bims-moremu 2025-06-15 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2025–06–15
34 papers selected by
Anna Vainshtein, Craft Science Inc.

The SUV39 Family of H3K9 Methyltransferases in Skeletal Muscle Stem Cells.
Convergent Skeletal Muscle Cytokine Responses to TFEB Overexpression and Voluntary Wheel Running Reflect Sex-Based Variability in Exercise Adaptations.
Insulin- and exercise-induced phosphoproteomics of human skeletal muscle identify REPS1 as a regulator of muscle glucose uptake.
Hibernation as a model for skeletal muscle preservation.
Physiological Muscle Function Is Controlled by the Skeletal Endocannabinoid System in Murine Skeletal Muscles.
Size, more than oxygen need, determines the number of capillaries around a muscle fibre.
Impact of sarcopenia and obesity on skeletal muscle size, gene expression, and mitochondrial function.
Expression of full-length dystrophin reverses muscular dystrophy defects in young and old mdx4cv mice.
Protein kinase ROCK1 activates mitochondrial fission linking to oxidative stress and muscle atrophy.
Proteomic profiling uncovers sexual dimorphism in the muscle response to wheel running exercise in the FLExDUX4 murine model of facioscapulohumeral muscular dystrophy.
Temporal single-cell sequencing analysis reveals that GPNMB-expressing macrophages potentiate muscle regeneration.
Live cell GLUT4 translocation assay reveals Per3 as a novel regulator of circadian insulin sensitivity in skeletal muscle cells.
Regulatory Landscapes of Muscle Satellite Cells: From Mechanism to Application.
Exercise modality-dependent mitochondrial respiratory capacity in satellite cells and conditioned serum-induced responses in cultured myotubes.
Reduction in Acetylation of Superoxide Dismutase 2 in Skeletal Muscle Improves Exercise Capacity in Mice With Heart Failure.
microRNA-1 Regulates Metabolic Flexibility by Programming Adult Skeletal Muscle Pyruvate Metabolism.
Exploring the Myostatin Activation Pathway: A Promising Target for Treating Muscle Atrophy.
Resistance exercise and skeletal muscle: protein synthesis, degradation, and controversies.
Upregulation of E3 ligase UBR2 in acetaldehyde-treated C2C12 myotubes and its potential involvement in fast-twitch muscle atrophy in alcohol-fed rats.
KLHL41 orchestrates sarcomere assembly and size to drive skeletal muscle hypertrophy in vivo.
Early endosome disturbance and endolysosomal pathway dysfunction in Duchenne muscular dystrophy.
Current understanding of skeletal muscle repeat expansion disorders.
MuSK cysteine-rich domain antibodies are pathogenic in a mouse model of autoimmune myasthenia gravis.
Extensive differential gene expression and regulation by sex in human skeletal muscle.
Diffusion and physical constraints limit oxidative capacity, capillary supply and size of muscle fibres in mice and humans.
Exercise orchestrates systemic metabolic and neuroimmune homeostasis via the brain-muscle-liver axis to slow down aging and neurodegeneration: a narrative review.
The myoblast methylome: multiple types of associations with chromatin and transcription.
Role of progesterone action in inguinal hernia formation via skeletal muscle fibrosis and atrophy.
miR-320-3p regulates apelin and TGF-β/SMAD3 signaling in hypobaric hypoxia exposed rats to induce skeletal muscle atrophy.
Contrasting Becker and Duchenne muscular dystrophy serum biomarker candidates by using data independent acquisition LC-MS/MS.
Pharmacological HIF-PH Inhibition Suppresses Myoblast Differentiation Through Continued HIF-1α Stabilization.
Mechanotransduction for therapeutic approaches: Cellular aging and rejuvenation.
On a Heart failure - Skeletal Muscle Axis.
Protocol for using MYOD1-transduced human urine-derived cells as a predictive platform for exon skipping therapy in Duchenne muscular dystrophy.

FASEB Bioadv. 2025 Jun;7(6): e70014

The SUV39 Family of H3K9 Methyltransferases in Skeletal Muscle Stem Cells.

Pauline Garcia, Slimane Ait-Si-Ali, Fabien Le Grand.

  Skeletal muscle repair is primarily driven by muscle stem cells (MuSCs) that regenerate damaged myofibers. The differentiation process of MuSCs into differentiated myofibers, known as adult myogenesis, is tightly regulated by various transcription factors, which involve precise spatio-temporal gene expression patterns. Epigenetic factors play an important role in this regulation, as they modulate gene expression to maintain the balance between the different myogenic states. Histone lysine methyltransferases KMT sare key epigenetic regulators, with the SUV39 family being of particular interest for their role in gene repression via H3K9 methylation. This family comprises SUV39H1, SUV39H2, SETDB1, SETDB2, G9A, and GLP. While the functions of SUV39 family members have been well characterized during development in embryonic stem cells and in disease contexts such as cancer, their functions in adult stem cell populations, especially in MuSCs, are still not fully understood. Recent studies shed new light on how the SUV39 family influences muscle biology, particularly in regulating MuSCs fate and adult myogenesis. These enzymes are critical for maintaining the epigenetic landscape essential for effective muscle repair, as they regulate the transition between different myogenic states and ensure coordinated gene expression during regeneration. Here, we present a comprehensive overview of the functions of the SUV39 KMTs family in skeletal muscle biology, emphasizing their role in adult myogenesis and exploring the broader implications for muscle regeneration and related diseases.

Keywords:  SUV39; gene repression; histone lysine methyltransferase; histone methylation; skeletal muscle

DOI:  https://doi.org/10.1096/fba.2024-00102
bioRxiv. 2025 May 28. pii: 2025.05.28.655862. [Epub ahead of print]

Convergent Skeletal Muscle Cytokine Responses to TFEB Overexpression and Voluntary Wheel Running Reflect Sex-Based Variability in Exercise Adaptations.

Dalton C Patterson, Allison Birnbaum, Ian Matthews, Constanza J Cortes.

Endurance exercise (running) promotes skeletal muscle remodeling through metabolic and inflammatory signaling cascades. However, the extent to which these responses are sex-dependent remains unclear. Here, we profiled cytokine responses in quadriceps muscle lysates from sedentary, voluntary wheel-running (VWR; 5 weeks), and muscle-specific TFEB-overexpressing (cTFEB;HSACre) male and female mice. Cytokine analysis revealed 40 differentially expressed factors associated with exercise and/or TFEB overexpression, many displaying sex-dimorphic expression patterns. In males, VWR induced significant increases in interleukins (e.g., IL-1α, IL-1β, IL-2, IL-5, IL-17) and chemokines (e.g., MCP-1, CCL5, CXCL9), as well as cytokines involved in TNF signaling (e.g., TNFα, sTNFR1/2, Fas ligand). TFEB overexpression in sedentary males recapitulated many of these cytokine elevations. In contrast, female runner muscle showed limited cytokine activation, with significant changes restricted to IL-3, IL-3Rb, IL-13, and CXCL16. Both sexes exhibited a reduction in IL-4 and an increase in IGFBP-5 with running. Several additional male-specific cytokine profiling responses, including increases in IFNγ, SCF, TPO, VCAM1A, and leptin, further underscored the sex-specificity of exercise-related inflammatory adaptations. These findings demonstrate that skeletal muscle cytokine responses to endurance-like stimuli are profoundly influenced by sex and suggest that male muscle exhibits a broader and/or later remodeling profile than female muscle. Our data also implicate skeletal muscle TFEB-overexpression as a partial molecular mediator of the cytokine shifts observed with exercise, particularly in males, and highlights their potential use as a new prioritization platform for exercise-associated phenotypes.

DOI: https://doi.org/10.1101/2025.05.28.655862
Cell Rep Med. 2025 May 29. pii: S2666-3791(25)00236-8. [Epub ahead of print] 102163

Insulin- and exercise-induced phosphoproteomics of human skeletal muscle identify REPS1 as a regulator of muscle glucose uptake.

Jeppe Kjærgaard, Cecilie B Lindqvist, Júlia Prats Quesada, Søren Jessen, Farina Schlabs, Amy M Ehrlich, Caio Y Yonamine, Mario García-Ureña, Johann H Schmalbruch, Lewin Small, Martin Thomassen, Anders Krogh Lemminger, Kasper Eibye, Alba Gonzalez-Franquesa, Jacob V Stidsen, Kurt Højlund, Juleen R Zierath, Tuomas O Kilpeläinen, Jens Bangsbo, Jonas T Treebak, Morten Hostrup, Atul S Deshmukh.

