bims-moremu 2025-10-19 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2025–10–19
34 papers selected by
Anna Vainshtein, Craft Science Inc.

Interplay Between mTORC1 Signaling and Iron Homeostasis in Muscle Atrophy.
Revealing the Specific Contributions of Mitochondrial CB1 Receptors to the Overall Function of Skeletal Muscle in Mice.
Influence of skeletal muscle heterogeneity on autophagic signaling and response.
Protein Arginine N-Methyltransferase 4 Activation Contributes to Glucose-Induced Skeletal Muscle Atrophy.
Response of UBR-box E3 ubiquitin ligases and protein quality control pathways to perturbations in protein synthesis and skeletal muscle size.
CXCL14 Promotes Skeletal Muscle Mass Growth and Attenuates Lipopolysaccharide- and Dexamethasone-Induced Muscle Atrophy in Cultured Myotubes and Mouse Models.
The role of exercise induced capillarization adaptations in skeletal muscle aging: a systematic review.
Special Issue "Skeletal Muscle Adaptations to Oxidative Stress".
Muscle-specific gene editing therapy via mammalian fusogen-directed virus-like particles.
Integrative strategies for accelerated recovery following musculoskeletal injuries.
Melatonin Activates AMPK Pathway to Regulate the Regeneration of Slow Muscle Fibers in Skeletal Muscle Injury Repair.
Insights into WDR5: unveiling its functions, regulation, and impact on skeletal muscle.
TSPO Expression and [18F]DPA-714 PET/CT Imaging as Pathogenetic and Diagnostic Biomarkers in Symptomatic Stages of Skeletal Muscle Fiber Degeneration in SOD1-G93A ALS Mice.
Massive reduction of RyR1 in muscle spindles of mice carrying recessive Ryr1 mutations alters proprioception and causes scoliosis.
Spinal motor neuron plasticity after hindlimb unloading in aged mice and its modulation by exercise with TRPM8-mediated cutaneous stimulation.
Exercise, Epigenetics, and Body Composition: Molecular Connections.
Characterization of a humanized mouse model of Duchenne muscular dystrophy to support the development of genetic medicines.
Sex-specific Phosphoproteome Responses to Calorie Restriction and Insulin in Skeletal Muscle from Older Rats.
Magnetic Bioprinting and Actuation of Stretchable Muscle Tissue.
Mixed twitch and tetanus electrical stimulation via belt-electrode effectively attenuates denervation-induced muscle atrophy.
Nuclear entry of AS160 as a transcriptional regulator of satellite cells for muscle regeneration.
Synthetic bottlebrush block copolymer prevents disease onset in Duchenne muscular dystrophy.
Extreme physical inactivity alters iron metabolism: mechanisms and health issues for astronauts and bedridden patients.
Lack of myotubularin phosphatase activity is the main cause of X-linked Myotubular Myopathy.
The Novel MuRF2 Target SNX5 Regulates PKA Activity Through Stabilization of RI-α and Controls Myogenic Differentiation.
The Diagnostic Potential of Urinary Titin Fragment in Neuromuscular Diseases.
Nicotinamide N-methyltransferase inhibition improves limb function in experimental peripheral artery disease.
Gestational low-protein diet impairs mitochondrial function and skeletal muscle development by inducing immune responses in male offspring.
Large-scale serum protein biomarkers discovery associated with function and clinical milestones in Duchenne muscular dystrophy.
The mitochondrial side of frailty.
Effects of statins on sarcopenia with focus on mechanistic insights and future perspectives.
Integrative Transcriptomic and Network-Based Analysis of Neuromuscular Diseases.
Impaired neuromusculoskeletal response to training stimuli associated with low energy availability: a systematic review.
Physical Activity and Exercise Intensity Terminology: A Joint American College of Sports Medicine (ACSM) Expert Statement and Exercise and Sport Science Australia (ESSA) Consensus Statement.

Free Radic Biol Med. 2025 Oct 12. pii: S0891-5849(25)01271-7. [Epub ahead of print]

Interplay Between mTORC1 Signaling and Iron Homeostasis in Muscle Atrophy.

Eunbin Jee, Walaa Ouf, Jonghan Kim, Yuho Kim.

  The mechanistic target of rapamycin complex 1 (mTORC1) plays an important role in maintaining skeletal muscle homeostasis by regulating cell growth, protein degradation, and nutrient sensing. Beyond its role in muscle growth and atrophy, recent findings suggest that mTORC1 also regulates cellular iron metabolism. Although iron is essential for energy production and mitochondrial function in skeletal muscle, both iron deficiency and overload contribute to muscle degeneration through dysfunctional mitochondria, oxidative stress, and activation of catabolic pathways. In this review, while focusing on the role of mTORC1 in iron-dependent muscle disorders such as cancer cachexia, sarcopenia, and Duchenne muscle dystrophy, we explore how altered mTORC1 activity affects major protein degradation systems, including the ubiquitin-proteasome system, autophagy, and mitophagy, under iron imbalance in skeletal muscle. We also highlight the emerging evidence linking mTORC1 signaling to iron metabolism in skeletal muscle, with a focus on the regulation of iron transport, ferritinophagy, and the autophagosome-lysosome system. The crosstalk between mTORC1 and iron metabolism in muscle atrophy provides novel insights into the molecular mechanisms underlying muscle disorders. Collectively, these perspectives suggest new therapeutic strategies for treating muscle diseases associated with disrupted iron homeostasis and impaired mTORC1 signaling.

Keywords:  Duchenne muscle dystrophy; autophagy; cachexia; iron deficiency; iron overload; mTORC1; mitophagy; sarcopenia; ubiquitin-proteasome system

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.10.257
Cells. 2025 Sep 28. pii: 1517. [Epub ahead of print]14(19):

Revealing the Specific Contributions of Mitochondrial CB1 Receptors to the Overall Function of Skeletal Muscle in Mice.

Zoltán Singlár, Péter Szentesi, Nyamkhuu Ganbat, Barnabás Horváth, László Juhász, Mónika Gönczi, Anikó Keller-Pintér, Attila Oláh, Zoltán Máté, Ferenc Erdélyi, László Csernoch, Mónika Sztretye.

  Skeletal muscle, constituting 40-50% of total body mass, is vital for mobility, posture, and systemic homeostasis. Muscle contraction heavily relies on ATP, primarily generated by mitochondrial oxidative phosphorylation. Mitochondria play a key role in decoding intracellular calcium signals. The endocannabinoid system (ECS), including CB1 receptors (CB1Rs), broadly influences physiological processes and, in muscles, regulates functions like energy metabolism, development, and repair. While plasma membrane CB1Rs (pCB1Rs) are well-established, a distinct mitochondrial CB1R (mtCB1R) population also exists in muscles, influencing mitochondrial oxidative activity and quality control. We investigated the role of mtCB1Rs in skeletal muscle physiology using a novel systemic mitochondrial CB1 deletion murine model. Our in vivo studies showed no changes in motor function, coordination, or grip strength in mtCB1 knockout mice. However, in vitro force measurements revealed significantly reduced specific force in both fast-twitch (EDL) and slow-twitch (SOL) muscles following mtCB1R ablation. Interestingly, knockout EDL muscles exhibited hypertrophy, suggesting a compensatory response to reduced force quality. Electron microscopy revealed significant mitochondrial morphological abnormalities, including enlargement and irregular shapes, correlating with these functional deficits. High-resolution respirometry further demonstrated impaired mitochondrial respiration, with reduced oxidative phosphorylation and electron transport system capacities in knockout mitochondria. Crucially, mitochondrial membrane potential dissipated faster in mtCB1 knockout muscle fibers, whilst mitochondrial calcium levels were higher at rest. These findings collectively establish that mtCB1Rs are critical for maintaining mitochondrial health and function, directly impacting muscle energy production and contractile performance. Our results provide new insights into ECS-mediated regulation of skeletal muscle function and open therapeutic opportunities for muscle disorders and aging.

