bims-moremu 2025-04-27 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2025–04–27
24 papers selected by
Anna Vainshtein, Craft Science Inc.

Oestrogen Receptor Alpha in Myocyte Maintains Muscle Regeneration in Duchenne Muscular Dystrophy.
At the Nexus Between Epigenetics and Senescence: The Effects of Senolytic (BI01) Administration on DNA Methylation Clock Age and the Methylome in Aged and Regenerated Skeletal Muscle.
Sirt2 deficiency aggravates intramuscular adipose tissue infiltration and impairs myogenesis with aging in male mice.
ExermiR-129-3p Enhances Muscle Function by Improving Mitochondrial Activity Through PARP1 Inhibition.
Premature skeletal muscle aging in VPS13A deficiency relates to impaired autophagy.
Phosphoproteomics Uncovers Exercise Intensity-Specific Skeletal Muscle Signaling Networks Underlying High-Intensity Interval Training in Healthy Male Participants.
A RETREG1/FAM134B isoform switch regulates reticulophagy during myogenesis.
The splicing factor Acin1 is essential for embryonic development but has limited effects on muscle structure and homeostasis.
Modulating phosphatase DUSP22 with BML-260 ameliorates skeletal muscle wasting via Akt independent JNK-FOXO3a repression.
The role of androgens and global and tissue-specific androgen receptor expression on body composition, exercise adaptation, and performance.
The Impact of Heritable Myopathies on Gastrointestinal Skeletal Muscle Function.
Skeletal muscle effects of antisense oligonucleotides targeting glycogen synthase 1 in a mouse model of Pompe disease.
Prepregnancy Obesity Reprograms Offspring Skeletal Muscle Fibre Transition Through H3K9me3.
Normal locomotion in zebrafish lacking the sodium channel NaV1.4 suggests that the need for muscle action potentials is not universal.
Targeted Therapy for Skeletal Muscle Fibrosis: Regulation of Myostatin, TGF-β, MMP, and TIMP to Maintain Extracellular Matrix Homeostasis.
Research progress on resistance exercise therapy for improving cognitive function in patients with AD and muscle atrophy.
Semaglutide-induced weight loss improves mitochondrial energy efficiency in skeletal muscle.
Keto Acids Attenuate Skeletal Muscle Atrophy in Chronic Kidney Disease via Inhibiting Pyroptosis and Upregulating Irisin Precursor FNDC5 Expression.
Myocellular adaptations to short-term weighted wheel-running exercise are largely conserved during C26-tumour induction in male and female mice.
Liraglutide enhances myotube differentiation and muscle contractile activity upon electric pulse stimulation in mouse skeletal muscle cells.
Functional MRP1 activity in human skeletal muscle.
Analysis of multiple insulin actions in single muscle fibres from insulin resistant mice reveals selective defect in endogenous GLUT4 translocation.
Investigating muscle protein synthesis using deuterium oxide: The impact of dietary protein interventions across the lifespan.
Anti-fibrotic, muscle-promoting antibody-drug conjugates for the improvement and treatment of DMD.

J Cachexia Sarcopenia Muscle. 2025 Apr;16(2): e13807

Oestrogen Receptor Alpha in Myocyte Maintains Muscle Regeneration in Duchenne Muscular Dystrophy.

Xiaofei Huang, Sijia Li, Huna Wang, Lei Zhao, Xihua Li, Shusheng Fan, Wanting Hu, Haowei Tong, Guangyao Guo, Dengqiu Xu, Luyong Zhang, Zhenzhou Jiang, Qinwei Yu.

   BACKGROUND: Oestrogen receptor alpha (ERα) plays an important role in maintaining mitochondrial function and regulating metabolism in skeletal muscle. However, its alterations and potential mechanisms in Duchenne muscular dystrophy (DMD) remain incompletely understood. In this study, we demonstrated the protective role of ERα in myocyte for skeletal muscle regeneration in mdx mice and explored the therapeutic effects of oestrogen receptor modulators on DMD.
METHODS: DMD patients' biopsies were obtained for histological analysis to explore the expression of ERα. The phenotype of muscle was analysed by histology and molecular biology. The therapeutical effect of different oestrogen receptor modulators was examined in mdx mice treated with fulvestrant (FVT, 20 mg/kg once a week) or oestradiol (E2, 1 mg/kg per day) for 4 weeks. The protective effect of ERα was performed on mdx mice after conditional knockout of ERα in skeletal muscle (ERαmKO mdx mice). Evidence of activation of ERα/oestrogen-related receptor alpha (ERRα)/myogenic differentiation 1 (MyoD) signalling pathway was inspected in the primary myoblasts isolated from mice, and C2C12 cells received intervention with E2/FVT/Esr1-siRNA/Esrra overexpression plasmid.
RESULTS: The ERα expression was increased in DMD patients' triceps (p < 0.05) and mdx mice muscles (p < 0.05). FVT reduced ERα levels in the mdx mice muscles (p < 0.01) but had no significant effect on skeletal muscle regeneration on mdx mice. Compared with mdx mice, E2 reduced the levels of creatine kinase (CK) and lactic dehydrogenase (LDH) (p < 0.001) in serum, enhanced skeletal muscle function, alleviated skeletal muscle atrophy and fibre loss and upregulated the expression of ERα in GAS (p < 0.001) and TA (p < 0.05). The myogenic factors such as myosin heavy chain (MyHC, p < 0.001), myogenin (MyoG, p < 0.05), MyoD (p < 0.05) and ERRα (p < 0.001) were increased in mdx mice GAS with E2. But E2 had no effect on ERαmKO mdx mice. The primary myoblasts and C2C12 were treated with E2 displayed an increased-on myocyte fusion index (p < 0.05), ERα MyoD and ERRα expressions (p < 0.05). The myocytes' fusion index (p < 0.05) and ERα, MyoD and ERRα expression (p < 0.05) were decreased in si-Esr1-transfected C2C12 cells and increased in OE-Esrra-transfected C2C12 cells.
CONCLUSION: We demonstrated that ERα in myocyte exerted a protective effect on skeletal muscle regeneration in DMD patients and mdx mice through the ERα-ERRα-MyoD pathway, which has potential implications for DMD therapy strategies.