  Skeletal muscle glucose uptake, essential for metabolic health, is regulated by both insulin and exercise. Using phosphoproteomics, we analyze skeletal muscle from healthy individuals following acute exercise or insulin stimulation, generating a valuable dataset. We identify 71 phosphosites on 55 proteins regulated by both stimuli in the same direction, suggesting a convergence of exercise and insulin signaling pathways. Among these, the vesicle-associated protein, REPS1, is highly phosphorylated at Ser709 in response to both stimuli. We identify p90 ribosomal S6 kinase (RSK) to be a key upstream kinase of REPS1 S709 phosphorylation and that the RSK-REPS1 signaling axis is involved in insulin-stimulated glucose uptake. Insulin-induced REPS1 Ser709 phosphorylation is closely linked to muscle and whole-body insulin sensitivity and is impaired in insulin-resistant mice and humans. These findings highlight REPS1 as a convergence point for insulin and exercise signaling, presenting a potential therapeutic target for treating individuals with insulin resistance.

Keywords:  REPS1; RSK; exercise; glucose metabolism; insulin; phosphoproteomics; skeletal muscle signaling

DOI:  https://doi.org/10.1016/j.xcrm.2025.102163
Ann N Y Acad Sci. 2025 Jun 09.

Hibernation as a model for skeletal muscle preservation.

Alexandra E Porczak, Ni Y Feng.

  Hibernation is an extreme adaptation that enables a diverse array of mammalian species to survive long-term nutrient deprivation. In many seasonal hibernators, winter hibernation is characterized by prolonged periods of immobility and starvation, conditions that induce muscular atrophy in nonhibernating animals. In humans, factors that contribute to muscle atrophy include muscle disuse under conditions of bedrest, casting, paralysis, microgravity, as well as aging. In laboratory mice and rats, muscle disuse can be induced by hindlimb unloading or casting-experimental paradigms that have revealed the molecular basis of muscle atrophy. Remarkably, hibernating mammals experience reduced atrophy and maintain muscle ultrastructure and function despite months of immobility and starvation, serving as excellent models for investigating protective mechanisms for muscular atrophy resistance. In this review, we explore skeletal muscle homeostasis at multiple levels of biological organization, from function, neural innervation, gross anatomy, cellular differentiation, ultrastructure, to biochemical pathways regulating regeneration, growth, and degeneration. At each level, we compare known mechanisms in hibernators, laboratory rodents, and humans. Finally, we highlight gaps in knowledge and propose future areas of investigation for elucidating mechanisms of muscle atrophy resistance in hibernation.

Keywords:  atrophy; degeneration; disuse; hibernation; muscle homeostasis; neuromuscular

DOI:  https://doi.org/10.1111/nyas.15389
Int J Mol Sci. 2025 May 30. pii: 5291. [Epub ahead of print]26(11):

Physiological Muscle Function Is Controlled by the Skeletal Endocannabinoid System in Murine Skeletal Muscles.

Nyamkhuu Ganbat, Zoltán Singlár, Péter Szentesi, Elena Lilliu, Zoltán Márton Kohler, László Juhász, Anikó Keller-Pintér, Xaver Koenig, Fabio Arturo Iannotti, László Csernoch, Mónika Sztretye.

  The endocannabinoid system (ECS) is known to regulate crucial bodily functions, including healthy muscle activity. However, its precise roles in normal skeletal muscle function and the development of muscle disorders remain unclear. Previously, we developed a tamoxifen-inducible, skeletal muscle-specific CB1 receptor knockdown (skmCB1-KD) mouse model using the Cre/LoxP system. In this study, we aimed to clarify the mechanisms behind the observed reduction in muscle force generation in these mice. To investigate this, we analyzed calcium dynamics following electrical stimulation-induced muscle fatigue, assessed store-operated calcium entry (SOCE), and performed functional analysis of mitochondrial respiration. Our findings suggest that the reduced muscle performance observed in vivo likely arises from interconnected alterations in ATP production by mitochondria. Moreover, in skmCB1-KD mice, we detected a significant decrease in a component of the respiratory chain (complex IV) and a slowed dissipation of mitochondrial membrane potential upon the addition of an un-coupler (FCCP).

Keywords:  calcium homeostasis; in vivo muscle force; mitochondrial respiration; murine skeletal muscle; skeletal endocannabinoid system; store-operated calcium entry

DOI:  https://doi.org/10.3390/ijms26115291
Exp Physiol. 2025 Jun 08.

Size, more than oxygen need, determines the number of capillaries around a muscle fibre.

Christopher S Fry, Carlo Reggiani.



Keywords:  capillary vessels; microcirculation; skeletal muscle

DOI:  https://doi.org/10.1113/EP092911
Geroscience. 2025 Jun 12.

Impact of sarcopenia and obesity on skeletal muscle size, gene expression, and mitochondrial function.

Hector G Paez, Christopher R Pitzer, Jessica L Halle, Peter J Ferrandi, James A Carson, Junaith S Mohamed, Stephen E Alway.

  Skeletal muscle is a primary tissue of dysfunction during both aging and obesity. Recently, the coincidence of obesity and aging has gained attention due to the intersection of the obesity epidemic with an aging demographic. Both aging and obesity are associated with marked defects in skeletal muscle metabolic health. Despite these findings, we have a poor understanding of how obesity and aging may interact to impact skeletal muscle mass and metabolic health. Therefore, we investigated the impact of high-fat diet (HFD)-induced obesity on skeletal muscle mass, mitochondrial function, transcriptomics, and whole-body metabolism in young and aged mice. We observed main effects of diet and age on several measures of whole-body metabolic function (VO2, VCO2, and RER). Complex I-driven mitochondrial proton leak was significantly elevated by HFD-induced obesity across both age groups; however, a main effect of aging for reduced complex I leak was detected in the soleus muscle. Interestingly, aged animals fed a HFD did not exhibit lower muscle mass than chow-fed young animals, but did present with stark increases in muscle triglyceride content and a unique transcriptional response to HFD. HFD-induced obesity impacted the muscle transcriptome differently in the muscles of young and aged mice, indicating that obesity can change altered gene expression with age. Our findings suggest that the presence of obesity can both compound and counteract age-associated changes to muscle mass, gene expression, and mitochondrial function.

Keywords:  Aging; Metabolism; Mitochondria; Obesity; Sarcopenic obesity; Skeletal muscle

DOI:  https://doi.org/10.1007/s11357-025-01726-2
J Clin Invest. 2025 Jun 10. pii: e189075. [Epub ahead of print]

Expression of full-length dystrophin reverses muscular dystrophy defects in young and old mdx4cv mice.

Hichem Tasfaout, Timothy S McMillen, Theodore R Reyes, Christine L Halbert, Rong Tian, Michael Regnier, Jeffrey S Chamberlain.

  Gene replacement therapies mediated by adeno-associated viral (AAV) vectors represent a promising approach for treating genetic diseases. However, their modest packaging capacity (~4.7 kb) remains an important constraint and significantly limits their application for genetic disorders involving large genes. A prominent example is Duchenne muscular dystrophy (DMD), whose protein product dystrophin is generated from an 11.2 kb segment of the DMD mRNA. Here, we explored methods that enable efficient expression of full-length dystrophin via triple AAV co-delivery. This method exploits the protein trans-splicing mechanism mediated by split inteins. We identified a combination of efficient and specific split intein pairs that enables the reconstitution of full-length dystrophin from three dystrophin fragments. We show that systemic delivery of low doses of the myotropic AAVMYO1 in mdx4cv mice leads to efficient expression of full-length dystrophin in the hindlimb, diaphragm, and heart muscles. Notably, muscle morphology and physiology were significantly improved in triple AAV-treated mdx4cv mice versus saline-treated controls. This method shows the feasibility of expressing large proteins from several fragments that are delivered using low doses of myotropic AAV vectors. It can be adapted to other large genes involved in disorders for which gene replacement remains challenged by the modest AAV cargo capacity.

Keywords:  Gene therapy; Genetic diseases; Genetics; Muscle biology; Skeletal muscle; Therapeutics

DOI:  https://doi.org/10.1172/JCI189075
Kidney Int. 2025 Jun 10. pii: S0085-2538(25)00431-4. [Epub ahead of print]

Protein kinase ROCK1 activates mitochondrial fission linking to oxidative stress and muscle atrophy.