Keywords:  ATP; calcium homeostasis; cannabinoid receptor type 1; mitochondria; mitochondrial cannabinoid receptor type 1; mtCB1 knockout; murine skeletal muscle; muscle force; skeletal endocannabinoid system

DOI:  https://doi.org/10.3390/cells14191517
Autophagy Rep. 2025 ;4(1): 2562429

Influence of skeletal muscle heterogeneity on autophagic signaling and response.

Fasih A Rahman, Joe Quadrilatero.

  Skeletal muscle is a heterogeneous tissue composed of fibers with distinct contractile, metabolic, and molecular characteristics. This intrinsic heterogeneity influences how individual fibers respond to physiological stimuli, pathological stress, and cellular remodeling processes such as autophagy. Skeletal muscle autophagy is essential for maintaining proteostasis and organelle quality, particularly in high-demand tissues like skeletal muscle. However, emerging evidence indicates that autophagy is not uniformly regulated across all muscles and fibers within a skeletal muscle. Fast/glycolytic fibers, characterized by faster contractile speed and high glycolytic capacity, exhibit greater autophagic flux potentially driven by activation of energy signals, calcium, and redox-sensitive pathways. In contrast, slow/oxidative fibers, characterized by slow contractile speed and higher oxidative metabolism, show lower inducible autophagy despite elevated basal expression of autophagy-related proteins. These differences are compounded by fiber type - specific organelle architecture, recruitment patterns during activity and disuse, and substrate availability and utilization. Further, pathological conditions such as disuse, chronic disease, and myopathies often induce fiber type alterations as well as changes to organelle content and function that are closely associated with changes in autophagy signaling. Additionally, species and strain variability add another layer of complexity, complicating both the interpretation and translational relevance of autophagy studies in skeletal muscle. This review synthesizes current evidence linking skeletal muscle phenotype to autophagy regulation and highlights the need to consider skeletal muscle heterogeneity as a central variable in skeletal muscle autophagy research. A deeper understanding of skeletal muscle type/fiber-specific autophagy will improve our ability to interpret experimental findings and develop targeted interventions for skeletal muscle dysfunction.

Keywords:  Skeletal muscle; autophagy; fiber type; heterogeneity; metabolic phenotype; muscle plasticity

DOI:  https://doi.org/10.1080/27694127.2025.2562429
FASEB J. 2025 Oct 31. 39(20): e71135

Protein Arginine N-Methyltransferase 4 Activation Contributes to Glucose-Induced Skeletal Muscle Atrophy.

Pawan Kumar, Farah Gulzar, Nikita Chhikara, Arvind K Maurya, Sushmita Singh, Ishbal Ahmad, Sanjeev Kanojiya, Akhilesh K Tamrakar.

  Protein arginine N-methyltransferase 4 (PRMT4; also known as Coactivator-Associated Arginine Methyltransferase 1/CARM1) plays a crucial role in cell-type-specific biological processes. In skeletal muscle, PRMT4 has been demonstrated to manage plasticity by regulating skeletal muscle development, regeneration, and glycogen metabolism. However, its impact on skeletal muscle metabolic homeostasis under pathologic conditions remains obscure. Here, we investigated the role of PRMT4 in skeletal muscle atrophy under diabetes. In L6 myotubes, high glucose exposure increased mRNA expression and protein level of PRMT4, correlating with the induction of atrophy features. Notably, the pharmacological inhibition or small interfering RNA (siRNA)-mediated downregulation of PRMT4 suppressed high glucose-induced atrophy features. The high glucose exposure elevated asymmetric dimethylarginine (ADMA) via PRMT4 activation, disrupting insulin signaling in L6 myotubes. Further, we have established the activation of the ubiquitin-proteasome-mediated protein degradation pathway in the high glucose-induced skeletal muscle atrophy program via PRMT4, without any significant effect on the autophagy pathway. Additionally, we have demonstrated that proteasome-mediated protein degradation released free amino acids that triggered mammalian target of rapamycin (mTOR) signaling in a PRMT4-dependent manner. Altogether, our findings establish PRMT4 as a critical regulator of glucose-induced skeletal muscle atrophy and propose it as a potential therapeutic target for the management of diabetes-associated skeletal muscle atrophy.

Keywords:  PRMT4; arginine methylation; post translational modification; skeletal muscle atrophy

DOI:  https://doi.org/10.1096/fj.202502570R
Am J Physiol Cell Physiol. 2025 Oct 13.

Response of UBR-box E3 ubiquitin ligases and protein quality control pathways to perturbations in protein synthesis and skeletal muscle size.

Leslie M Baehr, Luis Gustavo Oliveira de Sousa, Craig A Goodman, Adam P Sharples, David S Waddell, Sue C Bodine, David C Hughes.

  The N-degron pathway contributes to proteolysis by targeting N-terminal residues of destabilized proteins via E3 ligases that contain a UBR-box domain. Emerging evidence suggests the UBR-box family of E3 ubiquitin ligases (UBR1-7) are involved in the positive regulation of skeletal muscle mass. The purpose of this study was to explore the role of UBR-box E3 ubiquitin ligases under enhanced protein synthesis and skeletal muscle growth conditions. Cohorts of adult male mice were electroporated with constitutively active Akt (Akt-CA) or UBR5 RNAi constructs with a rapamycin diet intervention for 7 and 30 days, respectively. In addition, the UBR-box family was studied during the regrowth phase post nerve crush induced inactivity. Skeletal muscle growth with Akt-CA or regrowth following inactivity increased protein abundance of UBR1, UBR2, UBR4, UBR5 and UBR7. This occurred with corresponding increases in Akt-mTORC1/S6K and MAPK/p90RSK signaling and protein synthesis. The increases in UBR-box E3s, ubiquitination, and proteasomal activity occurred independently of mTORC1 activity and were associated with increases in markers related to autophagy, ER-stress, and protein quality control pathways. Finally, while UBR5 knockdown (KD) evokes atrophy, it occurs together with hyperactivation of mTORC1 and protein synthesis. In UBR5 KD muscles, we identified an increase in protein abundance for UBR2, UBR4 and UBR7, which may highlight a compensatory response to maintain proteome integrity. Future studies will seek to understand the role of UBR-box E3s towards protein quality control in skeletal muscle plasticity.

