruyne.

   BACKGROUND: Actin filament organization in cardiomyocytes critically depends on the formin Fhod3, but a role for Fhod3 in skeletal muscle development has not yet been described.
RESULTS: We demonstrate here that in zebrafish mutated for one of two fhod3 paralog genes, fhod3a, skeletal muscle of the trunk appears normal through 2 days post-fertilization, but afterward exhibits myofibril damage, including gaps between myofibrils and myofibril fragmentation. Despite the progressive nature of the myofibril damage, fhod3a mutants differ from muscular dystrophy models in that damage is exacerbated by inhibition of muscle activity, and fhod3a mutants show no evidence of sarcolemma disruption. Rather, myofibril damage appears to coincide with growth of the contractile apparatus. We find neither the second fhod3 paralog, fhod3b, nor the related fhod1 contribute to embryonic skeletal muscle development, but fish individually mutated for fhod3a, fhod3b, or fhod1 are viable and appear grossly normal as adults. This may reflect redundancy in adults, as all three are expressed in many adult organs.
CONCLUSIONS: These results indicate a fhod3-encoded formin is dispensable for initial myofibril assembly in skeletal muscle but promotes myofibril stability during muscle fiber growth. This is the first demonstration in a vertebrate that Fhod3 contributes to skeletal muscle development.

Keywords:  Fhod3; formin; muscular dystrophy; sarcomere; skeletal muscle; zebrafish

DOI:  https://doi.org/10.1002/dvdy.70108
J Neuromuscul Dis. 2025 Dec 19. 22143602251405918

Gne deletion in adult mice can cause thrombocytopenia, anemia, myopathy, bleeding, and death.

Patricia Lam, Deborah A Zygmunt, Macey Bennett, Anna Ashbrook, Jessica Hefty, Paul T Martin.

  The GNE gene encodes the UDP-GlcNAc-2-epimerase/ManNAc kinase, a bifunctional enzyme required for the synthesis of sialic acid. The mouse Gne gene is essential for embryonic development, but humans with recessive partial loss of function GNE mutations can develop infantile thrombocytopenia, juvenile amyotrophic lateral sclerosis, or adult-onset myopathy (GNE myopathy). We have created inducible Gnelox/lox gene deletion mice to study how loss of Gne in adult mice relates to these disease states. Systemic Gne gene deletion in tamoxifen-treated Rosa-CreERT2/Rosa-CreERT2Gnelox/lox mice caused uniform fatality within 30 days of gene deletion with spontaneous bleeding, thrombocytopenia, and anemia. Skeletal myofiber-specific Gne deletion in tamoxifen-treated HSA-CreERT2/+Gnelox/lox mice had no bleeding and no muscle pathology at 60 or 270 days post-treatment. Intramuscular injection of AAV.MCK.GFP-Cre in Gnelox/lox mice also showed little to no evidence of muscle pathology, while AAV.CMV.GFP-Cre caused extensive muscle damage, reduced muscle force, and changed expression of markers for muscle regeneration, muscle cell senescence, muscle denervation, and muscle atrophy. These data demonstrate that Gne is an essential gene in adult mice that can mimic aspects of human hematologic and muscle diseases caused by GNE mutations, but suggests induction of muscle disease requires loss of gene GNE expression in cell types beyond skeletal myofibers.

Keywords:  adeno associated virus; gene therapy; hematology; muscular dystrophy; sialic acid

DOI:  https://doi.org/10.1177/22143602251405918
Stem Cell Reports. 2025 Dec 18. pii: S2213-6711(25)00349-2. [Epub ahead of print] 102745

RBFOX2-dependent alternative splicing of Numb regulates Notch signaling during muscle stem cell activation.

Kangning Lin, Jing Liu, Erin H Y Tse, Yishu Yin, Indigo T C Chan, Anqi Dong, Lok Pui Ngan, Tom H Cheung.

  Satellite cells (SCs) are somatic stem cells essential for skeletal muscle regeneration. Most SCs remain quiescent in resting muscle, but they rapidly activate in response to stimuli. Although post-transcriptional regulation has been implicated in SC functions, the role of alternative splicing (AS) during SC activation remains unclear. Using in vivo fixation to preserve quiescent SCs, we uncovered rapid and extensive AS changes upon activation, affecting genes involved in fundamental pathways. We identified RBFOX2 as a key AS regulator in SCs; its loss delayed both SC activation and muscle regeneration. Particularly, RBFOX2 promotes the inclusion of exon 6 in Numb, a Notch pathway regulator. This exon is required for SC activation, and its skipping delays activation while upregulating Notch signaling. Altogether, our study provides the AS landscape during SC activation and demonstrates that a single-gene splicing change can significantly influence SC activation and essential pathways such as Notch signaling.