Meijun Si, Jihong Chen, Rizhen Yu, Hongchun Lin, Feng Li, Sungyun Jung, Sandhya S Thomas, Farhard R Danesh, Yanlin Wang, Hui Peng, Zhaoyong Hu.

   INTRODUCTION: Chronic kidney disease (CKD) is associated with protein-energy wasting, characterized by a reduction in muscle mass and strength. Although mitochondrial dysfunction and oxidative stress are implicated in the pathogenesis of muscle wasting, underlying mechanisms remain unclear.
METHODS: Here, we used transcriptomic analysis, metabolomics analyses, and mouse gene manipulation to investigate the effects of mitochondrial plasticity and oxidative stress on muscle wasting the subtotal nephrectomy mouse models of CKD. The mice with CKD were age- and sex-matched to sham-operated controls.
RESULTS: Through these approaches, Rho-associated kinase ROCK1 emerged as a key molecule responsible for the observed mitochondrial fission and oxidative stress. Specifically, our results showed that the expression of oxidative stress response genes increased, and that of oxidative phosphorylation genes decreased in the muscles of mice with CKD. This was accompanied by reduced oxygen consumption rates, decreased levels of mitochondrial electron transport chain proteins, and increased cellular oxidative damage. Excessive mitochondrial fission was also observed, and we found that the activation of ROCK1 was responsible for this process. Inducible expression of muscle-specific constitutively active ROCK1 exacerbated mitochondrial fragmentation and muscle wasting in CKD mice. Conversely, ROCK1 depletion (ROCK1-/-) alleviated these phenomena. Mechanistically, ROCK1 activation promoted the recruitment of dynamin-related protein 1 to mitochondria, thereby facilitating mitochondrial fission. Notably, pharmacological inhibition of ROCK1 mitigated muscle wasting by suppressing mitochondrial fission and oxidative stress.
CONCLUSIONS: Our findings demonstrate that ROCK1 participates in CKD-induced muscle wasting by promoting mitochondrial fission and oxidative stress. Pharmacological suppression of ROCK1 could be a therapeutic strategy for combating muscle wasting in CKD conditions.

Keywords:  Muscle atrophy; ROS; chronic kidney disease; mitochondrial fission; oxidative stress

DOI:  https://doi.org/10.1016/j.kint.2025.05.019
Mol Cell Proteomics. 2025 Jun 09. pii: S1535-9476(25)00112-4. [Epub ahead of print] 101013

Proteomic profiling uncovers sexual dimorphism in the muscle response to wheel running exercise in the FLExDUX4 murine model of facioscapulohumeral muscular dystrophy.

Yusuke Nishimura, Adam Bittel, Abhishek Jagan, Yi-Wen Chen, Jatin Burniston.

  FLExDUX4 is a murine experimental model of facioscapulohumeral muscular dystrophy (FSHD) characterized by chronic, low levels of leaky expression of the human full-length double homeobox 4 gene (DUX4-fl). FLExDUX4 mice exhibit mild pathologies and functional deficits similar to people affected by FSHD. Proteomic studies in FSHD could offer new insights into disease mechanisms underpinned by post-transcriptional processes. We used mass spectrometry-based proteomics to quantify the abundance of 1322 proteins in triceps brachii muscle, encompassing both male and female mice in control and free voluntary wheel running (VWR) in Wild-type (n=3) and FLExDUX4 (n=3) genotypes. We report the triceps brachii proteome of FLExDUX4 mice recapitulates key skeletal muscle clinical characteristics of human FSHD, including alterations to mitochondria, RNA metabolism, oxidative stress, and apoptosis. RNA-binding proteins exhibit a sex-specific difference in FLExDUX4 mice. Sexual dimorphism of mitochondrial protein adaptation to exercise was uncovered specifically in FLExDUX4 mice, where females increased, but males decreased mitochondrial proteins after a 6-week of VWR. Our results highlight the importance of identifying sex-specific diagnostic biomarkers to enable more reliable monitoring of FSHD therapeutic targets. Our data provides a resource for the FSHD research community to explore the burgeoning aspect of sexual dimorphism in FSHD.

Keywords:  DUX4; FSHD; RNA-binding proteins; apoptosis; exercise; mitochondria; oxidative stress; proteomics; skeletal muscle

DOI:  https://doi.org/10.1016/j.mcpro.2025.101013
Exp Mol Med. 2025 Jun 09.

Temporal single-cell sequencing analysis reveals that GPNMB-expressing macrophages potentiate muscle regeneration.

Yu-Fan Chen, Chien-Wei Lee, Yi-Shuan J Li, Wei-Ting Lin, Hsiao-Yun Chen, Yu-Chuan Chen, Chia-Hao Lin, Jennifer Hui-Chun Ho, Li-Fan Lu, Shu Chien, Oscar Kuang-Sheng Lee.

Macrophages play a crucial role in coordinating the skeletal muscle repair response, but their phenotypic diversity and the transition of specialized subsets to resolution-phase macrophages remain poorly understood. Here, to address this issue, we induced injury and performed single-cell RNA sequencing on individual cells in skeletal muscle at different time points. Our analysis revealed a distinct macrophage subset that expressed high levels of Gpnmb and that coexpressed critical factors involved in macrophage-mediated muscle regeneration, including Igf1, Mertk and Nr1h3. Gpnmb gene knockout inhibited macrophage-mediated efferocytosis and impaired skeletal muscle regeneration. Functional studies demonstrated that GPNMB acts directly on muscle cells in vitro and improves muscle regeneration in vivo. These findings provide a comprehensive transcriptomic atlas of macrophages during muscle injury, highlighting the key role of the GPNMB macrophage subset in regenerative processes. Our findings suggest that modulating GPNMB signaling in macrophages may represent a promising avenue for future research into therapeutic strategies for enhancing skeletal muscle regeneration.

DOI: https://doi.org/10.1038/s12276-025-01467-4
Biol Open. 2025 Jun 11. pii: bio.061941. [Epub ahead of print]

Live cell GLUT4 translocation assay reveals Per3 as a novel regulator of circadian insulin sensitivity in skeletal muscle cells.

Rashmi Sivasengh, Andrew Scott, Brendan M Gabriel.

  Type 2 diabetes (T2D) is a growing global health concern, with skeletal muscle playing a central role due to its contribution to postprandial glucose disposal. Insulin resistance in skeletal muscle often precedes the clinical onset of T2D and is characterised by impaired GLUT4 trafficking. Circadian disruption is increasingly recognised as a contributor to metabolic dysfunction, yet its impact on skeletal muscle insulin sensitivity remains poorly defined. We hypothesised that circadian regulators influence GLUT4 translocation and glucose uptake, contributing to the metabolic impairments observed in T2D. To investigate this, we developed a high-throughput, live-cell GLUT4 translocation assay capable of capturing circadian dynamics in skeletal muscle cells. Using publicly available transcriptomic data from primary human myotubes derived from individuals with and without T2D, our re-analysis identified altered rhythmic expression of several genes, including PER3, ARNTL, HOXB5, and TSSK6. Publicly available phenome-wide association study (PheWAS) data further supported associations between these genes and T2D-related traits. Functional validation using siRNA knockdown revealed that PER3 silencing significantly impaired GLUT4 translocation and glucose uptake in human skeletal muscle cells, while also abolishing rhythmic insulin responsiveness. ARNTL knockdown caused a moderate reduction in GLUT4 translocation, suggesting complementary roles in metabolic regulation. Our findings identify PER3 as a novel circadian regulator of GLUT4 translocation and insulin sensitivity in skeletal muscle. This work also introduces a sensitive, live-cell assay suitable for real-time assessment of GLUT4 dynamics and circadian regulation, offering a powerful platform for discovering new therapeutic targets in T2D.

Keywords:  And clock genes; Circadian rhythm; GLUT4 translocation; Skeletal muscle myotubes; Type 2 diabetes

DOI:  https://doi.org/10.1242/bio.061941
Int J Stem Cells. 2025 Jun 12.

Regulatory Landscapes of Muscle Satellite Cells: From Mechanism to Application.

Jeong Eun Lee, Sang Hoon Yoon, Kwan Seob Shim, Jeong Tae Do.

  Muscle satellite cells (SCs), also known as muscle stem cells, are crucial for the regeneration, maintenance, and growth of skeletal muscles. SCs possess a distinctive capability to self-renew and differentiate, rendering them highly promising candidates for regenerative therapies and emerging cellular agriculture applications, including cultured meat production. This review explores the mechanisms that govern SC activation, proliferation, and commitment, and emphasizes their functional heterogeneity across anatomical regions. Region-specific gene expression, including that of homeobox (Hox) genes, contributes to the positional identity and myogenic potential. Understanding these regulatory landscapes is essential for optimizing SC expansion and improving their applications in muscle repair, stem cell-based therapies, and cellular manufacturing systems.