Keywords:  N-degron pathway; UBR5; hypertrophy; proteasome system; protein turnover

DOI:  https://doi.org/10.1152/ajpcell.00602.2025
J Cachexia Sarcopenia Muscle. 2025 Oct;16(5): e70087

CXCL14 Promotes Skeletal Muscle Mass Growth and Attenuates Lipopolysaccharide- and Dexamethasone-Induced Muscle Atrophy in Cultured Myotubes and Mouse Models.

Bagus Sarmito, Younjeong Oh, Nurkyz Alymkulova, Jeong Kyo Yoon.

   BACKGROUND: Skeletal muscle mass is regulated by secretory factors derived from myofibers and muscle-resident cells. Identifying these factors and understanding their mechanisms is critical for combating muscle wasting disorders. This experimental study investigates the role of CXCL14, a chemokine primarily secreted by fibro-adipogenic progenitors (FAPs) residing in muscle, in regulating muscle mass.
METHODS: This study was conducted at the Soonchunhyang Institute of Medi-bio Science (SIMS), South Korea, between August 2020 and June 2025. Mouse C2C12 myotubes and primary human myotubes were treated with recombinant CXCL14, with or without co-treatment using Rps6kb1 siRNA, lipopolysaccharide (LPS) or dexamethasone (DEX). Myotube mass index (MMI) was measured. Expression of AKT-S6 kinase (S6K), FOXO-Atrogin-1/MuRF-1 signalling components and myosin heavy chains (MyHCs) was assessed via Western blotting. Eight-week-old male mice were used: ICR mice for electroporation experiments and C57BL/6N strain for LPS and DEX atrophy models. Cxcl14 expression plasmids were electroporated into tibialis anterior (TA) muscles, with or without LPS or DEX treatment. Cross-sectional area (CSA) of myofibers was measured; Western blotting and RNA sequencing were used to analyse molecular responses. Statistical analyses included one-way ANOVA with Tukey's post hoc test, repeated-measures ANOVA with Dunnett's post hoc test, Kruskal-Wallis test with Dunn's post hoc test and unpaired Student's t-test, as appropriate.
RESULTS: CXCL14 induced hypertrophy in C2C12-derived myotubes: (MMI [μm2]: 100 ng/mL CXCL14, 1345 ± 50.97 [95% CI: 1237-1453], vs. control, 897.9 ± 33.33 [95% CI: 829.8-996], p ≤ 0.0001). Cxcl14 overexpression in mouse TA muscles significantly increased muscle mass: (CSA [μm2]: HA-CXCL14: 1408 ± 15.42 [95% CI: 1378-1438]; CXCL14-Myc: 1499 ± 17.18 [95% CI: 1464-1534]; control: 870.1 ± 11.25 [95% CI: 848.1-892.2], p ≤ 0.0001). CXCL14 activated the AKT-S6K pathway and inhibited the FOXO-Atrogin-1/MuRF-1 pathway in both in vitro and in vivo models. CXCL14 effectively reversed LPS- and DEX-induced atrophy in both C2C12 myotubes and TA muscles, as demonstrated by corresponding increases MMI and CSA (all p ≤ 0.0001). CXCL14 also promoted hypertrophy in primary human myotubes in vitro (MMI [μm2]: 100 ng/mL CXCL14, 3481 ± 242.6 [95% CI: 2973-3989] vs. control, 2549 ± 114.7 [95% CI: 2310-2787], p ≤ 0.001) and significantly reversed atrophy induced by LPS and DEX (p ≤ 0.01 to p ≤ 0.0001), accompanying the activation of protein synthesis and inhibition of protein degradation pathways.
CONCLUSIONS: Our findings identify CXCL14 as a novel regulator of skeletal muscle mass and highlight its therapeutic potential in preventing or reversing muscle atrophy associated with ageing and diseases in humans.

Keywords:  CXCL14; protein metabolism; skeletal muscle atrophy; skeletal muscle homeostasis; skeletal muscle hypertrophy

DOI:  https://doi.org/10.1002/jcsm.70087
Front Physiol. 2025 ;16 1681184

The role of exercise induced capillarization adaptations in skeletal muscle aging: a systematic review.

Yi Ding, Qiliang Wan, Jae Cheol Kim, Wenduo Liu, Weiping Ji.

   Background: Skeletal muscle aging is often accompanied by capillary rarefaction, which limits the effective delivery and distribution of hormones, nutrients, and growth factors within skeletal muscle. Furthermore, exercise is widely regarded as having the potential to improve microcirculation and delay skeletal muscle aging. This review aims to explore exercise-induced improvements in capillarization and related adaptations to mitigate the adverse changes that occur during the aging process of skeletal muscle.
Methods: This systematic review was conducted in accordance with the PRISMA guidelines and registered in the PROSPERO database under the identifier CRD420251055873. Studies involving exercise interventions in older adults were included, with the requirement that at least one original outcome related to skeletal muscle capillarization was reported. Articles were rigorously screened based on the PICOS criteria, and the quality of the included studies was assessed.
Results: Studies have shown that older adults still possess the capacity to improve skeletal muscle capillarization through exercise. Moderate-intensity aerobic exercise not only significantly enhances the level of capillarization but also induces effects that can be maintained even after cessation of training. Capillarization adaptations induced by resistance training exhibit marked inter-individual variability, which is primarily determined by each individual's baseline level of capillarization, thereby resulting in distinct patterns of adaptation. The studies also revealed that the regulation of capillarization depends on the synergistic action of VEGF and eNOS, and that different types of exercise may elicit adaptations through distinct molecular pathways.
Conclusion: During the aging process, exercise-induced improvements in capillarization can enhance nutrient delivery, metabolic efficiency, and regenerative capacity in skeletal muscle. To some extent, these adaptations help suppress degenerative changes in muscle function and provide a targeted foundation for anti-aging intervention strategies.

Keywords:  aerobic exercise; capillarization; exercise adaptation; resistance training; skeletal muscle aging

DOI:  https://doi.org/10.3389/fphys.2025.1681184
Int J Mol Sci. 2025 Oct 09. pii: 9809. [Epub ahead of print]26(19):

Special Issue "Skeletal Muscle Adaptations to Oxidative Stress".

Guglielmo Duranti.

Skeletal muscle constitutes approximately 40% of total adult body weight, and its health is essential for overall well-being [...].

DOI: https://doi.org/10.3390/ijms26199809
Nat Commun. 2025 Oct 15. 16(1): 9145

Muscle-specific gene editing therapy via mammalian fusogen-directed virus-like particles.

Shi-Kun Zhou, Jing-Tong Luo, Yi-Fang Chen, Zi-Dong Lu, Qiu-Hong Jian, Shui-Qing Jiang, Jing Li, Xue-Qin Zhang, Xin-Yu Tan, Xian-Zhu Yang, Cong-Fei Xu, Jun Wang.