Keywords:  Notch; Numb; Rbfox2; alternative splicing; muscle stem cells; stem cell activation

DOI:  https://doi.org/10.1016/j.stemcr.2025.102745
Am J Pathol. 2025 Dec 12. pii: S0002-9440(25)00433-X. [Epub ahead of print]

Targeting Skeletal Muscle in Duchenne Muscular Dystrophy: Integrating In-Silico and Experimental Approaches to SGLT2 Inhibition.

Christopher Dostal, Johanna Reiner, Ana Isabel Antunes Goncalves, Laura Silva Sousa, Marlene Knapp, Joel Fischlein, Jessica Marksteiner, Jakob Sauer, Gavin Y Oudit, Anja Wagner, Dietmar Abraham, Karlheinz Hilber, Klaus Kratochwill, Bruno K Podesser, Attila Kiss.

Duchenne Muscular Dystrophy (DMD) is a severe X-linked disorder with progressive myofiber degeneration and fibrosis from dystrophin deficiency. Current therapies are largely supportive with limited anti-fibrotic benefit, prompting new strategies. Sodium-Glucose Co-Transporter-2 inhibitors (SGLT2i) show emerging anti-fibrotic and anti-inflammatory effects. We integrated open-access proteomic and transcriptomic datasets for in-silico analyses, including differential gene expression (DE), Weighted Gene Co-Expression Network Analysis (WGCNA), and pathway enrichment to identify dysregulated pathways potentially reversible by SGLT2i. Immune cell composition was estimated using CIBERSORTx in human and murine datasets. Therapeutic effects were tested with empagliflozin (EMPA) in mdx mice (30 mg/kg/day for 4 weeks starting at 12 weeks) and DMDmdx rats (10 mg/kg/day for 4 months starting at 5 months), with vehicle controls. Validation used RT-qPCR, grip-strength testing, and histological fibrosis staining. Analyses highlighted dysregulated extracellular matrix organization, cytokine signaling, and immune responses. Forty overlapping genes were identified; hub genes included COL3A1, COL5A2, and TGF-β1. EMPA reduced Tgfb1 expression in DMD rats and significantly decreased collagen deposition in skeletal muscle. Functional testing showed longer grip duration in EMPA-treated mice. Immune profiling revealed shifts in T cells and macrophages, indicating immunomodulation. Findings were consistent across species and data modalities analyzed. These results demonstrate that EMPA modulates fibrosis, inflammation, and muscle endurance in DMD models. These data support repurposing SGLT2i as a promising therapeutic strategy for DMD.

DOI: https://doi.org/10.1016/j.ajpath.2025.11.002
Aging Dis. 2025 Dec 01.

Glucagon Like Peptide-1 Receptor Agonists for Sarcopenia and Muscle Wasting Disorders: A Systematic Review of Efficacy and Mechanisms.

Abudureheman Maihemuti, Can Cui, Qianjin Wang, Reziwanguli Amuti, Wai Wang Chau, Senlin Chai, Ning Zhang, Ronald Man Yeung Wong, Ho Ko, Timothy Chi-Yui Kwok, Wing-Hoi Cheung.