Keywords:  Cell self renewal; Muscle development; Satellite cell; Skeletal muscle

DOI:  https://doi.org/10.15283/ijsc25037
Exp Physiol. 2025 Jun 13.

Exercise modality-dependent mitochondrial respiratory capacity in satellite cells and conditioned serum-induced responses in cultured myotubes.

Takanaga Shirai, Hayato Shinkai, Riku Tanimura, Kazuki Uemichi, Shunsuke Sugiyama, Kohei Takeda, Yu Kitaoka, Tohru Takemasa.

  Exercise-induced mitochondrial adaptations contribute to muscle function and metabolic health. We aimed to investigate the association of moderate-intensity swimming (MOD) and high-intensity interval training (HIIT) with mitochondrial function in skeletal muscle cells treated with exercise-conditioned serum. Male ICR mice (7-8 weeks old) were assigned to the Sedentary, MOD or HIIT group. The MOD group underwent five sessions of 60 min. The HIIT group performed weighted high-intensity swimming intervals. This study assessed mitochondrial enzyme activity in the plantaris muscle, mitochondrial respiratory capacity in isolated satellite cells, and mitochondrial function in C2C12 myotubes treated with exercise-derived serum. Serum was obtained immediately and 24 h postexercise to assess acute effects and chronic adaptations, respectively. The MOD and HIIT groups demonstrated significantly increased muscle citrate synthase and cytochrome c oxidase activities compared with the Sedentary group, but with no significant differences between the MOD and HIIT groups. Satellite cells exhibited higher basal respiration, ATP production and maximal respiratory capacity in the MOD group than in the Sedentary and HIIT groups. Acute serum notably improved maximal mitochondrial respiration in cultured C2C12 myotubes in the HIIT group, whereas serum from chronic training improved those parameters but demonstrated no modality-specific effects. MOD enhances mitochondrial respiratory function in satellite cells, probably owing to sustained aerobic metabolic signalling, whereas HIIT produces a potent but transient systemic response that acutely boosts mitochondrial function in muscle cells. The differential effects of exercise modalities emphasize the importance of timing and exercise modality in driving specific mitochondrial adaptations, thereby providing valuable insights for tailored exercise prescriptions for optimizing metabolic health.

Keywords:  exercise conditioned serum; exercise modality; mitochondrial respiration; satellite cell; skeletal muscle

DOI:  https://doi.org/10.1113/EP092922
J Cachexia Sarcopenia Muscle. 2025 Jun;16(3): e13850

Reduction in Acetylation of Superoxide Dismutase 2 in Skeletal Muscle Improves Exercise Capacity in Mice With Heart Failure.

Tomoka Masunaga, Tomoyasu Suenaga, Shouji Matsushima, Toru Hashimoto, Shingo Takada, Eri Noda, Yoshizuki Fumoto, Soichiro Hata, Takashi Yokota, Shintaro Kinugawa.

   BACKGROUND: Skeletal muscle abnormalities, including mitochondrial dysfunction, play a crucial role in decreasing exercise capacity in patients with heart failure (HF). Although enhanced reactive oxygen species (ROS) production in skeletal muscle mitochondria has been implicated in skeletal muscle abnormalities, the underlying mechanisms have not been fully elucidated to date. Superoxide dismutase 2 (SOD2), an antioxidant enzyme present in mitochondria, is modified by acetylation, which reduces its activity. The aim of this study was to clarify whether reducing SOD2 acetylation by sirtuins 3 (SIRT3) activation improves skeletal muscle mitochondrial function and exercise capacity in HF model mice.
METHODS: Myocardial infarction (MI) by ligation of the coronary artery or sham surgery was performed in male C57BL/6 J mice. Two weeks after surgery, these mice were treated with either the SIRT3 activator Honokiol (5 mg/kg body weight/day, i.p.) or vehicle. After 2 weeks of treatment, exercise capacity was evaluated by the treadmill test. Gastrocnemius muscle samples collected from the mice were used to measure mitochondrial function, as well as the levels of SIRT3, acetylated SOD2, and ROS production. Finally, the effect of adeno-associated virus serotype 9 (AAV9)-mediated overexpression of SIRT3 in the skeletal muscle on the exercise capacity of MI mice was investigated.
RESULTS: MI mice showed decreased cardiac function and skeletal muscle weight, but Honokiol did not affect these. Exercise capacity was significantly decreased in MI mice compared with sham mice by 24.9%, and Honokiol treatment improved the exercise capacity of MI mice by 40.4% (p < 0.05). The mitochondrial oxygen consumption rate was impaired in MI mice, but was improved by Honokiol treatment. SIRT3 expression was decreased by 26.8%, and SOD2 acetylation was increased by 36.9% in the skeletal muscle of MI mice compared with sham (p < 0.05), and Honokiol treatment resulted in complete recovery of these levels (p < 0.05). Consistent with SOD2 acetylation, ROS production in the skeletal muscle was increased in MI mice and was ameliorated by Honokiol (p < 0.05). SIRT3 expression was increased in MI + AAV9-SIRT3 mice compared with MI + AAV9-Control mice. The overexpression of SIRT3 improved exercise capacity without altering cardiac function.
CONCLUSIONS: The SIRT3 activator Honokiol improved exercise capacity in MI model mice with HF, by improving mitochondrial function in skeletal muscle through the reduction of SOD2 acetylation. SIRT3 activation may thus be a novel therapeutic target for improving exercise capacity in patients with HF.

Keywords:  acetylation; exercise intolerance; heart failure; skeletal muscle; superoxide dismutase

DOI:  https://doi.org/10.1002/jcsm.13850
Mol Metab. 2025 Jun 07. pii: S2212-8778(25)00089-4. [Epub ahead of print] 102182

microRNA-1 Regulates Metabolic Flexibility by Programming Adult Skeletal Muscle Pyruvate Metabolism.

Ahmed Ismaeel, Bailey D Peck, McLane M Montgomery, Benjamin I Burke, Jensen Goh, Abigail B Franco, Qin Xia, Katarzyna Goljanek-Whysall, Brian McDonagh, Jared M McLendon, Pieter J Koopmans, Daniel Jacko, Kirill Schaaf, Wilhelm Bloch, Sebastian Gehlert, Kevin A Murach, Kelsey H Fisher-Wellman, Ryan L Boudreau, Yuan Wen, John J McCarthy.

  Metabolic flexibility refers to the ability of a tissue to adjust cellular fuel choice in response to conditional changes in metabolic demand and activity. A loss of metabolic flexibility is now recognized as a defining feature of various diseases and cellular dysfunction. In this study, using an inducible, skeletal muscle-specific knockout (KO) mouse, we found microRNA-1 (miR-1), the most abundant microRNA (miRNA) in skeletal muscle, was necessary to maintain whole-body metabolic flexibility. This was demonstrated by a loss of diurnal oscillations in whole-body respiratory exchange ratio and higher fasting blood glucose in miR-1 KO mice. Argonaute 2 enhanced crosslinking and immunoprecipitation sequencing (AGO2 eCLIP-seq) and RNA-seq analyses identified, for the first time, bona fide miR-1 target genes in adult skeletal muscle that regulated pyruvate metabolism. Comprehensive bioenergetic phenotyping combined with skeletal muscle proteomics and metabolomics showed that miR-1 was necessary to maintain metabolic flexibility by regulating pyruvate metabolism through mechanisms including the alternative splicing of pyruvate kinase (Pkm). The loss of metabolic flexibility in the miR-1 KO mouse was rescued by pharmacological inhibition of the miR-1 target, monocarboxylate transporter 4 (MCT4), which redirects glycolytic carbon flux toward oxidation. The maintenance of metabolic flexibility by miR-1 was necessary for sustained endurance activity in mice and in C. elegans. The physiological down-regulation of miR-1 in response to a hypertrophic stimulus in both humans and mice caused a similar metabolic reprogramming necessary for muscle cell growth. Taken together, these data identify a novel post-transcriptional mechanism of whole-body metabolism regulation mediated by a tissue-specific miRNA.

Keywords:  MCT4; PKM; VB124; aerobic glycolysis; eCLIP-seq; resistance training

DOI:  https://doi.org/10.1016/j.molmet.2025.102182
J Chem Inf Model. 2025 Jun 12.