Muscle genetic defects can lead to impaired movement, respiratory failure, and other severe symptoms. The development of curative therapies is challenging due to the need for the delivery of gene-editing tools into skeletal muscle cells throughout the body. Here, we use muscular fusogens (Myomaker and Myomerger) to engineer muscle-specific virus-like particles (MuVLPs) for the systemic delivery of gene-editing tools. We demonstrate that MuVLPs can be loaded with diverse payloads, including EGFP, Cre and Cas9/sgRNA ribonucleoproteins (Cas9 RNPs), and can be delivered into skeletal muscle cells via targeted membrane fusion. Systemic administration of MuVLPs carrying Cas9 RNPs enables skeletal muscle-specific gene editing, which excised the exon containing a premature terminator codon mutation in a mouse model for Duchenne muscular dystrophy (DMD). This treatment restores dystrophin expression in various skeletal muscle tissues, including the diaphragm, quadriceps, tibialis anterior, gastrocnemius, and triceps. As a result, the treated mice exhibit a significantly increased capacity for exercise and endurance. This study established a platform for precise gene editing in skeletal muscle tissues.

DOI: https://doi.org/10.1038/s41467-025-64200-9
J Physiol. 2025 Oct 13.

Integrative strategies for accelerated recovery following musculoskeletal injuries.

Koyal Garg.



Keywords:  ligaments; regeneration; skeletal muscle; stem cells; tendon; volumetric muscle loss

DOI:  https://doi.org/10.1113/JP290094
FASEB J. 2025 Oct 31. 39(20): e71123

Melatonin Activates AMPK Pathway to Regulate the Regeneration of Slow Muscle Fibers in Skeletal Muscle Injury Repair.

Wei Xie, Zhengchao Hong, Yuxin Xie, Kangyan Hou, Songhan Li, Mingxin Fang, Yupeng Guan, Zhixuan Zhang, Miao Zhang.

  The process of skeletal muscle regeneration entails alterations in the relative composition of muscle fiber types, yet the regulatory mechanisms remain incompletely understood. This study aimed to investigate the role of melatonin in regulating the regeneration of slow muscle fibers during skeletal muscle repair and its underlying mechanisms. Using a tibialis anterior muscle frostbite model in 6-8-week-old male C57BL/6J mice, in vivo experiments revealed that intraperitoneal melatonin administration significantly increased Myh7/Myh2 protein expression while reducing Myh1/Myh4 levels. In vitro, melatonin-treated C2C12 myoblasts exhibited elevated oxygen consumption, mitochondrial mass, mitochondrial respiratory chain complexes activity, ATP production, mtDNA content, and membrane potential, alongside reduced LDH activity and ROS levels. Transcriptional upregulation of genes linked to mitochondrial complexes assembly, oxidative phosphorylation, and ATP synthesis was observed. Mechanistically, melatonin activated the AMPK/PGC-1α pathway, as evidenced by Compound C (AMPK inhibitor) pretreatment reversing these effects, decreasing p-AMPK/AMPK ratios, PGC-1α, and slow fiber markers (Myh7/Myh2), while increasing ROS and fast fiber marker (Myh4). The results indicate that melatonin facilitates the formation of slow-twitch fibers during muscle repair by augmenting mitochondrial function through the AMPK/PGC-1α signaling pathway. Consequently, these findings imply that melatonin improves mitochondrial function via AMPK/PGC-1α signaling, thereby promoting the regeneration of slow muscle fibers and facilitating the repair of skeletal muscle damage.

Keywords:  AMPK; melatonin; mitochondria; skeletal muscle injury repair; slow muscle fibers

DOI:  https://doi.org/10.1096/fj.202501549RR
Epigenetics. 2025 Dec;20(1): 2573998

Insights into WDR5: unveiling its functions, regulation, and impact on skeletal muscle.

Erick Bahena-Culhuac, Mauricio Hernández-Somilleda, José Manuel Hernández-Hernández.

  WD40-repeat-containing protein 5 (WDR5) is a highly conserved multifunctional scaffold protein with a toroidal structure, facilitating interactions with numerous partners through its WDR5-binding motif (WBM) and WDR5-interacting (WIN) sites. It plays a critical role in histone modifications, including H3K4 methylation (H3K4me), histone acetylation, and deacetylation, influencing stem cell maintenance and differentiation. Recent studies highlight its involvement in muscle homeostasis, particularly in skeletal muscle progenitor cells, where it regulates PAX7-driven myogenic factor expression. Additionally, WDR5 governs epigenetic programs in smooth muscle by modulating H3K4me marks on lineage-specific genes. Despite extensive research on its role in cancer and chromatin remodeling, its broader physiological functions remain underexplored. This review examines WDR5's regulatory mechanisms, including its modulation by long non-coding RNAs (lncRNAs), post-translational modifications (PTMs), and microproteins, while emphasizing its relevance to muscle biology. Understanding WDR5's interactome and regulatory networks could provide novel insights into muscle regeneration, stem cell dynamics, and potential therapeutic strategies for muscular disorders and regenerative medicine.

Keywords:  WDR5; chromatin remodeling; epigenetics; histone modifications; muscle regeneration

DOI:  https://doi.org/10.1080/15592294.2025.2573998
FASEB J. 2025 Oct 31. 39(20): e71129

TSPO Expression and [18F]DPA-714 PET/CT Imaging as Pathogenetic and Diagnostic Biomarkers in Symptomatic Stages of Skeletal Muscle Fiber Degeneration in SOD1-G93A ALS Mice.

Serenella Anzilotti, Nunzia De Iesu, Sara Gargiulo, Noemi Di Muraglia, Annunziata Gaetana Cicatiello, Monica Dentice, Mariarosaria Panico, Sandra Albanese, Lucio Annunziato, Marco Salvatore, Giuseppe Pignataro, Sabina Pappatà.

  Emerging evidence highlights the involvement of skeletal muscle in the pathogenesis of amyotrophic lateral sclerosis (ALS), through mechanisms involving inflammation and mitochondrial dysfunction in skeletal muscle fibers. The 18 kDa translocator protein (TSPO) is primarily expressed on the outer mitochondrial membrane, is implicated in inflammation, and serves as both a biomarker and a therapeutic target for neuroinflammation. This study investigated whether PET imaging targeting the TSPO, immunohistochemistry, and confocal microscopy can characterize skeletal muscle inflammation and muscular fiber damage in SOD1-G93A ALS transgenic mice. High-resolution PET/CT imaging with [18F]DPA-714 was employed to assess TSPO expression in the triceps brachii of SOD1-G93A mice at mild (age range: 98-112 days; Clinical Score (CS) range:1-1.5) and moderate-severe (age range: 120-137 days; CS range: 2-4) symptomatic stages. To support PET data, TSPO was analyzed by immunohistochemistry and confocal microscopy in the triceps skeletal muscle obtained from mild and moderate-severe SOD1-G93A mice. Inflammatory and anti-inflammatory macrophage cells in skeletal muscle tissues were detected by immunofluorescence. PET/CT revealed a progressive, significant increase of [18F]DPA-714 uptake in SOD1-G93A triceps brachii in mild and moderate-severe stages. Immunohistochemistry and confocal microscopy confirmed increased TSPO expression in the degenerating muscle fibers and in infiltrating macrophage cells. In vivo studies of TSPO expression in ALS-affected skeletal muscles may provide valuable insights into muscle inflammation and mitochondrial involvement during disease progression. In addition, TSPO and PET/CT imaging with [18F]DPA-714 might represent a noninvasive and promising diagnostic biomarker for detecting early muscle pathology in ALS.