Muscle wasting disorders, including sarcopenia and skeletal muscle atrophy, are increasingly prevalent among older adults and those with metabolic comorbidities. Sarcopenia, a progressive age-associated condition, involves the decline in skeletal muscle mass, strength, and physical performance, affecting millions of people globally. These disorders significantly elevate the risks of frailty, falls, and premature mortality, contributing to a growing burden on healthcare systems. Current interventions, including resistance exercise and dietary supplementation, have shown limited effectiveness, particularly among individuals with concurrent conditions such as type 2 diabetes (T2D). Notably, glucagon-like peptide-1 receptor agonists (GLP-1RAs), initially developed for glycemic and weight control, have demonstrated promising effects in preclinical models of muscle degeneration. In this review, we analyzed 20 preclinical and clinical studies on sarcopenia and muscle wasting disorders. Animal studies yielded promising results, including increased grip strength and enhanced skeletal muscle cross-sectional area (CSA), while body weight remained stable within a defined dosage range. Mechanistically, GLP-1RAs mitigate muscle wasting by upregulating myogenic factors (MyoD, MyoG), promoting mitochondrial biogenesis, and suppressing proteolysis (MuRF1, MAFbx) and inflammation via AMPK/SIRT1/NF-κB/Myostatin signaling. In contrast, limited clinical studies showed body weight reduction accompanied by a decline in lean mass following GLP-1RA treatment. Collectively, these results highlight the low dose-dependent anabolic potential of GLP-1RAs on skeletal muscle, while clinical evidence indicates simultaneous weight and lean mass loss. These findings suggest low-dose GLP-1RAs as potential therapy for sarcopenic obesity or early sarcopenia with metabolic comorbidities, warranting comprehensive clinical trials that incorporate multimodal strategies to preserve muscle mass during treatment.

DOI: https://doi.org/10.14336/AD.2025.1165
Skelet Muscle. 2025 Dec 19.

Long-term DNA methylation changes induced by age and elevated CO2 in skeletal muscle.

Joseph Balnis, Andy Madrid, Emily L Jackson, Lisa A Drake, Catherine E Vincent, Harold A Singer, Reid S Alisch, Ariel Jaitovich.

   BACKGROUND: Skeletal muscle dysfunction and elevated CO2 in the blood, or hypercapnia, are both associated with higher mortality in acute and chronic pulmonary diseases. Hypercapnia-, aging and autophagy dysfunction-induced skeletal muscle phenotypes are highly overlapping. While DNA methylation regulates aging-associated cellular processes, no comparative study of CO2- and age-induced changes in skeletal muscle has ever been conducted. Moreover, while previously reported skeletal muscle DNA methylation analyses involve about 1% of the genomic areas susceptible to this epigenetic modification, hypercapnia- and age-induced DNA methylation changes have never been investigated at the whole genome level.
METHODS: C57BL/6 mice previously exposed to normo- and hypercapnia were compared with room air-maintained aged animals of similar background. Muscles from these mice were processed for whole genome methylation sequencing (WGMS) and RNA sequencing. The overlap between hypercapnia- and age-induced DNA methylation and transcript expression levels were established. Skeletal muscle-specific autophagy genetic ablation and mass spectrometry analyses were conducted to investigate the potential mechanisms regulating hypercapnia-induced DNA methylation changes.
RESULTS: Hypercapnic mice demonstrate aberrant DNA methylation patterns in comparison to animals never exposed to elevated CO2. These animals also elicit changes in myofiber type composition and protracted muscle mass deterioration even after returning to normocapnia. While aging leads to consistent DNA methylation changes over time, these epigenetic changes do not overlap with CO2-induced differential methylation. Hypercapnia does not regulate the methylome via autophagy or substrate imbalance-related mechanisms.
CONCLUSION: Hypercapnia causes durable muscle wasting that persists even after regaining ambient air environment, which is associated with a perturbed methylome landscape. High CO2-induced DNA methylation changes do not overlap with age-induced differentially methylation positions and are independent of substrate imbalances and autophagy regulation.

Keywords:  Aging; Autophagy; Hypercapnia; Skeletal muscle DNA methylation

DOI:  https://doi.org/10.1186/s13395-025-00406-1
Curr Cardiol Rep. 2025 Dec 16. 28(1): 2

Preserving the Metabolic Engine: Muscle as the Therapeutic Target for Cardiovascular Prevention in Obesity Pharmacotherapy.

Fabian Sanchis-Gomar, Ian J Neeland, Pilar Ruiz-Lozano, Osama Alnahar, Fatima Rodriguez.

   PURPOSE OF REVIEW: This review examines the impact of incretin-based therapies and related incretin therapies on skeletal muscle health during pharmacologic weight loss. It explores the extent to which lean mass reduction contributes to total weight loss and highlights strategies to preserve muscle as a determinant of cardiovascular resilience.
RECENT FINDINGS: Emerging data indicate that 25-40% of incretin-based therapies-induced weight loss derives from loss of lean mass, with skeletal muscle being a key component. Although incretin-based therapies may improve the quality of skeletal muscle by reducing muscle fat infiltration, its function and strength remain underexplored. Exercise, adequate protein intake, and creatine supplementation mitigate these effects, whereas novel adjuncts such as myostatin/activin inhibitors and selective androgen receptor modulators show promise in early trials. Preserving muscle during incretin-based pharmacotherapy weight reduction is key to sustain long-term metabolic and cardiovascular benefits. Future trials should assess body composition, functional outcomes, and integrate muscle-preserving co-therapies into obesity management.