Keywords:  Duchenne muscular dystrophy; fulvestrant; oestradiol; oestrogen receptor alpha; skeletal muscle regeneration

DOI:  https://doi.org/10.1002/jcsm.13807
Aging Cell. 2025 Apr 21. e70068

At the Nexus Between Epigenetics and Senescence: The Effects of Senolytic (BI01) Administration on DNA Methylation Clock Age and the Methylome in Aged and Regenerated Skeletal Muscle.

Toby L Chambers, Jaden Wells, Pieter Jan Koopmans, Francielly Morena, Zain B Malik, Nicholas P Greene, Antonio Filareto, Michael Franti, Patrizia Sini, Harald Weinstabl, Robert T Brooke, Milda Milčiūtė, Juozas Gordevičius, Steve Horvath, Yuan Wen, Cory M Dungan, Kevin A Murach.

  Senescent cells emerge with aging and injury. The contribution of senescent cells to DNA methylation age (DNAmAGE) in vivo is uncertain. Furthermore, stem cell therapy can mediate "rejuvenation", but how tissue regeneration controlled by resident stem cells affects whole tissue DNAmAGE is unclear. We assessed DNAmAGE with or without senolytics (BI01) in aged male mice (24-25 months) 35 days following muscle healing (BaCl2-induced regeneration versus non-injured). Young injured mice (5-6 months) without senolytics were comparators. DNAmAGE was decelerated by up to 68% after injury in aged muscle. DNAmAGE was modestly but further significantly decelerated by injury recovery with senolytics. ~1/4 of measured CpGs were altered by injury then recovery regardless of senolytics in aged muscle. Specific methylation changes caused by senolytics included differential regulation of Col, Hdac, Hox, and Wnt genes, which likely contributed to improved regeneration. Altered extracellular matrix remodeling using histological analysis aligned with the methylomic findings with senolytics. Without senolytics, regeneration had a contrasting effect in young mice and tended not to influence or modestly accelerate DNAmAGE. Comparing young to old injury recovery without senolytics using methylome-transcriptome integration, we found a more coordinated molecular profile in young and differential regulation of genes implicated in muscle stem cell performance: Axin2, Egr1, Fzd4, Meg3, and Spry1. Muscle injury and senescent cells affect DNAmAGE and aging influences the transcriptomic-methylomic landscape after resident stem cell-driven tissue reformation. Our data have implications for understanding muscle plasticity with aging and developing therapies aimed at collagen remodeling and senescence.

Keywords:  DNAmAGE; aging; extracellular matrix; methylation clock; omics integration

DOI:  https://doi.org/10.1111/acel.70068
Biogerontology. 2025 Apr 21. 26(3): 93

Sirt2 deficiency aggravates intramuscular adipose tissue infiltration and impairs myogenesis with aging in male mice.

Eun-Joo Lee, SunYoung Park, Kyu-Shik Jeong.

  Sarcopenia, closely associated with other diseases such as diabetes, metabolic syndrome, and osteoporosis, significantly impacts aging populations. It is characterized by muscle atrophy, increased intramuscular adipose tissue, impaired myogenesis, chronic low-grade inflammation, and reduced muscle function. The mechanisms behind aging muscle remain incompletely understood. This study aims to elucidate the role of Sirt2 in the aging process of skeletal muscles and enhance our understanding of the underlying mechanisms. Sirt2 expression was reduced in aging muscle of male mice by 40%, compared to young muscle. Aged male Sirt2 knockout mice exhibit increased intramuscular adipose tissue infiltration by 8.5-fold changes. Furthermore, the deletion of Sirt2 exacerbated myogenesis impairment in aged muscle by decreasing the expression of Pax7 (50%) and NogoA (80%), compared to age- and sex- matched counterparts, emphasizing the role of Sirt2 in pathology of aging muscle. Additionally, long-term Sirt2 deletion affected other Sirtuin subfamily members, with decreased expressions of Sirt1 (65%), Sirt4 (94%), and Sirt5 (71%), and increased expressions of Sirt6 (4.6-fold) and Sirt7 (2.8-fold) in old male Sirt2 knockout mice, while there was no difference of these gene expression in young male mice. This study underscores the critical need for a deeper investigation into Sirt2, promising new insights that could lead to targeted therapies for sarcopenia, ultimately improving the quality of life in the elderly.

Keywords:  Aging; Intramuscular adipose tissue infiltration; Myogenesis; Sarcopenia; Sirt2; Skeletal muscle

DOI:  https://doi.org/10.1007/s10522-025-10238-7
J Cachexia Sarcopenia Muscle. 2025 Apr;16(2): e13823

ExermiR-129-3p Enhances Muscle Function by Improving Mitochondrial Activity Through PARP1 Inhibition.

Yeo Jin Shin, Jae Won Yang, Heeyeon Jeong, Joyeong Kim, Bora Lee, Ji-Won Kim, Seung-Min Lee, Ju Yeon Kwak, Young Hoon Son, Kap Jung Kim, Yong Ryoul Yang, Chuna Kim, Ki-Sun Kwon, Kwang-Pyo Lee.

   BACKGROUND: Physical exercise has beneficial effects on various organs, including skeletal muscle. However, not all patients are capable of engaging in exercise to maintain muscle function, which underscores the importance of identifying molecular mechanisms of physical training that could lead to the discovery of exercise-mimicking molecules.
METHODS: This study sought to identify molecular mediators of exercise that could improve muscle function. We focused on the exercise-induced microRNA (miR)-129-3p, investigating its role and effects on mitochondrial activity both in vivo and in vitro. The expression of miR-129-3p was analysed in skeletal muscle following exercise, and its downstream effects on the poly (ADP-ribose) polymerase-1 (Parp1)-SIRT1-PGC1α signalling pathway were elucidated. Functional studies were conducted using muscle-specific overexpression of miR-129-3p in adult mice and intramuscular injection of AAV9-miR-129-3p in obese mice to assess exercise capacity and muscle strength.
RESULTS: Exercise was found to upregulate miR-129-3p in skeletal muscle (p < 0.05), which directly inhibits Parp1, a major NAD+-consuming enzyme. This inhibition leads to increased NAD+ levels (p < 0.05), activating SIRT1 and subsequently reducing the acetylation of PGC1α, thereby enhancing mitochondrial function. Muscle-specific overexpression of miR-129-3p in adult mice significantly enhanced exercise capacity (> 130%, p < 0.0001), while AAV9-miR-129-3p injections ameliorated muscle weakness (twitch force, > 140%, p < 0.05; tetanic force, > 160%, p < 0.01) in obese mice. In human skeletal muscle myoblasts, miR-129-3p improved mitochondrial function via the PARP1-SIRT1-PGC1α signalling pathway.
CONCLUSION: Our findings suggest that miR-129-3p, induced by exercise, can mimic the beneficial effects of physical exercise. This highlights miR-129-3p as a potential therapeutic target for improving muscle health, especially in individuals unable to exercise.