Keywords:  18F‐DPA‐714; TSPO; amyotrophic lateral sclerosis; macrophages; mitochondrial fission; positron emission tomography; skeletal muscle

DOI:  https://doi.org/10.1096/fj.202502450R
J Physiol. 2025 Oct 15.

Massive reduction of RyR1 in muscle spindles of mice carrying recessive Ryr1 mutations alters proprioception and causes scoliosis.

Alexis Ruiz, Sofia Benucci, Hervé Meier, Georg Schultz, Katarzyna Buczak, Christoph Handschin, Rodrigo C G Pena, Susan Treves, Francesco Zorzato.

  Muscle spindles are stretch receptors lying deep within the muscle belly involved in detecting changes in muscle length and playing a fundamental role in motor control, posture and synchronized gait. They are made up of an external capsule surrounding three to five intrafusal muscle fibres and a nuclear bag complex. Dysfunction of muscle spindles leads to abnormal proprioceptor function, which has been linked to aberrant bone and cartilage development, scoliosis, kyphosis and joint contractures. RYR1, the gene encoding the calcium release channel of the sarcoplasmic reticulum, is the most common target of mutations linked to human congenital myopathies, a condition often accompanied by skeleton alterations and joint contractures. So far, the link between RYR1 mutations, altered muscle spindles and skeletal defects has not been investigated. To this end, we investigated heterozygous mice carrying recessive Ryr1 mutations isogenic to those present in a severely affected child. Here, we show that: (i) the RyR1 protein localizes to the polar regions of intrafusal fibres and exhibits a doubled row distribution pattern, typical for junctional sarcoplasmic reticulum proteins; (ii) muscle spindles of compound heterozygous mice show structural defects; and (iii) in intrafusal muscle fibres from dHT mice, RyR1-mediated Ca2+ release is significantly impaired and RyR1 protein content is reduced by 54%. These results support the hypothesis that Ryr1 mutations not only affect the function of extrafusal muscles, but also might affect that of intrafusal muscles. The latter may be one of the underlying causes of skeletal abnormalities seen in patients affected by recessive RYR1 mutations. KEY POINTS: Dysfunction of muscle spindles leads to abnormal proprioceptor function, which can cause abnormal bone and cartilage development, scoliosis, kyphosis and joint contractures. Muscle spindles contain intrafusal muscle fibres, which are made up of nuclear bag and nuclear chain fibres; the polar regions of intrafusal muscle fibres contain contractile filaments and sarcotubular membranes. Patients with RYR1 mutations often present skeleton alterations and joint contractures from birth. Using the dHT mouse model carrying recessive Ryr1 mutations, we investigated whether muscle spindles from dHT mice show structural defects and altered RyR1 content and function. Our results support the hypothesis that RYR1 mutations also affect the function of intrafusal muscles and this may be one of the underlying causes of the skeletal abnormalities seen in patients.

Keywords:  congenital myopathy; intrafusal muscle fibres; muscle spindles; mutations; ryanodine receptor 1

DOI:  https://doi.org/10.1113/JP287832
Exp Gerontol. 2025 Oct 15. pii: S0531-5565(25)00261-X. [Epub ahead of print] 112932

Spinal motor neuron plasticity after hindlimb unloading in aged mice and its modulation by exercise with TRPM8-mediated cutaneous stimulation.

Kotaro Tamura, Satoshi Sugita, Tadayuki Tokunaga, Tomomi Ishii, Yoshihiko Minegishi, Noriyasu Ota.

  Age-related motor decline is influenced not only by muscle atrophy but also by deterioration of the neuromuscular system. However, the effects of aging and disuse on spinal motor neuron (MN) plasticity remain poorly understood. In this study, we examined how short-term hindlimb unloading (HU)-a disuse model-affects neuromuscular junction (NMJ) integrity and spinal motor neuron (MN) synaptic inputs in young (3 months) and aged (22 months) mice. We also assessed whether TRPM8-mediated skin cooling (SC), which activates MN via spinal interneurons, could enhance neuromuscular recovery when applied during low-intensity treadmill exercise. Two weeks of HU induced comparable muscle atrophy in both age groups; however, motor function, assessed by the beam walking test, declined only in aged mice. NMJs in aged mice showed fragmentation and partial denervation, which were not exacerbated by HU. In contrast, HU significantly reduced the number of C-boutons-cholinergic synaptic inputs on MNs-exclusively in aged mice, indicating selective vulnerability of spinal cholinergic circuits to aging and disuse. Glutamatergic (VGLUT1-positive) inputs declined with age but were unaffected by HU. Notably, exercise combined with TRPM8-mediated SC during reloading restored C-bouton density and improved motor function in aged mice, whereas exercise alone had no effect. These findings suggest that aging and disuse jointly disrupt spinal cholinergic circuits and that TRPM8-mediated cutaneous stimulation can promote recovery of spinal synaptic inputs. Our results identify C-boutons as a potential therapeutic target to mitigate age-related physical decline and highlight SC as a strategy to preserve or restore motor control in older individuals.

Keywords:  Aging; C-bouton; Hindlimb unloading; Motor neuron; TRPM8

DOI:  https://doi.org/10.1016/j.exger.2025.112932
Cells. 2025 Oct 06. pii: 1553. [Epub ahead of print]14(19):

Exercise, Epigenetics, and Body Composition: Molecular Connections.

Ashley Williams, Danielle D Wadsworth, Thangiah Geetha.

  Exercise plays a crucial role in promoting overall health by activating molecular pathways that contribute to the prevention and management of chronic diseases, slowing epigenetic aging, improving body composition, and reducing the risk of obesity. In skeletal muscle, these benefits are largely mediated by exercise-induced transcriptional and epigenetic responses. Recent advances in epigenetics have intensified interest in understanding how physical activity influences long-term health and body composition at the molecular level. Epigenetic modifications, which regulate gene expression without altering the DNA sequence, are key mechanisms in this process. Emerging research has provided deeper insights into the processes such as DNA methylation, histone modification, and non-coding RNAs, and their connection to exercise. While numerous studies have demonstrated the influence of exercise on the epigenome, fewer have directly examined how these molecular changes relate to alterations in fat mass, lean body mass, and other components of body composition. This comprehensive review synthesizes the current evidence on the interplay between exercise, epigenetic regulation, and body composition, with a focus on adolescents and adults. We highlight key genes involved in metabolism, fat storage, muscle development, and epigenetic aging, and explore how their regulation may contribute to individual variability in exercise response. Understanding these molecular pathways may provide valuable insights for optimizing exercise interventions aimed at improving health outcomes across the lifespan.

Keywords:  DNA methylation; body composition; epigenetics; exercise; histone modifications; non-coding RNAs; skeletal muscle

DOI:  https://doi.org/10.3390/cells14191553
Dis Model Mech. 2025 Oct 01. pii: dmm052182. [Epub ahead of print]18(10):

Characterization of a humanized mouse model of Duchenne muscular dystrophy to support the development of genetic medicines.