Keywords:  Body composition; Cardiometabolic health; GLP-1 receptor agonists; Lean mass preservation; Obesity pharmacotherapy; Skeletal muscle

DOI:  https://doi.org/10.1007/s11886-025-02334-4
J Gerontol A Biol Sci Med Sci. 2025 Dec 13. pii: glaf271. [Epub ahead of print]

High-fat diet exacerbates skeletal muscle mass loss via Nrf2/Prdx6 pathway in sarcopenic obesity mice.

Danni Wang, Xinyue Zheng, Yang Zhu, Wen Zhang, Sujuan Liu, Yanmei Niu.

  Sarcopenic obesity (SO), a dual condition characterized by the coexistence of sarcopenia and obesity, elevates the risk of metabolic disorders, disability, and mortality to magnitudes exceeding the combined risks of both conditions individually, demonstrating a "super-additive impairment" effect on health. Therefore, this study aims to investigate the mechanisms underlying the pathogenesis and progression of SO. We utilized natural aging mice fed high-fat diets (HFD) to simulate the progression of muscle mass decline observed in geriatric populations and high-calorie diets prevalent in modern societies, creating an SO animal model with exceptional clinical relevance. Our study demonstrates that HFD exacerbates age-related reductions in muscle mass, accompanied by decreased physical performance and increased lipid accumulation. Importantly, HFD-induced lipid infiltration emerges as a significant contributor to the further decline in skeletal muscle mass in SO mice, and the Nrf2/Prdx6 pathway is a mechanism regulating this factor. Aerobic exercise, a safe and reliable means for older adults, is particularly effective for fat loss and muscle maintenance. In our study, aerobic exercise effectively alleviated the detrimental effects of HFD on muscle health in aging mice. Mechanistic studies revealed that Nrf2 and Prdx6 protein expression was significantly suppressed in vivo by HFD and in vitro following palmitic acid (PA) exposure. Conversely, overexpression of Nrf2 and Prdx6 in vitro was able to mimic the protective effects of aerobic exercise. Our results indicate that the Nrf2/Prdx6 pathway plays a crucial role in counteracting muscle mass loss induced by HFD and may underlie beneficial effects of aerobic exercise on skeletal muscle.

Keywords:  Aerobic exercise; HFD; Nrf2; Prdx6; SO

DOI:  https://doi.org/10.1093/gerona/glaf271
ACS Appl Bio Mater. 2025 Dec 15.

Myogenesis and Inflammatory Response of Fibro-Adipogenic Progenitors are Regulated by Hydrogel Biophysical Properties.

Thi Thai Thanh Hoang, Katherine H Griffin, Harmony Aragon, J Kent Leach.

  Stem cell-based interventions to treat volumetric muscle loss (VML) and other skeletal muscle disorders offer promising avenues for muscle repair. Fibro-adipogenic progenitors (FAPs) support satellite cell function, yet under dysregulated conditions, FAPs can contribute to pathological adipogenesis and fibrosis. FAPs are highly responsive to biophysical cues of their environment that can alter cell fate, and their responsiveness to such cues can be readily interrogated using hydrogels. However, current approaches to study FAPs are often limited by the tunability of underlying substrates. Gelatin hydrogels exhibit favorable cell compatibility but are relatively elastic. In contrast, alginate hydrogels possess more physiologically relevant viscoelastic properties but lack essential cell-adhesive ligands. To overcome these limitations, we blended alginate into horseradish peroxidase-catalyzed gelatin hydrogels (cGA), forming a viscoelastic interpenetrating polymer network (IPN) structure termed ciGA, through covalent cross-linking of gelatin and ionic crosslinking of alginate. These hydrogels mimic the native mechanical properties of muscle, providing enhanced stiffness, tunable gelation, and improved viscoelasticity. ciGA hydrogels supported FAP viability, proliferation, and spreading while preserving mitochondrial dynamics, enhancing metabolic activity, and potentiating pro-myogenic paracrine functions. While elastic hydrogels promoted myotube formation and M1-like macrophage polarization, FAPs entrapped in ciGA did not induce macrophage polarization, suggesting their suitability for applications following the inflammatory phase. These findings highlight viscoelastic hydrogels as promising biomaterials for muscle repair, capable of supporting key stromal cell functions and modulating regenerative signaling via biophysical cues without compromising immunogenicity.