Keywords:  PARP1; TRIM63; exercise mimic; exermiR; microRNA; skeletal muscle

DOI:  https://doi.org/10.1002/jcsm.13823
Acta Neuropathol Commun. 2025 Apr 24. 13(1): 83

Premature skeletal muscle aging in VPS13A deficiency relates to impaired autophagy.

Veronica Riccardi, Carlo Fiore Viscomi, Marco Sandri, Angelo D'Alessandro, Monika Dzieciatkowska, Daniel Stephenson, Enrica Federti, Andreas Hermann, Leonardo Salviati, Angela Siciliano, Immacolata Andolfo, Seth L Alper, Jacopo Ceolan, Achille Iolascon, Gaetano Vattemi, Adrian Danek, Ruth H Walker, Alexander Mensch, Markus Otto, Marcus Deschauer, Moritz Armbrust, Cristiane Beninca', Valentina Salari, Paolo Fabene, Kevin Peikert, Lucia De Franceschi.

  VPS13A disease (chorea-acanthocytosis), is an ultra-rare autosomal recessive neurodegenerative disorder caused by mutations of the VPS13A gene encoding Vps13A. Increased serum levels of the muscle isoform of creatine kinase associated with often asymptomatic muscle pathology are among the poorly understood early clinical manifestations of VPS13A disease. Here, we carried out an integrated analysis of skeletal muscle from Vps13a-/- mice and from VPS13A disease patient muscle biopsies. The absence of Vps13A impaired autophagy, resulting in pathologic metabolic remodeling characterized by cellular energy depletion, increased protein/lipid oxidation and a hyperactivated unfolded protein response. This was associated with defects in myofibril stability and the myofibrillar regulatory proteome, with accumulation of the myocyte senescence marker, NCAM1. In Vps13a-/- mice, the impairment of autophagy was further supported by the lacking effect of starvation alone or in combination with colchicine on autophagy markers. As a proof of concept, we showed that rapamycin treatment rescued the accumulation of terminal phase autophagy markers LAMP1 and p62 as well as NCAM1, supporting a connection between impaired autophagy and accelerated aging in the absence of VPS13A. The premature senescence was also corroborated by local activation of pro-inflammatory NF-kB-related pathways in both Vps13a-/- mice and patients with VPS13A disease. Our data link for the first time impaired autophagy and inflammaging with muscle dysfunction in the absence of VPS13A. The biological relevance of our mouse findings, supported by human muscle biopsy data, shed new light on the role of VPS13A in muscle homeostasis.

Keywords:  Autophagy; Energy; Inflammaging; Metabolome; NF-kB

DOI:  https://doi.org/10.1186/s40478-025-01997-y
Sports Med. 2025 Apr 21.

Phosphoproteomics Uncovers Exercise Intensity-Specific Skeletal Muscle Signaling Networks Underlying High-Intensity Interval Training in Healthy Male Participants.

Nolan J Hoffman, Jamie Whitfield, Di Xiao, Bridget E Radford, Veronika Suni, Ronnie Blazev, Pengyi Yang, Benjamin L Parker, John A Hawley.

BACKGROUND: In response to exercise, protein kinases and signaling networks are engaged to blunt homeostatic threats generated by acute contraction-induced increases in skeletal muscle energy and oxygen demand, as well as serving roles in the adaptive response to chronic exercise training to blunt future disruptions to homeostasis. High-intensity interval training (HIIT) is a time-efficient exercise modality that induces superior or similar health-promoting skeletal muscle and whole-body adaptations compared with prolonged, moderate-intensity continuous training (MICT). However, the skeletal muscle signaling pathways underlying HIIT's exercise intensity-specific adaptive responses are unknown.
OBJECTIVE: We mapped human muscle kinases, substrates, and signaling pathways activated/deactivated by an acute bout of HIIT versus work-matched MICT.
METHODS: In a randomized crossover trial design (Australian New Zealand Clinical Trials Registry number ACTRN12619000819123; prospectively registered 6 June 2019), ten healthy male participants (age 25.4 ± 3.2 years; BMI 23.5 ± 1.6 kg/m2; V˙O2max 37.9 ± 5.2 ml/kg/min, mean values ± SD) completed a single bout of HIIT and MICT cycling separated by ≥ 10 days and matched for total work (67.9 ± 10.2 kJ) and duration (10 min). Mass spectrometry-based phosphoproteomic analysis of muscle biopsy samples collected before, during (5 min), and immediately following (10 min) each exercise bout, to map acute temporal signaling responses to HIIT and MICT, identified and quantified 14,931 total phosphopeptides, corresponding to 8509 phosphorylation sites.
RESULTS: Bioinformatic analyses uncovered exercise intensity-specific signaling networks, including > 1000 differentially phosphorylated sites (± 1.5-fold change; adjusted P < 0.05; ≥ 3 participants) after 5 min and 10 min HIIT and/or MICT relative to rest. After 5 and 10 min, 92 and 348 sites were differentially phosphorylated by HIIT, respectively, versus MICT. Plasma lactate concentrations throughout HIIT were higher than MICT (P < 0.05), and correlation analyses identified > 3000 phosphosites significantly correlated with lactate (q < 0.05) including top functional phosphosites underlying metabolic regulation.
CONCLUSIONS: Collectively, this first global map of the work-matched HIIT versus MICT signaling networks has revealed rapid exercise intensity-specific regulation of kinases, substrates, and pathways in human skeletal muscle that may contribute to HIIT's skeletal muscle adaptations and health-promoting effects. Preprint: The preprint version of this work is available on medRxiv, https://doi.org/10:1101/2024.07.11.24310302 .

DOI: https://doi.org/10.1007/s40279-025-02217-2
Autophagy. 2025 Apr 25. 1-3

A RETREG1/FAM134B isoform switch regulates reticulophagy during myogenesis.

Viviana Buonomo, Michele Cillo, Paolo Grumati.