Kara Braunreiter, Amber Kempton, Maria Katherine Mejia-Guerra, Andrew Murray, Stephen Baine, Kaitlin Adegboye, Alex Haile, Suruchi Jai Kumar Ahuja, Alessandra Fedoce, Chang Liu, Peter Burch, Ami Meda Kabadi.

  Duchenne muscular dystrophy (DMD) is a rare, progressive neuromuscular disease resulting from DMD variants, leading to loss of functional dystrophin. To evaluate human-targeted genetic medicines for functional dystrophin restoration, humanized genetic models containing the full human locus are required. This study characterized the hDMDΔ52/mdx mouse model previously reported by Pickar-Oliver and colleagues. Genomic characterization confirmed complete DMD duplication with identical exon 52 deletion junctions on both copies. Histological analysis showed increased diaphragm fibrosis and skeletal muscle central nuclei in hDMDΔ52/mdx mice versus hDMD/mdx controls. hDMDΔ52/mdx mice demonstrated reduced tibialis anterior specific force, decreased skeletal muscle fiber diameter, decreased resistance to eccentric contraction-induced damage and cardiac defects. Multiple serum biomarkers of disease were identified. Using a CRISPR/Cas9 gene-editing strategy to restore human functional dystrophin protein expression, detectable dystrophin expression in the heart and skeletal muscle and increased resistance to injury in the tibialis anterior muscle were observed. In summary, hDMDΔ52/mdx mice display multiple physiological and functional deficits associated with DMD pathology, which can be restored by human-targeted therapy, confirming the suitability of this model for developing human-targeted genetic medicines.

Keywords:  Duchenne muscular dystrophy; Dystrophin; Gene editing; Mouse model; Preclinical

DOI:  https://doi.org/10.1242/dmm.052182
J Gerontol A Biol Sci Med Sci. 2025 Oct 17. pii: glaf231. [Epub ahead of print]

Sex-specific Phosphoproteome Responses to Calorie Restriction and Insulin in Skeletal Muscle from Older Rats.

Haiyan Wang, Søren Madsen, Elise J Needham, Sean J Humphrey, Amy Zheng, Edward B Arias, Jacqueline Stöckli, Harry B Cutler, David E James, Gregory D Cartee.

  Calorie restriction (CR; calorie intake reduced by ∼20-40% below ad libitum, AL, intake) potentiates skeletal muscle insulin sensitivity during old age by incompletely understood mechanisms. We aimed to identify CR-induced changes in muscle insulin signaling that may explain this enhanced sensitivity. We examined how CR (65% of AL intake for 8-weeks) alters muscle insulin action and signaling in aged rats (24-months-old) of both sexes. We assessed insulin-stimulated glucose uptake (ISGU) in muscle together with deep phosphoproteomic profiling. CR enhanced ISGU in both sexes, with higher ISGU in females regardless of diet. We identified 590 diet-responsive phosphosites, indicating extensive CR-induced remodelling of muscle phosphorylation, particularly within structural and contractile pathways. Strikingly, 70% of these sites were sex-specific. Numerous insulin-responsive sites were identified (193 in females; 107 in males) with 60 overlapping sites. The magnitude of the insulin-effects among all significantly regulated sites correlated between sexes. S1443 phosphorylation on EH domain-binding protein 1-like protein-1 (Ehbp1l1; a potential regulator of Rab proteins that control GLUT4 glucose transporter trafficking) was insulin-responsive in both sexes but only associated to ISGU in females. Personalized phosphoproteomic analysis also identified insulin-responsive sites on Leiomodin-1 (Lmod1) that correlated with ISGU across individuals. Both Lmod1 and Ehbp1l1 have strong genetic association with glycemic traits in humans, reinforcing their translational relevance. This study revealed sex-dependent and sex-independent phosphosignaling mechanisms that associate with muscle insulin responsiveness as well as hundreds of sex-specific, CR-responsive phosphosites. These findings provide a rich resource for future research on CR and insulin sensitivity.

Keywords:  Ehpb1l1; Lmod1; glucose transport; insulin resistance; mTOR

DOI:  https://doi.org/10.1093/gerona/glaf231
Adv Healthc Mater. 2025 Oct 12. e03035

Magnetic Bioprinting and Actuation of Stretchable Muscle Tissue.

Noam Demri, Lise Morizur, Simon Dumas, Giacomo Gropplero, Cécile Martinat, Stéphanie Descroix, Claire Wilhelm.

  Engineering tissues with precise, long-lasting shapes and the capability for mechanical stimulation remains challenging. This study addresses this challenge by developing a next-generation magnetic bioprinting approach to create anisotropic, shape-controlled, scaffold-free, and stretchable skeletal muscle constructs. Murine skeletal muscle cells and human induced pluripotent stem cell-derived skeletal muscle cells, labeled with iron oxide nanoparticles, are magnetically bioprinted into wrench-shaped tissues. Their magnetic properties allow these tissues to be clipped onto magnetic needles, preserving their shape over two weeks of culture while promoting anisotropic differentiation and myoblast fusion. Additionally, the magnetic tissues can be stretched by up to 100%, enhancing their anisotropy and improving muscle maturation. This magnetic toolbox demonstrates significant advancements in muscle tissue engineering, as evidenced by enhanced indicators of myoblast differentiation, including cell fusion, increased myogenic maturation, and contractility. These findings highlight the potential of magnetic-based techniques for developing advanced muscle-on-chip systems and other complex tissue constructs.

Keywords:  bioprinting; magnetic nanoparticles; muscle; stretching; tissue engineering

DOI:  https://doi.org/10.1002/adhm.202503035
PLoS One. 2025 ;20(10): e0334691

Mixed twitch and tetanus electrical stimulation via belt-electrode effectively attenuates denervation-induced muscle atrophy.

Hiroyuki Uno, Mako Isemura, Shohei Kamiya, Ryuji Akimoto, Katsu Hosoki, Shunta Tadano, Karina Kouzaki, Yuki Tamura, Takaya Kotani, Koichi Nakazato.

Belt electrode skeletal muscle stimulation (B-SES) is a method of applying electricity to contract muscles using belt-shaped electrodes. We previously reported that twitch contractions increase mitochondrial synthesis and suppress muscle proteolysis. In contrast, tetanus contraction increases muscle protein synthesis and suppresses muscle proteolysis. This study aimed to determine whether combining twitch- and tetanus-mode stimulations, which are known to differentially regulate mitochondrial and protein synthesis pathways, can more effectively attenuate muscle atrophy induced by denervation. Male Sprague-Dawley rats were subjected to acute or chronic B-SES. In the acute study, animals were assigned to control (CONT), tetanus (60 Hz), or Combined Stimulation (CS: 7-8 Hz for 15 min to 60 Hz for 3 min) groups. Four groups were tested in the chronic study: CONT, denervation (DEN), DEN + 60 Hz, and DEN + CS groups. Acute stimulation resulted in significantly lower muscle glycogen level, increased phosphorylated AMPK and p70S6K in the gastrocnemius muscle (GAS、n = 4) at 60 and CS compared to CONT, with no difference between 60 and CONT. After seven days, both muscle wet weight and cross-sectional area (CSA) were significantly reduced in the DEN group. Although both 60 Hz and CS attenuated atrophy, CS resulted in greater preservation (GAS CSA: DEN + CS, 71% CONT; DEN + 60, 61% CONT). In conclusion, the combination of different stimulation modalities (frequencies) was more effective than continuous tetanus stimulation in preventing denervation-induced muscle atrophy owing to an increase in muscle protein synthesis and inhibition of mitochondrial reduction.