Keywords:  alginate; gelatin; hydrogels; immunomodulation; muscle regeneration

DOI:  https://doi.org/10.1021/acsabm.5c01833
Clin Endocrinol (Oxf). 2025 Dec 17.

Effect of Exercise-Induced Hormonal Changes on Skeletal Muscle Physiology.

Shengwen Shi.

   BACKGROUND: The purpose of the study was to determine changes in anabolic and catabolic hormone levels in response to various training regimens and to analyse their effect on skeletal muscle adaptation mechanisms through experimental measurement of physiological changes.
DESIGN: The study used laboratory biochemical assays to assess anabolic and catabolic hormone levels, clinical observation to measure physiological changes (muscle mass, strength, endurance), and statistical methods (ANOVA, t-tests, correlation analysis) to assess group differences.
METHODS AND MEASUREMENTS: The study conducted an experimental analysis of hormonal changes in response to various types of physical activity, in particular, strength training, HIIT, and aerobic exercise.
RESULTS: It was found that strength training contributed to the greatest increase in the level of anabolic hormones, which correlated with an increase in muscle mass (+12%) and strength (+35%), while HIIT provided a balanced improvement in strength indicators and endurance. Aerobic exercise caused minor changes in anabolic hormone levels but a significant increase in VO₂max (+30%) with an increase in cortisol (+5%). Changes in the levels of myokines were also found; in particular, irisin and osteocalcin, which play an important role in metabolic adaptation. The anabolic response was more pronounced in the younger participants (18-35 years), while in the older groups (36-50 and 51-60 years), the increase in muscle mass was less significant.
CONCLUSIONS: The identified patterns are important for sports medicine, endocrinology, and rehabilitation, in particular, for maintaining muscle mass and correcting hormonal changes in different age groups.

Keywords:  aerobic exercise; anabolism; catabolism; interleukin‐6; irisin; myokines

DOI:  https://doi.org/10.1111/cen.70086
Biomol Ther (Seoul). 2025 Dec 19.

β-Catenin and AMPK/AKT/FOXO Signaling Mediate Doxorubicin-Induced Senescence and Lipid Accumulation in C2C12 Myoblasts.

Chawon Yun, Sou Hyun Kim, Doyoung Kwon, RanJu Woo, Ki Wung Chung, Jaewon Lee, Yun-Hee Lee, Young-Suk Jung.

  Skeletal muscle atrophy is a major complication associated with aging, chronic disease, and chemotherapy. Doxorubicin (Dox), a widely used anticancer agent, accelerates muscle wasting; however, the underlying cellular mechanisms remain poorly understood. In this study, we examined the effects of Dox on myogenic differentiation, senescence, and lipid metabolism using C2C12 myoblasts. Dox exposure impaired myotube formation without causing overt cytotoxicity. Mechanistically, Dox disrupted myogenic differentiation by inhibiting protein kinase B/mammalian target of rapamycin (AKT/mTOR) signaling, thereby de-repressing forkhead box O1/3 (FOXO1/3) and upregulating the muscle-specific ubiquitin ligases muscle atrophy F-box (MAFbx) and muscle RING finger 1 (MuRF1), which promote proteolysis. Dox also decreased glycogen synthase kinase 3β (GSK3β) phosphorylation while paradoxically increasing total and phosphorylated β-catenin, indicating dysregulated Wnt/β-catenin signaling. These alterations were accompanied by a senescence-like phenotype, characterized by elevated senescence-associated β-galactosidase (SA-β-gal) activity, increased phosphorylated histone variant γH2AX, and activation of the p53-p21 axis. Notably, cellular senescence coincided with excessive lipid accumulation in myotubes. Dox reduced phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) while enhancing expression of key lipogenic regulators, thereby creating a metabolic environment favoring lipid storage. Collectively, these findings demonstrate that Dox not only suppresses myogenic differentiation but also induces premature senescence and metabolic reprogramming toward lipid accumulation. Targeting these pathways through AMPK activation, FOXO inhibition, or senolytic interventions may offer therapeutic strategies to preserve skeletal muscle integrity in patients undergoing chemotherapy.