Exploring the Myostatin Activation Pathway: A Promising Target for Treating Muscle Atrophy.

Daniel B Quintanilha, Hélio F Dos Santos.

Myostatin is a myokine found in skeletal muscle that acts as a negative regulator of muscle growth. Elevated levels of this protein are linked to muscle atrophy, making it a promising target for therapies aimed at muscle regeneration, particularly in muscular dystrophies. In this study, we investigate the molecular interactions involved in myostatin activation to develop a model for peptide-based inhibitors. Our simulations align with experimental data, identifying the forearm domain of the myostatin precursor as being essential for maintaining its inactive state. Key residues, such as Ile and Leu, play a primary role in stabilizing this interaction. Based on these findings, we propose a peptide-based drug model identifying essential residues and mutable sites to enhance inhibition. Additionally, we identified a previously unreported target site emerging during the final step of myostatin activation. Targeting this site with small molecules could offer a new strategy for preventing myostatin activity and promoting muscle growth.

DOI: https://doi.org/10.1021/acs.jcim.5c00639
Eur J Appl Physiol. 2025 Jun 13.

Resistance exercise and skeletal muscle: protein synthesis, degradation, and controversies.

Fujue Ji, Hae Sung Lee, Jong-Hee Kim.

  Maintaining and enhancing skeletal muscle mass and strength are essential for optimizing metabolic function and preventing chronic diseases. Resistance exercise plays a pivotal role in this process by modulating the balance between synthesis and degradation of skeletal muscle protein. While the efficacy of such exercise in stimulating these processes is well established, uncertainties persist regarding the fibre-type specificity and contraction mode-dependent regulation of key signalling pathways, including mTORC1, AMPK, and the ubiquitin-proteasome system. Furthermore, the interplay between metabolic stressors-such as biopsy timing, muscle damage, inflammation, and oxidative stress-and skeletal muscle adaptation remains insufficiently characterized, posing challenges to mechanistic research. To address these gaps, this review systematically synthesizes current evidence on fibre-specific and contraction mode-specific regulation of skeletal muscle protein turnover. We critically examine the influence of these factors on major signalling pathways and muscle adaptation, identifying key areas of uncertainty and methodological limitations in existing studies. Based on these insights, we propose a novel theoretical framework and predictive model to guide future investigations. By providing a comprehensive and mechanistically driven analysis, this review advances the understanding of resistance exercise-induced muscle adaptations and their physiological implications. Our findings offer valuable insights for optimizing exercise strategies and developing targeted interventions for muscle-related conditions, including sarcopenia, cachexia, and metabolic disorders.

Keywords:  Concentric; Contraction; Eccentric; Fibre-type specific; Hypertrophy; Signalling pathway

DOI:  https://doi.org/10.1007/s00421-025-05832-z
Alcohol Clin Exp Res (Hoboken). 2025 Jun 13.

Upregulation of E3 ligase UBR2 in acetaldehyde-treated C2C12 myotubes and its potential involvement in fast-twitch muscle atrophy in alcohol-fed rats.

Kaori Shintani-Ishida, Hiroshi Ikegaya.

   BACKGROUND: Chronic alcohol intake induces atrophy of type II (anaerobic, fast-twitch) muscle fibers in preference to type I (aerobic, slow-twitch) muscle fibers. However, the molecular mechanism underlying the preferential atrophy of type II muscle fibers remains unclear. The ubiquitin-proteasome system (UPS) mediates the degradation of myofibrillar proteins in skeletal muscle loss. This study investigated whether E3 ubiquitin ligases, including UBR2 and MuRF1, are involved in ethanol-induced type II muscle fiber-specific atrophy.
METHODS: In a chronic alcohol intake rat model, 4- to 5-week-old male Wistar rats were fed the Lieber-DeCarli liquid diet for 8 weeks. Muscle specimens were collected from the extensor digitorum longus (EDL) and soleus muscles of both legs. In an in vitro model, myotubes differentiated from murine C2C12 myoblasts were treated with culture medium containing 100 mM ethanol or 1 mM acetaldehyde for 6 h.
RESULTS: The muscle weight of the EDL seemed to be lesser in the ethanol group compared to the control group, and there was no difference in the muscle weight of the soleus between these groups. Cross-sectional area (CSA) of type IIA, IIB, and IIX muscle fibers in the EDL of ethanol-fed rats was smaller compared to the control rats, and CSA of type I muscle fibers in the soleus was larger in ethanol-fed rats. UBR2 protein levels seem to increase in the EDL but not in the soleus, whereas MuRF1 protein level remained unchanged in both muscles. C2C12 myotubes expressing MHC IIb, characteristics of type IIB muscle fibers, showed reduced myotube diameter after ethanol or acetaldehyde treatment. Acetaldehyde treatment increased UBR2 expression, but not MuRF1 expression, and enhanced ubiquitination. Knockdown of UBR2 using siRNA prevented acetaldehyde-induced myotube atrophy.
CONCLUSION: This study demonstrated that the E3 ligase UBR2 may play a role in alcohol-induced type II muscle-preferential atrophy.

Keywords:  UBR2; alcohol; muscle atrophy; skeletal muscle; ubiquitin ligase

DOI:  https://doi.org/10.1111/acer.70102
bioRxiv. 2025 Jun 01. pii: 2025.05.30.655367. [Epub ahead of print]

KLHL41 orchestrates sarcomere assembly and size to drive skeletal muscle hypertrophy in vivo.

Hyewon Han, Janet Shi, Alfredo H Bongiorno, Arian Mansur, Jeffrey Widrick, Grace Tate, Sehajpreet Gill, Esmat Karimi, Henk Granzier, Jeffrey R Moore, Vandana A Gupta.

Sarcomere assembly and growth are fundamental processes essential for the development, function, and repair of skeletal muscle. However, the mechanisms underlying sarcomere formation and assembly in vivo , which are critical for the formation of functional myofibers in vertebrates, remain poorly understood. Defects in sarcomeres contribute to muscle dysfunction in numerous genetic and acquired myopathies, yet the lack of a clear understanding of specific sarcomeric defects has hindered the development of effective therapies. Nemaline myopathy (NM) is caused by mutations in genes that primarily affect sarcomere structure and function. The disease is clinically heterogeneous, with the congenital form being the most severe. Using zebrafish models of congenital forms of NM, we investigated sarcomere assembly in vivo during skeletal muscle development to identify key steps contributing to myofibril formation and muscle growth under both normal and disease conditions. Our findings demonstrate that the gene encoding the sarcomeric protein KLHL41 plays a critical role in the formation and directional organization of new sarcomeres within developing myofibrils, facilitating both radial and longitudinal muscle growth. Dysregulation of sarcomeric proteins and impaired protein turnover in the KLHL41-NM zebrafish model resulted in the development of sarcomeric defects. Moreover, we show that the interaction between the KLHL41-troponin complex is essential for muscle growth and cross-bridge regulation in developing muscle. These studies address a significant gap in the understanding of sarcomeric defects in myopathies and will help guide the development of targeted therapies aimed at rescuing these processes.

DOI: https://doi.org/10.1101/2025.05.30.655367
Am J Pathol. 2025 Jun 09. pii: S0002-9440(25)00189-0. [Epub ahead of print]

Early endosome disturbance and endolysosomal pathway dysfunction in Duchenne muscular dystrophy.

Julie Chassagne, Nathalie Da Silva, Ines Akrouf, Bruno Cadot, Laura Julien, Ines Barthélémy, Stéphane Blot, Caroline Le Guiner, Mai Thao Bui, Norma B Romero, Jeanne Lainé, France Pietri-Rouxel, Pierre Meunier, Kamel Mamchaoui, Stéphanie Lorain, Marc Bitoun, Sofia Benkhelifa-Ziyyat.

Duchenne muscular dystrophy (DMD) is a lethal dystrophy characterized by the progressive loss of muscle fibers caused by mutations in DMD gene and absence of the dystrophin protein. While autophagy and lysosome biogenesis defects have been described in DMD muscles, the endosomal pathway has never been studied. Here, we showed that impaired lysosome formation is associated with altered acidification and reduced degradative function of the endolysosomal pathway in muscle cells derived from DMD patients. Our data demonstrated that early endosomes are increased in these cells as well as in muscle biopsies from DMD patients and two animal models of DMD, mdx mice and GRMD dogs. We determined that these abnormalities are due to the lack of dystrophin per se and could be correlated with disease progression and severity. We further identified an abnormal upregulation of the Rab5 GTPase protein, one key actor of early endosomal biogenesis and fusion, in the three DMD models which may underlie the endosomal defects. Finally, we demonstrated that Rab5 knock-down in human DMD muscle cells as well as dystrophin restoration in GRMD dogs, normalize Rab5 expression levels and rescue endosomal abnormalities. This study unveils a defect in a pathway essential for muscle homeostasis and for the efficacy of DMD therapies.