DOI: https://doi.org/10.1371/journal.pone.0334691
Nat Commun. 2025 Oct 15. 16(1): 9162

Nuclear entry of AS160 as a transcriptional regulator of satellite cells for muscle regeneration.

Xinyu Yang, Ye Cao, Yuwei Zhou, Qing Yao, Ping Rong, Xu Wang, Qiaoli Chen, Weikuan Feng, Li Zhang, Heng Ai, Dahai Zhu, Lei Fang, Tong-Jin Zhao, Xinhua Ye, Hong-Yu Wang, Shuai Chen.

Dysfunction of muscle satellite cells is linked to diabetic myopathy. The mechanisms vitiating muscle satellite cell proliferative activity in diabetes are not well understood. Here, we show that AS160, a key cytosolic Rab-GTPase activating protein (RabGAP) in insulin signaling, is a moonlighting protein regulating muscle satellite cell proliferation as a transcriptional co-factor. Deletion of AS160, but not its GAP-inactive mutation, impairs muscle satellite cell proliferation and consequent muscle regeneration, and exacerbates age-related sarcopenia. Mechanistically, Thr642 phosphorylation of AS160 promotes its translocation into the nucleus where AS160 functions as a co-factor of Signal Transducer and Activator of Transcription 3 (STAT3). AS160 binds to STAT3 to enhance the transcription of myogenic cascades and consequent muscle satellite cell proliferation. Disruption of the AS160-STAT3 interaction, or inhibition of AS160-Thr642 phosphorylation, inhibits muscle satellite cell proliferation and impairs muscle regeneration. Together, our findings reveal a moonlighting function of AS160 as a transcriptional co-factor in the nucleus, and have therapeutic implications for muscle regeneration.

DOI: https://doi.org/10.1038/s41467-025-64220-5
Proc Natl Acad Sci U S A. 2025 Oct 21. 122(42): e2513599122

Synthetic bottlebrush block copolymer prevents disease onset in Duchenne muscular dystrophy.

Houda Cohen, Addeli Bez Batti Angulski, Joseph D Quick, Taylor S Kuebler, Brian R Thompson, John Bauer, Dongwoo Hahn, DeWayne Townsend, Joseph F Hassler, Benjamin J Hackel, Timothy P Lodge, Yuk Y Sham, Frank S Bates, Joseph M Metzger.

  Duchenne muscular dystrophy (DMD) is a fatal genetic disease of progressive muscle deterioration with no cure. DMD treatment requires a body-wide approach to target all diseased striated muscles: limb, respiratory, and heart. To address this, we focus studies on blocking the onset of muscle membrane instability, the primary defect in DMD, as a promising yet unmet druggable target. Here, data show the remarkable potency of a synthetic poly(ethylene oxide)/poly(propylene oxide) side chain-based bottlebrush block copolymer, ~150,000 times more potent than linear polymers, to rapidly restore contractile function to DMD skeletal muscle fibers in vitro. Strikingly, upon bottlebrush polymer delivery to DMD animals, results show highly efficacious prevention of the onset of skeletal and diaphragm muscle damage and the blocking of stress-induced cardiac injury and death in vivo. These data suggest bottlebrush polymers as a potent stand-alone muscle membrane-stabilizing therapeutic for DMD. Given DMD's early childhood onset, together with newborn screening for DMD, bottlebrush macromolecules could be envisioned as an early therapy to preserve and protect viable muscle and potentially for other acquired or inherited diseases involving membrane damage.

Keywords:  Duchenne muscular dystrophy; bottlebrush block copolymer; membrane damage

DOI:  https://doi.org/10.1073/pnas.2513599122
J Physiol. 2025 Oct 16.

Extreme physical inactivity alters iron metabolism: mechanisms and health issues for astronauts and bedridden patients.

Mathieu Horeau, Maelys Auffret, Olivier Loréal, Frédéric Derbré.

  Iron is a biologically indispensable yet potentially harmful element: essential for numerous metabolic processes but toxic in excess, potentially leading to organ damage. Under conditions of extreme physical inactivity, such as microgravity or prolonged bed-rest, physical deconditioning occurs, adversely affecting functional capacities and health. Anaemia and muscle atrophy may contribute to systemic iron redistribution, as red blood cells and skeletal muscle collectively concentrate most body iron. Here we summarize a decade of research conducted in rodent and human ground-based models to investigate how extreme physical inactivity alters systemic and cellular iron homeostasis, and explore the underlying mechanisms. During the first days an increase in plasma iron availability occurs in both men and premenopausal women, likely due to accelerated erythrophagocytosis in spleen and redistribution of iron from degraded erythrocytes. Despite the rapid onset of muscle fibre atrophy under these conditions, skeletal muscle appears to accumulate iron rather than release it and therefore may not necessarily contribute to the systemic redistribution of iron. Increased circulating hepcidin levels observed during this early phase could contribute to both redistribution and tissue iron sequestration. After several weeks of exposure plasma iron availability remains elevated in men exposed to extreme physical inactivity, potentially exposing to chronic tissue iron accumulation. In contrast a return to baseline seems to occur in premenopausal women. These findings point to a broad and persistent redistribution of iron metabolism in men in response to extreme physical inactivity. However the long-term effects on iron metabolism in women remain poorly understood and warrant further investigation.

Keywords:  disuse; haemoglobin; skeletal muscle; spaceflight; trace elements

DOI:  https://doi.org/10.1113/JP289149
JCI Insight. 2025 Oct 14. pii: e189286. [Epub ahead of print]

Lack of myotubularin phosphatase activity is the main cause of X-linked Myotubular Myopathy.

Foteini Moschovaki-Filippidou, Christine Kretz, David Reiss, Gaetan Chicanne, Bernard Payrastre, Jocelyn Laporte.

  The MTM1 gene encodes myotubularin (MTM1), a phosphatidylinositol 3-phosphate (PI(3)P) lipid phosphatase. Loss-of-function mutations in MTM1 cause X-linked myotubular myopathy (XLMTM), a severe congenital myopathy with no available cure and a poorly understood pathomechanism. The importance of MTM1 enzymatic activity and its PI(3)P substrate in physiology under normal conditions and in XLMTM is unclear. We generated the Mtm1 KI C375S mice in which the endogenous MTM1 was converted to a phosphatase-dead protein. Mutant mice survived a median of 12 weeks and demonstrated progressively impaired motor skills. Observed muscle hypotrophy and reduced force production compared to their WT littermates (~3.9-fold reduction in absolute maximal force) were responsible for these severe phenotypes. A significantly higher level of PI(3)P was found in the muscle of Mtm1 KI C375S mice. Muscle histology and molecular characterization revealed XLMTM hallmarks, with alteration of the mTOR and autophagy pathways correlating with muscle hypotrophy, and abnormal myofiber intracellular organization correlating with impaired muscle force. Overall, this study reveals the importance of MTM1 phosphatase activity and related PI(3)P substrate for postnatal muscle maintenance, and highlights the significance of MTM1 phosphatase activity in the development of X-linked myotubular myopathy.