Keywords:  AKT; AMPK; Doxorubicin; FOXO; Senescence; β-Catenin

DOI:  https://doi.org/10.4062/biomolther.2025.217
J Biomed Sci. 2025 Dec 15. 32(1): 107

CXCL5 neutralization mitigates cancer cachexia by disrupting CAF-cancer cell crosstalk.

Hyun-Jun Kim, Seon-Wook Kim, Jun-Hyeong Kim, Sang-Hoon Lee, Kyoung-Hwan Joo, Soo Young Lee, Hyunju Lee, Jung-Joon Min, Sang-Hee Cho, Da-Woon Jung, Darren R Williams.

   BACKGROUND: Advanced metastasis produces cachexia, a complex skeletal muscle wasting syndrome that accounts for one-third of patient deaths. There is currently no approved drug therapy for cancer cachexia. Cancer-associated fibroblasts (CAF) within tumors have been hypothesized to contribute to cachexia, but the detailed mechanism(s) are unknown.
METHODS: Myotubes were treated with conditioned media (CM) from CAF or CAF activated by cancer cells. Upregulated chemokines in the cancer-activated CAF CM were identified by cytokine array. The effects of chemokine neutralization were investigated using in vitro myotube cultures and in vivo mouse models. The mechanism of action was characterized by in vivo RNA Seq and validated in human muscle cells. Immunostaining delineated the chemokine expression pattern in a patient tumor type highly associated with cachexia.
RESULTS: Cancer-activated CAF induced myotube atrophy. CXCL5 was as the major chemokine highly upregulated in the cancer-activated CAF. CXCL5 treatment alone induced myotube atrophy and inhibited myogenic ERK1/2 signaling, similar to cancer-activated CAF treatment. CXCL5 neutralization inhibited cachexia in mice co-injected with HCT 116 colon cancer cells and CAF. RNA Seq showed that CXCL5 neutralization upregulated hypertrophy-related PI3K-AKT-MyoG signaling and remodeled the muscle ECM. CXCL5 neutralization ameliorated muscle wasting induced by CXCL5 and IL-6 co-treatment, and also prevented atrophy in cancer-activated CAF CM-treated human myotubes. CAF were the major detectable source of CXCL5 in a patient tumor highly associated with cachexia.
CONCLUSION: CAF contribute to cachexia via cancer cell crosstalk that upregulates CXCL5 secretion. CXCL5 neutralization offers a novel therapeutic approach to maintain muscle mass in cancer patients.

Keywords:  CXCL5; Cancer cachexia; Cancer-associated fibroblasts; Crosstalk; Skeletal muscle wasting; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12929-025-01192-0
Sci Rep. 2025 Dec 17.

Validation of an in vitro muscle platform to evaluate myogenesis and calcium handling in control and dystrophic human myotubes.

Laura Mosqueira-Martín, Carolina Prendes-García, Camila Vesga-Castro, Pablo Marco-Moreno, Ainhoa Irastorza, Ander Izeta, Iratxe Madarieta, Itxaso Martí-Carrera, Jacobo Paredes, Adolfo López de Munain, Ainara Vallejo-Illarramendi.

Electrical impedance has emerged as a powerful tool for real-time, label-free, and non-invasive monitoring of cellular processes. Here, we employed an impedance-based assay to characterize the myogenic process of control and dystrophic human myoblasts. First, we conducted a comprehensive analysis of control myoblast differentiation, assessing the effects of initial seeding density and various extracellular matrix coatings. We also evaluated the influence of electrode presence and current application, both of which improved myoblast alignment. Immortalized myoblasts from Duchenne muscular dystrophy patients exhibited marked alterations in early differentiation and maturation, which were readily detected via impedance measurements. We further compared two differentiation protocols using one control and one dystrophic representative cell line. While both protocols supported the formation of mature myotubes, impedance profiles differed depending on the culture medium. Notably, we identified the protocol with superior impedance profile reproducibility over the culture lifespan. Finally, we successfully assessed calcium homeostasis in control and dystrophic myotubes differentiated on 96-well impedance plates. Our findings underscore the potential of impedance-based assays for monitoring myogenesis and identifying disease-associated phenotypes. Moreover, 96-well impedance plates represent a robust tool for high-throughput and high-content functional analysis in muscle disease modeling and therapeutic screening.

DOI: https://doi.org/10.1038/s41598-025-31522-z