  During skeletal muscle development, the sarcoplasmic reticulum forms through the homotypic fusion of ER membranes from individual myoblasts. This involves significant ER remodeling, characterized by an overhaul of its proteomic landscape and the activation of reticulophagy. We described how RETREG1/FAM134B is implicated in both shaping ER morphology and degrading ER membranes through reticulophagy. Following myoblast differentiation, the classic RETREG1/FAM134B1 undergoes lysosomal degradation and is progressively replaced by the shorter RETREG1/FAM134B2 isoform. RETREG1/FAM134B2 is a truncated variant of RETREG1/FAM134B1 maintaining an identical C-terminal region, including the functional LIR, but with a partial loss of its reticulon homology domain. The switch between these two isoforms plays a crucial role in ER morphology and muscle development. Re-expressing Retreg1/Fam134b2 in retreg1/fam134b-knockout myoblasts is both necessary and sufficient to rescue the abnormal proteomic landscape and prevent ER dilation. Conversely, the re-expression of Retreg1/Fam134b1 only partially rescues ER defects. We highlighted the role of RETREG1/FAM134B isoforms and reticulophagy in maintaining proper ER dynamics during myogenesis.

Keywords:  Autophagy; FAM134B; RETREG1; myogenesis; reticulophagy

DOI:  https://doi.org/10.1080/15548627.2025.2494803
Sci Rep. 2025 Apr 23. 15(1): 14017

The splicing factor Acin1 is essential for embryonic development but has limited effects on muscle structure and homeostasis.

Mamoru Aoto, Hiroshi Sakai, Naohito Tokunaga, Mei Miyazaki, Takeshi Kiyoi, Nobutaka Ohkubo, Yuuki Imai, Noriaki Mitsuda.

  Apoptotic chromatin condensation inducer 1 (Acin1) is an RNA-binding protein involved in the regulation of alternative splicing, but its physiological function remains unclear. Global deletion of Acin1 causes embryonic lethality around E11.5, with mutants exhibiting developmental delays and increased apoptosis. Using conditional knockout mice, we found that skeletal muscle myofiber-specific Acin1 knockout mice (Acin1 MKO) are viable and fertile and that Acin1 MKO mice show enlarged myofibers and ongoing muscle damage and regeneration, characterized by increased central nuclei and embryonic myosin heavy chain expression. RNA-seq analysis revealed that Acin1 deletion altered the expression and splicing patterns of genes crucial for muscle function. Notable changes included modified splicing of genes associated with muscle disease and mitochondrial function, often resulting in the expression of gene variants typical of immature or diseased muscle. These findings suggest that Acin1 is essential for embryonic development and has limited effects on muscle structure and homeostasis via its regulation of gene expression and alternative splicing.

Keywords:  Acin1; Alternative splicing; Embryonic development; Muscle damage; Muscle regeneration

DOI:  https://doi.org/10.1038/s41598-025-98851-x
EMBO Mol Med. 2025 Apr 22.

Modulating phosphatase DUSP22 with BML-260 ameliorates skeletal muscle wasting via Akt independent JNK-FOXO3a repression.

Sang-Hoon Lee, Hyun-Jun Kim, Seon-Wook Kim, Hyunju Lee, Da-Woon Jung, Darren Reece Williams.

  Skeletal muscle wasting results from numerous conditions, such as sarcopenia, glucocorticoid therapy or intensive care. It prevents independent living in the elderly, predisposes to secondary diseases, and ultimately reduces lifespan. There is no approved drug therapy and the major causative mechanisms are not fully understood. Dual specificity phosphatase 22 (DUSP22) is a pleiotropic signaling molecule that plays important roles in immunity and cancer. However, the role of DUSP22 in skeletal muscle wasting is unknown. In this study, DUSP22 was found to be upregulated in sarcopenia patients and models of skeletal muscle wasting. DUSP22 knockdown or treatment with BML-260 (a small molecule previously reported to target DUSP22) prevented multiple forms of muscle wasting. Mechanistically, targeting DUSP22 suppressed FOXO3a, a master regulator of skeletal muscle wasting, via downregulation of the stress-activated kinase JNK, which occurred independently of aberrant Akt activation. DUSP22 targeting was also effective in human skeletal muscle cells undergoing atrophy. In conclusion, phosphatase DUSP22 is a novel target for preventing skeletal muscle wasting and BML-260 treatment is therapeutically effective. The DUSP22-JNK-FOXO3a axis could be exploited to treat sarcopenia or related aging disorders.

Keywords:  BML-260; DUSP22; FOXO3a; Myofiber Atrophy; Skeletal Muscle Wasting

DOI:  https://doi.org/10.1038/s44321-025-00234-2
Biol Sex Differ. 2025 Apr 23. 16(1): 28

The role of androgens and global and tissue-specific androgen receptor expression on body composition, exercise adaptation, and performance.

Sabrina Tzivia Barsky, Douglas Ashley Monks.

  Gonadal testosterone stimulates skeletal muscle anabolism and contributes to sexually differentiated adipose distribution through incompletely understood mechanisms. Observations in humans and animal models have indicated a major role for androgen receptor (AR) in mediating sex differences in body composition throughout the lifespan. Traditional surgical, genetic and pharmacological studies have tested systemic actions of circulating androgens, and more recent transgenic approaches have allowed for tests of AR gene function in specific androgen responsive niches contributing to body composition, including: skeletal muscle and surrounding interstitial cells, white and brown adipose, as well as trabecular and cortical bone. Less well understood is how these functions of gonadal androgens interact with exercise. Here, we summarize the understood mechanisms of action of AR and its interactions with exercise, specifically on outcomes of body composition and muscle function, and the global- and tissue-specific role of AR in regulating skeletal muscle, adipose, and bone morphology. Additionally, we describe the known effects of androgen and AR manipulation on female body composition, muscle morphology, and sport performance, while highlighting a need for greater inclusion of female subjects in human and animal muscle physiology and endocrinology research.

Keywords:  Adipose; Androgen receptor; Body composition; Bone; Exercise; Skeletal muscle; Testosterone

DOI:  https://doi.org/10.1186/s13293-025-00707-6
Cell Mol Gastroenterol Hepatol. 2025 Apr 21. pii: S2352-345X(25)00063-3. [Epub ahead of print] 101522

The Impact of Heritable Myopathies on Gastrointestinal Skeletal Muscle Function.

Aishwarya Iyer, Madeline Alizadeh, Jennifer Megan Mariano, Aikaterini Kontrogianni-Konstantopoulos, Jean-Pierre Raufman.