DOI: https://doi.org/10.1016/j.ajpath.2025.05.007
Curr Opin Neurol. 2025 Jun 10.

Current understanding of skeletal muscle repeat expansion disorders.

Manon Boivin, Gianina Ravenscroft.

   PURPOSE OF REVIEW: Here, we summarize the current knowledge about the genetics and proposed mechanisms of disease underlying skeletal muscle short tandem repeat (STR) expansion disorders.
RECENT FINDINGS: The human genome contains up to 2 million STRs (also known as microsatellites), which are highly variable repetitions of two to six nucleotide-long DNA motifs. These elements, present in both coding and noncoding sequences, are highly instable, and their polymorphic variations have important roles in genes regulation and human phenotypic trait diversity. Importantly, expansion over a threshold size of a subset of these STR is the cause of approximately 60 neurological diseases, including some major muscle disorders such as myotonic dystrophy, oculopharyngodistal myopathy (OPDM) and oculopharyngeal muscular dystrophy. The discovery and characterisation of a number of these STR expansion disorders, in particular for OPDM, has been enabled in recent years by advanced genomic technologies.
SUMMARY: Many recently described STR expansion disorders are now recognized and genetic testing of patients is possible on a research basis, clinical testing for these newly described repeat loci is not yet readily available and is complicated by the reduced penetrance seen in some families, rendering clinical interpretation more difficult. The phenotypic spectrums associated with these STR expansion disorders are also evolving as unbiased sequencing approaches identified expansions at known loci in individuals with phenotypes that are quite different to those in which the STR expansions were first characterized. The pathomechanisms associated with these newer STR expansion disorders is still poorly understood, however there is evidence of both RNA toxicity and polyGly toxicity. Additional STR expansions underlying skeletal muscle diseases are likely to be identified in coming years and may shed further light onto the complex genetics, epigenetics and disease mechanisms underlying these disorders.

Keywords:  PLIN4-related myopathy; myotonic dystrophy; oculopharyngeal muscular dystrophy; oculopharyngodistal myopathy; repeatome; short tandem repeat expansions

DOI:  https://doi.org/10.1097/WCO.0000000000001394
J Clin Invest. 2025 Jun 12. pii: e173308. [Epub ahead of print]

MuSK cysteine-rich domain antibodies are pathogenic in a mouse model of autoimmune myasthenia gravis.

Marius Halliez, Steve Cottin, Axel You, Céline Buon, Antony Grondin, Léa S Lippens, Megane Lemaitre, Jérome Ezan, Charlotte Isch, Yann Rufin, Mireille Montcouquiol, Nathalie Sans, Bertrand Fontaine, Julien Messéant, Rozen Le Panse, Laure Strochlic.

  The neuromuscular junction (NMJ), synapse between the motor neuron terminal and a skeletal muscle fiber is crucial, throughout life, in maintaining the reliable neurotransmission required for functional motricity. Disruption of this system leads to neuromuscular disorders, such as auto-immune myasthenia gravis (MG), the most common form of NMJ diseases. MG is caused by autoantibodies directed mostly against the acetylcholine receptor (AChR) or the muscle-specific kinase MuSK. Several studies report immunoreactivity to the Frizzled-like cysteine-rich Wnt-binding domain of MuSK (CRD) in patients, although the pathogenicity of the antibodies involved remains unknown. We showed here that the immunoreactivity to MuSK CRD induced by the passive transfer of anti-MuSKCRD antibodies in mice led to typical MG symptoms, characterized by a loss of body weight and a locomotor deficit. The functional and morphological integrity of the NMJ was compromised with a progressive decay of neurotransmission and disruption of the structure of pre- and post-synaptic compartments. We found that anti-MuSKCRD antibodies completely abolished Agrin-mediated AChR clustering by decreasing the Lrp4-MuSK interaction. These results provide the first demonstration of the role of the MuSK CRD in MG pathogenesis and improve our understanding of the underlying pathophysiological mechanisms.

Keywords:  Autoimmune diseases; Immunology; Muscle biology; Neuromuscular disease; Neuroscience; Skeletal muscle

DOI:  https://doi.org/10.1172/JCI173308
Cell Genom. 2025 May 29. pii: S2666-979X(25)00171-5. [Epub ahead of print] 100915

Extensive differential gene expression and regulation by sex in human skeletal muscle.

Sarah C Hanks, Abigail S Mauger, Arushi Varshney, Dan L Ciotlos, Nandini Manickam, Narisu Narisu, Alexandria J Shumway, Peter Orchard, Michael R Erdos, Michael D Sweeney, Jeffrey Okamoto, Anne U Jackson, Heather M Stringham, Lori L Bonnycastle, Xiang Zhou, Timo A Lakka, Karen L Mohlke, Jaakko Tuomilehto, Markku Laakso, Michael Boehnke, Praveen Sethupathy, Francis S Collins, Heikki A Koistinen, Stephen C J Parker, Laura J Scott.

  The identification of sex-differential gene regulatory elements is essential for understanding sex-differential patterns of health and disease. We leveraged bulk and single-nucleus RNA sequencing (RNA-seq) and single-nucleus ATAC-seq data from 281 skeletal muscle biopsies to characterize sex differences in gene expression and regulation at the cell-type and whole-tissue levels. We found highly concordant sex-biased expression of over 2,100 genes across the three muscle fiber types and bulk tissue. Gene pathways related to mitochondrial activity and energy metabolism were enriched for male-biased expression, whereas those related to signal transduction and cell differentiation were enriched for female-biased expression. We found widespread sex-biased chromatin accessibility enriched in proximal and distal gene regulatory states; in gene promoters, sex-biased chromatin accessibility was positively associated with sex-biased expression. Long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) also showed extensive sex-biased expression in the fiber-type and bulk data, respectively. Together, these results highlight nuclear and cytoplasmic mechanisms for sex-differential gene regulation in skeletal muscle.

Keywords:  chromatin accessibility; gene expression; gene regulation; miRNA; sex differences; single nucleus; skeletal muscle; snATAC-seq; snRNA-seq

DOI:  https://doi.org/10.1016/j.xgen.2025.100915
Exp Physiol. 2025 Jun 07.

Diffusion and physical constraints limit oxidative capacity, capillary supply and size of muscle fibres in mice and humans.

Hans Degens, Guy A M Messa, Jason Tallis, Alessandra Bosutti, Tomas Venckunas, Ismail Adeniran, Rob C I Wüst, Paul W Hendrickse.

  It has been suggested that angiogenesis during skeletal muscle fibre hypertrophy allows escape from the 'size constraint', which is the inverse relationship between oxidative capacity and muscle fibre cross-sectional area (FCSA). It is, however, not known whether there are any limitations to the combinations of FCSA, oxidative capacity and capillary supply to an individual fibre. We determined the FCSA, oxidative capacity and capillary supply to fibres from highly resistance-trained men before and after superimposed endurance training, recreationally active men and women, and different mouse muscles. Both the oxidative capacity and the number of capillaries around a fibre (CAF) per FCSA (CAF/FCSA) showed an upper limit at each FCSA, irrespective of species, muscle origin or training status. The upper limit of fibre oxidative capacity was likely determined by diffusion constraints. The upper limit of CAF/FCSA was determined by physical constraints where (i) there is no further reduction in maximal diffusion distance to the core of a fibre beyond a CAF of 2, and (ii) the reduction in fibre area supplied by a capillary diminishes exponentially with an increase in CAF. The calculated upper limits of oxidative capacity and CAF/FCSA of a fibre of a given FCSA were linearly related. Irrespective of species, sex, muscle of origin and training status, our data indicate that diffusion limitations and physical limitations to capillary placement around a fibre place an upper limit on the oxidative capacity and capillary supply to a fibre of a given size, respectively.

Keywords:  capillarisation; capillary domain; microvasculature; muscle fibre; oxidative capacity

DOI:  https://doi.org/10.1113/EP092750
Eur J Med Res. 2025 Jun 12. 30(1): 475

Exercise orchestrates systemic metabolic and neuroimmune homeostasis via the brain-muscle-liver axis to slow down aging and neurodegeneration: a narrative review.