  Amongst other contributions to gastrointestinal (GI) function, skeletal muscles regulate transit at both ends of the GI tract by providing propulsive forces for ingested nutrients and controlling the excretion of waste products. At the oropharynx, skeletal muscles provide necessary forces for effective mastication and the transfer of food boluses from the mouth into the proximal esophagus, where skeletal muscle-mediated peristalsis initiates propulsion of food boluses towards the stomach, a function supplanted by the upper esophagus smooth muscle. Consequently, the most prominent manifestation of proximal GI tract skeletal muscle dysfunction is transfer and oropharyngeal dysphagia that may result in repeated episodes of life-threatening choking and pulmonary aspiration. At the anal canal, the external anal sphincter controls the release of gas, liquids, and solids. Skeletal muscles within the pelvic floor play a synergistic role in regulating defection. Hence, distal GI tract skeletal muscle dysfunction may result in the leakage of flatus and fecal matter while, in contrast, pelvic floor dysfunction may contribute to constipation. The balance between such defects may severely impact nutritional status and quality of life. Herein, we provide a comprehensive review of the genetics, molecular biology, and mechanisms underlying heritable disorders of skeletal muscle and how these may impact GI tract function and overall well-being. For organizational purposes, we separate discussions of congenital, mitochondrial, and myofibrillar myopathies and muscular dystrophies. For the sake of completeness, we also briefly consider acquired myopathies that affect GI tract function. As treatment options are currently limited, disorders of skeletal muscle function provide exciting therapeutic opportunities, including innovative approaches to target specific gene modifications.

Keywords:  GI tract skeletal muscle; dysphagia; hereditary myopathies

DOI:  https://doi.org/10.1016/j.jcmgh.2025.101522
Clin Transl Med. 2025 Apr;15(4): e70314

Skeletal muscle effects of antisense oligonucleotides targeting glycogen synthase 1 in a mouse model of Pompe disease.

Lan Weiss, Michele Carrer, Alyaa Shmara, Angela Martin, Hong Yin, Pallabi Pal, Cheng Cheng, Lac Ta, Victoria Boock, Yasamin Fazeli, Mindy Chang, Marvin Paguio, Jonathan Lee, Howard Yu, John Weiss, Tamar R Grossman, Nina Raben, Paymaan Jafar-Nejad, Virginia Kimonis.

  Pompe disease (PD) is a progressive myopathy caused by the aberrant accumulation of glycogen in skeletal and cardiac muscle resulting from the deficiency of the enzyme acid alpha-glucosidase (GAA). Administration of recombinant human GAA as enzyme replacement therapy (ERT) works well in alleviating the cardiac manifestations of PD but loses sustained benefit in ameliorating the skeletal muscle pathology. The limited efficacy of ERT in skeletal muscle is partially attributable to its inability to curb the accumulation of new glycogen produced by the muscle enzyme glycogen synthase 1 (GYS1). Substrate reduction therapies aimed at knocking down GYS1 expression represent a promising avenue to improve Pompe myopathy. However, finding specific inhibitors for GYS1 is challenging given the presence of the highly homologous GYS2 in the liver. Antisense oligonucleotides (ASOs) are chemically modified oligomers that hybridise to their complementary target RNA to induce their degradation with exquisite specificity. In the present study, we show that ASO-mediated Gys1 knockdown in the Gaa-/- mouse model of PD led to a robust reduction in glycogen accumulation in skeletal muscle. In addition, combining Gys1 ASO with ERT slightly further reduced glycogen content in muscle, eliminated autophagic buildup and lysosomal dysfunction, and improved motor function in Gaa-/- mice. Our results provide a strong foundation for validation of the use of Gys1 ASO, alone or in combination with ERT, as a therapy for PD. We propose that early administration of Gys1 ASO in combination with ERT may be the key to preventative treatment options in PD. KEY POINTS: Antisense oligonucleotide (ASO) treatment in a mouse model of Pompe disease achieves robust knockdown of glycogen synthase (GYS1). ASO treatment reduces glycogen content in skeletal muscle. Combination of ASO and enzyme replacement therapy (ERT) further improves motor performance compared to ASO alone in a mouse model of Pompe disease.

Keywords:  Enzyme replacement therapy (ERT); Gaa‐/‐ mouse model; Pompe disease; antisense oligonucleotides (ASOs); glycogen synthase 1 (GYS1); skeletal muscle

DOI:  https://doi.org/10.1002/ctm2.70314
J Cachexia Sarcopenia Muscle. 2025 Apr;16(2): e13825

Prepregnancy Obesity Reprograms Offspring Skeletal Muscle Fibre Transition Through H3K9me3.

Yichi Wu, Sujuan Li, Jingyi Zhang, Anran Tian, Xiangyao Wang, Xi Yang, Fucheng Meng, Qing Li, Yuan Gao, Yingying Li, Furong Liang, Minglan Yao, Xiaoping Luo, Cai Zhang.

   BACKGROUND: Maternal prepregnancy obesity predisposes offspring to obesity and metabolic disorders, yet its impact on skeletal muscle fibre transition remains unclear. Given that skeletal muscle plays a crucial role in systemic metabolism, we investigated how maternal prepregnancy high-fat diet (HFD) influences muscle fibre composition and metabolic function in offspring.
METHODS: We established mouse models with a prepregnancy chow diet (CD) and a prepregnancy high-fat diet (HFD) for 8 weeks to compare metabolic phenotypes in offspring. Skeletal muscles from offspring were analysed using RNA sequencing, quantitative reverse transcription polymerase chain reaction and western blot to understand the changes in metabolic and signalling pathways. siRNA knockdown and lentiviral-mediated overexpression experiments were conducted in vitro and in vivo to validate molecular mechanisms. Chromatin immunoprecipitation followed by qPCR (ChIP-qPCR) was used to assess histone modification levels at promoter regions.
RESULTS: Male and female offspring of prepregnancy obese dams (mHFD) exhibited a significant reduction in slow-twitch oxidative fibres (p < 0.001) and an increase in fast-twitch glycolytic fibres compared with controls. This was accompanied by impaired glucose tolerance (AUC increased by 12.87%, p < 0.01), insulin resistance and mitochondrial dysfunction (mtDNA copy number reduced by 31%, p < 0.01). RNA sequencing identified IDH2 as the most significantly downregulated gene (29.67% decrease, p < 0.001), with protein levels further reduced in male (30.15%, p < 0.01) and female (46.02%, p < 0.0001) offspring. IDH2 knockdown in C2C12 cells impaired mitochondrial biogenesis and led to higher oxidative stress (NADP+/NADPH ratio elevated by 32%, p < 0.01), while IDH2 overexpression restored mitochondrial integrity, enhanced slow-twitch fibre proportion (26.43 ± 0.6936% in mHFD-LV-IDH2, p < 0.01) and improved glucose metabolism (fasting glucose reduced by 14.7%, p < 0.01). ChIP-qPCR revealed increased H3K9me3 enrichment at the IDH2 promoter (2.54-fold in males, 2.55-fold in females, p < 0.0001), suggesting transgenerational epigenetic regulation.
CONCLUSIONS: Maternal prepregnancy obesity induces a metabolic shift in offspring skeletal muscle by promoting a slow-to-fast fibre transition and impairing mitochondrial biogenesis. This effect is mediated by IDH2 suppression via H3K9me3 histone modification, contributing to systemic insulin resistance. Targeting IDH2 may represent a potential therapeutic strategy to mitigate metabolic dysfunction in offspring exposed to maternal prepregnancy obesity.

Keywords:  epigenetic; insulin resistance; muscle fibre type; prepregnancy obesity; skeletal muscle

DOI:  https://doi.org/10.1002/jcsm.13825
PLoS Biol. 2025 Apr;23(4): e3003137

Normal locomotion in zebrafish lacking the sodium channel NaV1.4 suggests that the need for muscle action potentials is not universal.

Chifumi Akiyama, Souhei Sakata, Fumihito Ono.

Extensive studies over decades have firmly established the concept that action potentials (APs) in muscles are indispensable for muscle contraction. To re-examine the significance of APs, we generated zebrafish lacking APs by editing the scn4aa and scn4ab genes, which together encode NaV1.4 (NaVDKO), using the CRISPR-Cas9 system. Surprisingly, the escape response of NaVDKOs to tactile stimuli, both in the embryonic and adult stages, was indistinguishable from that of wild-type (WT) fish. Ca2+ imaging using the calcium indicator protein GCaMP revealed that myofibers isolated from WT fish could be excited by the application of acetylcholine (ACh), even in the presence of tetrodotoxin (TTX) indicating that NaVs are dispensable for skeletal muscle contraction in zebrafish. Mathematical simulations showed that the end-plate potential was able to elicit a change in membrane potential large enough to activate the dihydropyridine receptors of the entire muscle fiber owing to the small fiber size and the disseminated distribution of neuromuscular synapses in both adults and embryos. Our data demonstrate that NaVs are not essential for muscle contraction in zebrafish and that the physiological significance of NaV1.4 in muscle is not uniform across vertebrates.

DOI: https://doi.org/10.1371/journal.pbio.3003137
Biologics. 2025 ;19 213-229

Targeted Therapy for Skeletal Muscle Fibrosis: Regulation of Myostatin, TGF-β, MMP, and TIMP to Maintain Extracellular Matrix Homeostasis.

Nurrani Mustika Dewi, Anna Meiliana, Irma Ruslina Defi, Riezki Amalia, Cynthia Retna Sartika, Andi Wijaya, Melisa Intan Barliana.

  Muscle fibrosis, defined by the excessive deposition of extracellular matrix (ECM) components, is a key pathological process that hinders muscle regeneration following injury. Despite muscle's inherent regenerative potential, severe or chronic injuries often result in fibrosis, which compromises muscle function and impedes healing. This review explores a range of therapeutic strategies aimed at modulating the molecular pathways involved in muscle fibrosis, with a focus on the inhibition of myostatin and transforming growth factor-β (TGF-β), as well as the regulation of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). Some therapy modalities, including physiotherapy and exercise therapy, which are commonly used, have demonstrated the ability to regulate extracellular matrix (ECM) components and promote muscle repair. In addition, the use of TGF-β inhibitors, herbal plants, and other biochemically relevant compounds, holds promise in controlling fibrosis by targeting key signaling pathways that drive ECM accumulation as well as having anti-fibrotic and anti-inflammatory properties. Regenerative medicine, including therapies using stem cell, secretome, and platelet-rich plasma (PRP), have also been used as single or adjuvant treatment for muscle fibrosis, and represents a novel and minimally invasive approach. Although these therapeutic strategies show considerable promise, translating preclinical findings to clinical practice remains challenging owing to variability in patient responses and the complexity of human muscle injuries. In conclusion, a multifaceted approach targeting ECM regulation, either as single treatment or combined treatment, offers a promising avenue for the treatment of muscle fibrosis.

Keywords:  MMP; TGF-β; TIMP; extracellular matrix; muscle fibrosis; myostatin

DOI:  https://doi.org/10.2147/BTT.S508221
Front Aging Neurosci. 2025 ;17 1552905

Research progress on resistance exercise therapy for improving cognitive function in patients with AD and muscle atrophy.

Wenyao Li, Wei Fang, Yier Zhang, Qiulu Chen, Wuyue Shentu, Qilun Lai, Lin Cheng, Sicheng Yan, Qi Kong, Song Qiao.

  Alzheimer's disease (AD) significantly reduces the quality of life of patients and exacerbates the burden on their families and society. Resistance exercise significantly enhances the overall cognitive function of the elderly and patients with AD while positively improving memory, executive function, and muscle strength, reducing fall risks, and alleviating psychological symptoms. As AD is a neurodegenerative disorder, some nerve factors are readily activated and released during exercise. Therefore, several prior studies have concentrated on exploring the molecular mechanisms of resistance exercise and their impact on brain function and neural plasticity. Recent investigations have identified an intrinsic relationship between individuals with AD and the pathological mechanisms of skeletal muscle atrophy, establishing a correlation between patients with AD cognitive level and skeletal muscle content. Resistance exercise primarily targets the skeletal muscle, which improves cognitive impairment in patients with AD by reducing vascular and neuroinflammatory factors and further enhances cognitive function in patients with AD by restoring the structural function of skeletal muscle. Furthermore, the effects of resistance training vary among distinct subgroups of cognitive impairment. Individuals exhibiting lower cognitive function demonstrate more pronounced adaptive responses in physical performance over time. Consequently, further investigation is warranted to determine whether tailored guidelines-such as variations in the frequency and duration of resistance exercise-should be established for patients with varying levels of dementia, in order to optimize the benefits for those experiencing cognitive impairment. This study aimed to review the relationship between AD and skeletal muscle atrophy, the impact of skeletal muscle atrophy on AD cognition, the mechanism by which resistance exercise improves cognition through skeletal muscle improvement, and the optimal resistance exercise mode to elucidate the additional advantages of resistance exercise in treating cognitive function in patients with AD and skeletal muscle atrophy.