Jianda Kong, Yingao Xie, Rao Fan, Qinglu Wang, Ying Luo, Panpan Dong.

  Aging is a systemic process marked by progressive multi-organ dysfunction, metabolic dysregulation, and chronic low-grade inflammation ("inflammaging"), which collectively drive neurodegenerative diseases such as Alzheimer's Disease (AD) and Parkinson's Disease (PD). Emerging evidence underscores the brain-muscle-liver axis as a central hub for maintaining energy homeostasis and neuroimmune crosstalk during aging. Here, we elucidate how exercise orchestrates inter-organ communication to counteract age-related decline through metabolic reprogramming, immunomodulation, and neuroprotection. Mechanistically, exercise enhances mitochondrial biogenesis and oxidative capacity in skeletal muscle via AMPK/PGC-1α signaling, restoring fatty acid oxidation and glucose metabolism while producing myokines (e.g., BDNF and IL-6) that promote neuronal survival and synaptic plasticity. Concurrently, hepatic SIRT1 activation promotes lipid metabolism, mitigates insulin resistance, and reduces systemic inflammation, hence preserving brain energy supply. In the aging brain, exercise stimulates neurogenesis, suppresses neuroinflammation via NF-κB inhibition, and elevates BDNF levels, which synergistically enhance cognitive resilience. vitally, exercise modulates the neuro-immunometabolic axis by balancing pro- and anti-inflammatory cytokines (e.g., IL-6's hormetic role), optimizing immune cell function, and enhancing autophagy-mediated clearance of toxic aggregates (Aβ, α-synuclein). These adaptations are further amplified by epigenetic reprogramming, including but not limited to Nrf2-driven antioxidant responses and circadian rhythm synchronization. Our synthesis highlights exercise as a pleiotropic intervention that transcends single-organ influences, instead leveraging multi-tissue networks to delay aging and neurodegeneration. Unresolved challenges-personalized exercise regimens, molecular biomarkers for efficacy prediction, and combinatorial therapies with pharmacologic agents-underscore the need for translational studies integrating omics technologies and circadian biology. By bridging mechanistic insights with clinical applications, this review positions exercise as a cornerstone of precision medicine for aging populations.

Keywords:  Aging; Brain–muscle–liver axis; Cross-organ regulation; Energy metabolism; Exercise; Neuro-immuno-metabolic crosstalk; Neurodegenerative diseases

DOI:  https://doi.org/10.1186/s40001-025-02751-9
Epigenetics. 2025 Dec;20(1): 2508251

The myoblast methylome: multiple types of associations with chromatin and transcription.

Sagnik Sen, Michelle Lacey, Carl Baribault, V K Chaithanya Ponnaluri, Pierre Olivier Esteve, Kenneth C Ehrlich, Mia Meletta, Sriharsa Pradhan, Melanie Ehrlich.

  Epigenetic changes are implicated in development, repair, and physiology of postnatal skeletal muscle (SkM). We generated methylomes for human myoblasts (SkM progenitor cells) and determined myoblast differentially methylated regions (DMRs) for comparison to the epigenomics and transcriptomics of diverse cell types. Analyses were from global genomic and single-gene perspectives and included reporter gene assays. One atypical finding was the association of promoter-adjacent hypermethylation in myoblasts with transcription turn-on, but at downmodulated levels, for certain genes (e.g., SIM2 and TWIST1). In contrast, brain-specific OLIG2 was in repressed chromatin and silent in most cell types but linked to hypermethylated DMRs specifically in myoblasts. The OLIG2-linked DMRs might be needed because of the overlapping or nearby binding of myogenic differentiation protein 1 (MYOD). We found genome-wide overlap of DMRs with MYOD or CCCTC-binding factor (CTCF) binding sites in myoblasts that is consistent with the importance of MYOD, as well as CTCF, in organizing myoblast transcription-enhancing chromatin interactions. We also observed some gene upregulation correlated with a special association of regional DNA hypomethylation with H3K36me3, H3K27ac, and H3K4me1 enrichment. Our study highlights unusual relationships between epigenetics and gene expression that illustrate the interplay between DNA methylation and chromatin epigenetics in the regulation of transcription.

Keywords:  CTCF; DNA methylation; MYOD; Myoblasts; enhancers; enzymatic methyl-seq (EM-seq); skeletal muscle; whole-genome bisulfite sequencing (WGBS)

DOI:  https://doi.org/10.1080/15592294.2025.2508251
JCI Insight. 2025 Jun 12. pii: e193208. [Epub ahead of print]

Role of progesterone action in inguinal hernia formation via skeletal muscle fibrosis and atrophy.

Tianming You, Mehrdad Zandigohar, Tanvi Potluri, Natalie Piehl, John S Coon V, Elizabeth Baker, Maya Kafali, Yang Dai, Jonah J Stulberg, David J Escobar, Richard L Lieber, Hong Zhao, Serdar E Bulun.

  More than one in four men will undergo surgery for inguinal hernia, which is commonly associated with fibrotic degeneration of the lower abdominal muscle (LAM) in the groin region. Utilizing a male mouse model expressing the human aromatase gene (Aromhum), previous studies showed that locally produced estradiol acting via estrogen receptor alpha in LAM fibroblasts leads to fibrosis, myofiber atrophy, and hernia development. Here, we found that upregulation of progesterone receptor (PGR) in a LAM fibroblast population mediates this estrogenic effect. A PGR-selective progesterone antagonist in Aromhum mice decreased LAM fibrosis and atrophy, preventing hernia formation and stopping progression of existing hernias. Addition of progesterone to estradiol treatment was essential for early-onset development of LAM fibrosis and large hernias in wild type mice, which was averted by a progesterone antagonist. Single-nuclei multiomics sequencing of herniated LAM revealed a unique population of Pgr-expressing fibroblasts that promotes fibrosis and myofiber atrophy through transforming growth factor beta-2 signaling. Multiomics findings were validated in vivo in herniated LAM tissues of both mice and adult men. Our findings suggest an important and rare pathologic role of progesterone signaling in males and provide evidence for progesterone antagonists as a non-surgical alternative for inguinal hernia management.

Keywords:  Cell biology; Endocrinology; Fibrosis; Muscle biology; Sex hormones; Skeletal muscle

DOI:  https://doi.org/10.1172/jci.insight.193208
J Physiol Biochem. 2025 Jun 11.

miR-320-3p regulates apelin and TGF-β/SMAD3 signaling in hypobaric hypoxia exposed rats to induce skeletal muscle atrophy.

Samrita Mondal, Sukanya Srivastava, Swati Srivastava, Richa Rathor, Geetha Suryakumar.

  Emerging research on microRNA has decoded its crucial role in gene regulation, development and diseases. Skeletal muscle atrophy is reported in several chronic diseases as well as prolonged stay at high altitude. miR-320-3p is reported to be upregulated in various chronic diseases including cancer, heart diseases, diabetes, and chronic kidney diseases. The present study evaluates the role of miR-320-3p expression in regulating apelin and its downstream signaling under hypobaric hypoxia (HH) at high altitude. The expression of miR-320-3p was found to be upregulated during 7days HH (7DHH) exposure at 25,000 ft as compared to control group. The targets for miR-320-3p were retrieved from miRWalk 3.0, TargetScan 8.0, miRTarBase 10.0 databases in Rattus norvegicus. Using in silico approach, 26 myokines were screened out of total 14,435 targets of rno-miR-320-3p and levels of few myokines were experimentally validated. The expression of apelin, decorin, osteocrin, meteorin-like myokines were found to be significantly decreased while myostatin was significantly increased during HH exposure as compared to control rats. Enhanced expression of Tgfb and p-Smad3 under 7DHH indicated activation of protein degradation pathways. Expression of Pgc1a and Nrf2, the critical regulators of mitochondrial biogenesis, were significantly decreased under HH. Thus, increased expression of miR-320-3p regulate apelin and modulate downstream signaling via attenuation of mitochondrial biogenesis and myogenesis. Hence, miR-320-3p and myokines play pivotal role to regulate skeletal muscle atrophy. Further research on potential targets of miR-320-3p regulating the muscle mass may lead to the development of novel therapeutics in personalized medicine to combat skeletal muscle diseases.

Keywords:  Apelin; Atrophy; Skeletal muscle; Therapeutics; miR-320-3p; miRNA

DOI:  https://doi.org/10.1007/s13105-025-01100-y
Skelet Muscle. 2025 Jun 07. 15(1): 15

Contrasting Becker and Duchenne muscular dystrophy serum biomarker candidates by using data independent acquisition LC-MS/MS.

Camilla Johansson, Esther J Schrama, David Kotol, Andreas Hober, Zaïda Koeks, Nienke M van de Velde, Jan J G M Verschuuren, Erik H Niks, Fredrik Edfors, Pietro Spitali, Cristina Al-Khalili Szigyarto.

   BACKGROUND: Becker muscular dystrophy (BMD) is a rare and heterogeneous form of dystrophinopathy caused by expression of altered dystrophin proteins, as a consequence of in-frame genetic mutations. The majority of the BMD biomarker studies employ targeted approaches and focus on translating findings from Duchenne Muscular Dystrophy (DMD), a more severe disease form with clinical similarities but caused by out-of-frame mutations in the dystrophin gene. Importantly, DMD therapies assume that disease progression can be slowed by promoting the expression of truncated dystrophin comparable to what occurs in BMD patients. In this study, we explore similarities and differences in protein trajectories over time between BMD and DMD serum, and explore proteins related to motor function performance.
METHODS: Serum samples collected from 34 BMD patients, in a prospective longitudinal 3-year study, and 19 DMD patients, were analyzed by using Data Independent Acquisition Tandem Mass Spectrometry (DIA-MS). Subsequent normalization, linear mixed effects model was employed to identify proteins associated with physical tests and dystrophin expression in skeletal muscle. Analysis was also performed to explore the discrepancy between DMD and BMD biomarker abundance trajectories over time.
RESULTS: Linear mixed effects models identified 20 proteins with altered longitudinal signatures between DMD and BMD, including creatine kinase M-type (CKM) pyruvate kinase (PKM), fibrinogen gamma chain (FGG), lactate dehydrogenase B (LDHB) and alpha-2-macroglobulin (A2M). Furthermore, several proteins related to innate immune response were associated with motor function in BMD patients. In particular, A2M displayed an altered time-dependent decline in relation to dystrophin expression in the tibialis anterior muscle.
CONCLUSIONS: Our study revealed differences in the serum proteome between BMD and DMD, which comprises proteins involved in the immune response, extracellular matrix organization and hemostasis but not muscle leakage proteins significantly associated with disease progression in DMD. If further evaluated and validated, these biomarker candidates may offer means to monitor disease progression in BMD patients. A2M is of particular interest due to its association with dystrophin expression in BMD muscle and higher abundance in DMD patients in comparison to BMD. If validated, A2M could be used as a pharmacodynamic biomarker in therapeutic clinical trials aiming to restore dystrophin expression.

Keywords:  Becker muscular dystrophy; DIA; Disease progression biomarkers; Duchenne muscular dystrophy; Proteomics; SRM

DOI:  https://doi.org/10.1186/s13395-025-00385-3
Int J Mol Sci. 2025 Jun 05. pii: 5410. [Epub ahead of print]26(11):

Pharmacological HIF-PH Inhibition Suppresses Myoblast Differentiation Through Continued HIF-1α Stabilization.

Yuya Miki, Akinobu Ochi, Hideki Uedono, Yoshinori Kakutani, Mitsuru Ichii, Yuki Nagata, Katsuhito Mori, Yasuo Imanishi, Tetsuo Shoji, Tomoaki Morioka, Masanori Emoto.

  Hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitors continually stabilize hypoxia-inducible factor-1α (HIF-1α). These inhibitors are effective in the clinical treatment of renal anemia. However, the effects of continued HIF-1α stabilization on skeletal muscle differentiation remain unclear. This study aimed to investigate the effects of continued HIF-1α stabilization on skeletal muscle differentiation using a HIF-PH inhibitor in both in vitro and in vivo models. We cultured mouse C2C12 myoblasts to differentiate into myotubes with or without FG-4592, a HIF-PH inhibitor. Additionally, we treated nine-week-old male C57BL/6 mice with either FG-4592 or vehicle via intraperitoneal injections three times a week for four weeks. In vitro, FG-4592 treatment stabilized HIF-1α continually. Morphological analysis revealed that 72 h FG-4592 treatment suppressed differentiation of C2C12 myoblasts into myotubes. This treatment decreased the gene and protein expression of MyoD and myogenin, reduced the protein expression of myosin heavy chain (MHC), and increased the gene and protein expression of myostatin. HIF-1α knockdown mitigated the decrease in MHC protein expression induced by FG-4592. In vivo, FG-4592 treatment increased HIF-1α protein expression and decreased MyoD, myogenin, and MHC protein expression in gastrocnemius muscle. These findings suggest that pharmacological HIF-PH inhibition suppresses myoblast differentiation through continued HIF-1α stabilization.

Keywords:  HIF-1α stabilization; HIF-PH inhibitor; muscle differentiation

DOI:  https://doi.org/10.3390/ijms26115410
APL Bioeng. 2025 Jun;9(2): 021502

Mechanotransduction for therapeutic approaches: Cellular aging and rejuvenation.

Hye-Min Han, Su-Yeon Kim, Dong-Hwee Kim.

Mechanotransduction regulates cytoskeletal remodeling, nuclear mechanics, and metabolic adaptation, which are central to cellular aging and rejuvenation. These responses restore mechanical balance in aged cells, reprogram longevity-related gene expression, and alleviate age-related disorders, including neurodegeneration, musculoskeletal decline, and cardiovascular dysfunction. These insights indicate that mechanotransduction is pivotal in cellular and systemic processes underlying aging. The key signaling pathways, including the Hippo/Yes-associated protein (YAP), mechanistic target of rapamycin (mTOR), and transforming growth factor-beta (TGF-β)/Smad, have been explored in mediating age-related physiological decline, showing potential as therapeutic targets. Aging-dependent stiffening of the extracellular matrix (ECM) is associated with accelerated senescence. Interventions targeting ECM remodeling, such as mechanochemical therapies and nanoparticle delivery systems, provide promising strategies for counteracting cellular deterioration. Research progress has elucidated the critical role of mechanotransduction in organ-specific aging, enabling targeted interventions that align mechanical and biochemical therapeutic strategies. This review highlights the integration of mechanical modulation into therapeutic approaches, emphasizing its potential to restore cellular functionality, improve health, and extend lifespan. Advances in mechanomedicine have opened innovative frontiers in combating aging and age-associated diseases by addressing the interplay between mechanical forces and cellular processes. Cellular rejuvenation-the restoration of aged cells to a functionally younger state through the regulation of mechanotransduction pathways-involves the reversal of senescence-associated phenotypes, including nuclear deformation, mitochondrial alterations, and ECM stiffness. Furthermore, mechanotransduction plays a critical role in cellular rejuvenation by modulating YAP/TAZ activity, promoting autophagy, and maintaining cytoskeletal integrity.

DOI: https://doi.org/10.1063/5.0263236
Am J Physiol Heart Circ Physiol. 2025 Jun 10.

On a Heart failure - Skeletal Muscle Axis.

Jens P Goetze, Dijana Terzic.

DOI: https://doi.org/10.1152/ajpheart.00385.2025
STAR Protoc. 2025 Jun 06. pii: S2666-1667(25)00262-X. [Epub ahead of print]6(2): 103856

Protocol for using MYOD1-transduced human urine-derived cells as a predictive platform for exon skipping therapy in Duchenne muscular dystrophy.

Katsuhiko Kunitake, Takami Ishizuka, Eri Takeshita, Hirofumi Komaki, Yoshitsugu Aoki.

  Antisense oligonucleotide (ASO)-based exon skipping is a splice-modulating therapy effective for Duchenne muscular dystrophy (DMD) caused by dystrophin deficiency. Here, we present a protocol for evaluating exon skipping efficacy in MYOD1-transduced human urine-derived cells (MYOD1-UDCs) from patients. We describe steps for isolating UDCs, selecting CD90-positive cells, inducing myogenic differentiation, and assessing the restoration of DMD mRNA and proteins after exon skipping. This platform enhances the predictability of ASO screening, promoting early-stage drug discovery and translational research in DMD. For complete details on the use and execution of this protocol, please refer to Komaki et al.1.

Keywords:  Cell Biology; Cell Differentiation; Cell culture; Cell isolation; Genetics; Health Sciences; Molecular Biology; Stem Cells

DOI:  https://doi.org/10.1016/j.xpro.2025.103856