Keywords:  Alzheimer's disease; cognitive function; neuromuscular; resistance exercise; skeletal muscle atrophy

DOI:  https://doi.org/10.3389/fnagi.2025.1552905
Obesity (Silver Spring). 2025 May;33(5): 974-985

Semaglutide-induced weight loss improves mitochondrial energy efficiency in skeletal muscle.

Ran Hee Choi, Takuya Karasawa, Cesar A Meza, J Alan Maschek, Allison M Manuel, Linda S Nikolova, Kelsey H Fisher-Wellman, James E Cox, Amandine Chaix, Katsuhiko Funai.

OBJECTIVE: Glucagon-like peptide-1 receptor agonists (e.g., semaglutide) potently induce weight loss, thereby reducing obesity-related complications. However, weight regain occurs when treatment is discontinued. An increase in skeletal muscle oxidative phosphorylation (OXPHOS) efficiency upon diet-mediated weight loss has been described, which may contribute to reduced systemic energy expenditure and weight regain. We set out to determine the unknown effect of semaglutide on muscle OXPHOS efficiency.
METHODS: C57BL/6J mice were fed a high-fat diet for 12 weeks before receiving semaglutide or vehicle for 1 or 3 weeks. The rates of ATP production and oxygen (O2) consumption were measured via high-resolution respirometry and fluorometry to determine OXPHOS efficiency in muscle at these two time points.
RESULTS: Semaglutide treatment led to significant reductions in fat and lean mass. Semaglutide improved skeletal muscle OXPHOS efficiency, measured as ATP produced per O2 consumed in permeabilized muscle fibers. Mitochondrial proteomic analysis revealed changes restricted to two proteins linked to complex III assembly (LYRM7 and TTC19; p < 0.05 without multiple corrections) without substantial changes in the abundance of OXPHOS subunits.
CONCLUSIONS: These data indicate that weight loss with semaglutide treatment increases skeletal muscle mitochondrial efficiency. Future studies could test whether it contributes to weight regain.

DOI: https://doi.org/10.1002/oby.24274
Calcif Tissue Int. 2025 Apr 24. 116(1): 63

Keto Acids Attenuate Skeletal Muscle Atrophy in Chronic Kidney Disease via Inhibiting Pyroptosis and Upregulating Irisin Precursor FNDC5 Expression.

Peixin Wang, Qi Pang, Aihua Zhang.

  It is widely accepted that keto acids supplementation can protect skeletal muscle from atrophy. Pyroptosis has been considered to be one of the new mechanisms of muscle atrophy. This study aimed to explore the effects and mechanisms of keto acids supplementation on chronic kidney disease (CKD)-induced skeletal muscle atrophy. In vitro, C2C12 myoblast cells were treated with indoxyl sulfate (IS, 1 mM) and leucine (Leu, 0 ng/mL, 50 ng/mL or 100 ng/mL). In animal experiment, animals were divided into four groups: normal control (NC) group (wildtype mice), CKD group (wildtype mice with CKD modeling), keto acids (KAs) group (CKD wildtype mice treated with KA), and FNDC5-/- group (Fndc5 (irisin precursor) gene knockout mice with CKD modeling and KA treatment). Results showed that leucine improved IS-induced myotube atrophy, decreased percentage of Propidium Iodide (PI)-positive cells, upregulated FNDC5 expression levels, and downregulated the pyroptosis-related protein levels, such as NLRP3, cleaved CASP1, and GSDMD-N. KA supplementation improved renal function and skeletal muscle atrophy. Furthermore, KA supplementation suppressed the expression of pyroptosis-related proteins and increased the expression of FNDC5. However, Fndc5 gene knockout partially reversed the protective effects of keto acids in CKD. In conclusion, our results showed for the first time that KA supplementation improves CKD-induced skeletal muscle atrophy by inhibiting pyroptosis and increasing expression of irisin/FNDC5. Our findings provide a novel insight into the treatment of the CKD-induced skeletal muscle atrophy.

Keywords:  Chronic kidney disease; Irisin/FNDC5; Keto acids; Pyroptosis; Skeletal muscle atrophy

DOI:  https://doi.org/10.1007/s00223-025-01372-y
Exp Physiol. 2025 Apr 24.

Myocellular adaptations to short-term weighted wheel-running exercise are largely conserved during C26-tumour induction in male and female mice.

Stavroula Tsitkanou, Pieter Koopmans, Calvin Peterson, Ana Regina Cabrera, Ruqaiza Muhyudin, Francielly Morena, Sabin Khadgi, Eleanor R Schrems, Tyrone A Washington, Kevin A Murach, Nicholas P Greene.

  This study investigated whether performing a translatable murine model of concurrent training after tumour induction affects adaptations in juvenile male and female tumour-bearing mice. Male and female Balb/c mice were injected bilaterally with colon-26 adenocarcinoma (C26) cells or PBS at 8 weeks of age. Half the mice then performed 24 days of voluntary wheel running with progressively increased load (PoWeR training), whereas the rest remained sedentary. Deuterium oxide-based protein synthesis, muscle fibre-type composition and size, protein turnover and mitochondrial markers were assessed 25 days after tumour induction. Average gastrocnemius muscle fibre size was smaller with PoWeR regardless of tumour in males and females, concomitant with a pronounced faster-to-slower fibre-type transition. In male tumour-bearing mice, PoWeR training resulted in greater Redd1, Murf1 and Pgc1α mRNA content than all the other groups, along with lower overall running volume, food consumption and protein synthesis relative to control animals. Molecular measures followed a similar pattern in tumour-bearing female mice with PoWeR, but food consumption, running volume and muscle protein synthesis were maintained. PoWeR training lowered gonadal fat during cancer cachexia in both sexes, and greater heart weight was observed regardless of tumour presence. A negative correlation was found between tumour weight and running distance. Collectively, PoWeR has a similar effect on muscle cellular phenotype in both sexes regardless of tumour presence, and a training effect in male mice with cancer cachexia was present despite molecular and protein synthesis dysregulation.

Keywords:  catabolism; colorectal cancer; concurrent training; exercise training; muscle fibre‐type transition

DOI:  https://doi.org/10.1113/EP092504
Biosci Biotechnol Biochem. 2025 Apr 21. pii: zbaf060. [Epub ahead of print]

Liraglutide enhances myotube differentiation and muscle contractile activity upon electric pulse stimulation in mouse skeletal muscle cells.

Risa Mukai, Ayumu Kojima, Mizuki Morisasa, Wakako Tawara, Tsukasa Mori, Naoko Goto-Inoue.

  Glucagon-like peptide-1 (GLP-1) is a potent incretin hormone produced by L-cells in the ileum and colon. Skeletal muscle, the most important organ for glucose metabolism, is also affected by GLP-1. Short-term administration of liraglutide, a GLP-1 analog, ameliorated glucose uptake in palmitate-treated type II diabetes models; however, the influence of long-term liraglutide administration on normal muscle cells has not been evaluated. We analyzed the effects of chronic (3 consecutive days) administration of liraglutide at various concentrations on healthy C2C12 skeletal muscle cells by investigating morphological changes, muscle contractile properties, and glucose uptake. Liraglutide administration at an appropriate dose (0.5 μM) had positive effects, including the promotion of muscle hypertrophy, in C2C12 cells; however, excessive administration (10 μM) had atrophic effects. Therefore, proper liraglutide dosing is very important.

Keywords:  glucose metabolism; muscle contraction; myotube

DOI:  https://doi.org/10.1093/bbb/zbaf060
Br J Pharmacol. 2025 Apr 24.

Functional MRP1 activity in human skeletal muscle.

Matthias Jackwerth, Severin Mairinger, Markus Zeitlinger, Oliver Langer.

DOI: https://doi.org/10.1111/bph.70062
Diabetes. 2025 Apr 24. pii: db250022. [Epub ahead of print]

Analysis of multiple insulin actions in single muscle fibres from insulin resistant mice reveals selective defect in endogenous GLUT4 translocation.

Sebastian Judge, Stewart Wc Masson, Søren Madsen, Meg Potter, David E James, James G Burchfield, Alexis Diaz-Vegas.

Accurate measurement of GLUT4 translocation is crucial for understanding insulin resistance in skeletal muscle, a key factor in the development of metabolic diseases. However, current methods rely on overexpressed epitope-tagged GLUT4 constructs or indirect measurements, limiting their physiological relevance and applicability. To overcome these challenges, we developed an innovative high-sensitivity imaging-based method that enables the direct assessment of endogenous GLUT4 translocation in primary skeletal muscle fibres. This approach utilises antibodies targeting exofacial epitopes on native GLUT4. Our method allows multiplexed analysis of multiple insulin-sensitive processes, including transferrin receptor trafficking and FOXO nuclear exclusion, alongside mitochondrial oxidative stress. This comprehensive approach provides a unique opportunity to simultaneously assess insulin action across different signalling branches within individual muscle fibres. We validated this method across multiple inbred mouse strains and models of insulin resistance, including chronic insulin exposure, palmitate treatment, and high-fat diet-induced obesity. Notably, we identified a selective defect in GLUT4 trafficking in insulin-resistant muscle fibres, while other insulin-dependent processes remained intact. By offering a high-fidelity model that maintains physiological relevance, this novel approach represents a significant advancement in the study of skeletal muscle insulin resistance and provides a powerful tool for dissecting gene-environment interactions that underlpin metabolic disease.

DOI: https://doi.org/10.2337/db25-0022
Exp Physiol. 2025 Apr 24.

Investigating muscle protein synthesis using deuterium oxide: The impact of dietary protein interventions across the lifespan.

Matthew S Brook.

  This review highlights recent advancements in our understanding of muscle protein synthesis (MPS) across the lifespan, with a focus on dietary protein strategies to support muscle health. Given that skeletal muscle is crucial for whole-body metabolism, movement and independence, maintaining muscle mass throughout life is essential. However, the gradual decline in muscle mass and strength with age, known as sarcopenia, represents a significant health concern. Muscle mass is regulated by the balance of MPS and muscle protein breakdown, with dietary protein intake playing a central role in stimulating MPS and maintaining a positive protein balance. Much of our current understanding of protein intake, specifically its quantity, quality and distribution, comes from stable isotope-labelled amino acid methods. These techniques, however, are limited by time constraints and controlled settings, providing only brief snapshots of MPS dynamics. The use of deuterium oxide (D₂O) has provided new insights, enabling long-term measures of muscle protein metabolism in free-living conditions. Measurements of longer-term MPS using D₂O suggest that older adults might benefit from protein intakes of >1.2 g/kg/day to enhance MPS. Additionally, replacing protein in the diet with higher-quality sources or enriching lower protein intakes with leucine can further increase MPS. Nevertheless, discrepancies remain regarding optimal protein requirements and the long-term efficacy of supplementing with enriched suboptimal protein doses. The continued application of D₂O in dietary protein research has the potential to provide further insights into the prolonged effects of various protein strategies on muscle preservation across the lifespan.

Keywords:  deuterium oxide; protein synthesis; skeletal muscle; stable isotopes

DOI:  https://doi.org/10.1113/EP092016
iScience. 2025 May 16. 28(5): 112335

Anti-fibrotic, muscle-promoting antibody-drug conjugates for the improvement and treatment of DMD.

Anas Odeh, Mor Sela, Shelly Zaffryar-Eilot, Ariel Shemesh, Maher Abu Saleh, Ido Mizrahi, Lavi Coren, Avi Schroeder, Peleg Hasson.

  Fibrosis, characterized by the deposition of excess and disorganized extracellular matrix (ECM), is a key pathological hallmark of multiple diseases, including Duchenne muscular dystrophy (DMD). Aiming to inhibit fibrosis progression, we generated an antibody-drug conjugate (ADC) that delivers an innovative small molecule conjugate to inhibit the ECM-modifying enzyme Lysyl oxidase (LOX) specifically in fibrotic lesions by targeting M2 macrophages. Administration of the ADC to mdx mice, the murine model of DMD, results in ADC accumulation in fibrotic muscles without affecting healthy tissues. Long-term ADC treatments of adult mdx mice lead to inhibition of the fibrotic process and to significant improvement of cardiac and skeletal muscle function. Our study demonstrates that targeted inhibition of LOX-dependent fibrotic diseases, such as DMD, facilitates improved outcomes for muscular dystrophies.

Keywords:  Biological sciences; Immunology; Natural sciences; Neuroscience; Physiology

DOI:  https://doi.org/10.1016/j.isci.2025.112335