Keywords:  Genetics; Mitochondria; Mouse models; Muscle biology; Skeletal muscle

DOI:  https://doi.org/10.1172/jci.insight.189286
J Cachexia Sarcopenia Muscle. 2025 ;16(5): e70103

The Novel MuRF2 Target SNX5 Regulates PKA Activity Through Stabilization of RI-α and Controls Myogenic Differentiation.

Ning Li, Jida Hamati, Yi Li, Björn Brinschwitz, Mohamed Ghait, Elisa Martin, Dörte Lodka, Elke Hammer, Britta Fielitz, Uwe Völker, Gunnar Dittmar, Thomas Sommer, Friedrich C Luft, Jens Fielitz.

   BACKGROUND: Muscle RING finger (MuRF) proteins are striated muscle-specific E3 ubiquitin ligases essential for muscle homeostasis. Whereas MuRF1 is well known for its role in muscle atrophy, MuRF2 and MuRF3 contribute to microtubule stabilization, influencing muscle differentiation and function. Their cooperative functions in regulating myogenesis are unclear. This study aimed to identify novel MuRF2 and MuRF3 interaction partners and investigate their function in myogenic differentiation.
METHODS: Interaction partners of MuRF2 and MuRF3 were identified using stable isotope labelling with amino acids in cell culture (SILAC), followed by affinity purification and quantitative mass spectrometry (AP-MS). Mechanistic analyses included co-immunoprecipitation, domain mapping, ubiquitination assays, protein stability measurements and endosome isolation. Myogenic differentiation was evaluated by immunocytochemistry, qRT-PCR and western blotting. Functional effects were assessed using CRISPR-Cas9-mediated knockout and siRNA silencing.
RESULTS: We identified sorting nexin 5 (SNX5), a BAR and PX domain-containing retromer component involved in retrograde vesicular transport, as a novel MuRF2 and MuRF3 binding partner. Both coiled-coil domains of MuRF3 were required for SNX5 binding, and the BAR domain of SNX5 mediated interaction with MuRF2 and MuRF3. Immunofluorescence staining demonstrated MuRF3-SNX5 interaction and colocalization on early endosomes along microtubules in myocytes. MuRF2 promoted ubiquitination of SNX5 at lysines 290 and 324, leading to proteasomal degradation, whereas MuRF3 counteracted this effect. Mass spectrometry revealed the protein kinase A regulatory subunit (PKA-RI-α) as cargo of SNX5-coated early endosomes in myocytes. SNX5 knockout (SNX5-KO) reduced RI-α stability in myocytes, enhanced PKA activity and increased HDAC5 degradation via the autophagy-lysosomal pathway, leading to MEF2-mediated upregulation of myostatin. SNX5-KO impaired myogenesis, with significant reductions in myogenin/Myog (p < 0.005), myomaker/Mymk (p < 0.01), myomerger/Mymx (p < 0.005) and MyHC isoforms Myh2 and Myh4 (p < 0.01). Myostatin treatment mimicked the SNX5-KO phenotype, reducing fast-twitch MyHC isoforms Myh1, Myh2, Myh3 and Myh4 (p < 0.05 for all) and significantly lowering Myomaker, Myomerger and MyHC expression throughout differentiation (p < 0.05 for all). Morphologically, myostatin-treated cells were shorter and thinner and had fewer nuclei. Quantification showed reduced differentiation and fusion indices (p < 0.001) and fewer nuclei per myosin-positive cell (p < 0.01).
CONCLUSIONS: MuRF2 and MuRF3 exert opposing effects on SNX5-mediated retrograde transport, influencing PKA signalling and myogenic differentiation. SNX5 stabilizes RI-α within early endosomes, facilitating ordered myogenic differentiation. Our findings expand the known functions of MuRF proteins beyond proteasomal degradation and identify SNX5 as a key regulator of PKA activity in muscle cells. These insights may provide novel therapeutic targets for muscle-related disorders.

Keywords:  RI‐α; muscle RING‐finger protein; myostatin; protein kinase A; sorting nexin 5

DOI:  https://doi.org/10.1002/jcsm.70103
Int J Mol Sci. 2025 Oct 03. pii: 9652. [Epub ahead of print]26(19):

The Diagnostic Potential of Urinary Titin Fragment in Neuromuscular Diseases.

Andrea Sipos, Dávid Varga, Endre Pál.

  Biomarkers are important for the diagnosis and follow-up of neuromuscular diseases. Creatine kinase (CK) is a widely used marker of active muscle damage; however, it is not suitable for assessing muscle mass loss. Therefore, additional biomarkers are required to monitor skeletal muscle damage and loss. Titin plays an essential role in the structure and function of muscle fibers. It provides stability and elasticity to the sarcomeres. During sarcomere damage, fragments of titin and other proteins are released from muscle fibers and can be detected in blood and urine. Urinary titin-N fragment (UTN) detection is a noninvasive method for assessing and monitoring the extent of muscle damage. In addition to muscular dystrophies, elevated UTN levels have been observed in patients with sarcopenia. The UTN level increased significantly during eccentric muscle strain, indicating muscle damage, whereas the concentric load was associated with only a minimal increase in UTN. As titin is also present in the heart muscle, UTN can help diagnose cardiomyopathies and predict disease prognosis. In summary, the detection of urinary titin fragments is a promising tool for diagnosing and monitoring neuromuscular and cardiac diseases. While both CK and UTN rise and are related in acute conditions, their relationship is less clear in chronic diseases where muscle tissue damage and muscle mass loss are combined.

Keywords:  biomarker; cardiomyopathy; muscular dystrophy; myopathy; urinary titin

DOI:  https://doi.org/10.3390/ijms26199652
Physiol Rep. 2025 Oct;13(20): e70615

Nicotinamide N-methyltransferase inhibition improves limb function in experimental peripheral artery disease.

Gengfu Dong, Jaewon Choi, Yufen Li, Diana C Muller, Zhuoxin Li, Yangyi E Luo, Terence E Ryan.

  Peripheral artery disease (PAD) impairs limb perfusion, walking ability, and increases the risk of amputation. Although current therapies reduce cardiovascular events, few interventions improve skeletal muscle function in PAD. Nicotinamide adenine dinucleotide (NAD+) metabolism is disrupted in PAD. Thus, it was hypothesized that inhibition of nicotinamide N-methyltransferase (NNMT), an enzyme that diverts precursors from the NAD+ salvage pathway, would improve ischemic limb function. We analyzed NAD+ pathway expression in gastrocnemius muscle from patients with and without PAD using RNA sequencing and proteomics datasets. Single-cell RNA sequencing data were used to assess NNMT expression in muscle stem cells (MuSCs) from BALB/cJ and C57BL/6J mice following hindlimb ischemia (HLI). Male BALB/cJ mice (n = 24) were randomized to either placebo or a NNMT inhibitor (NNMTi) delivered 3 h prior to HLI and daily thereafter. Functional assessments included laser Doppler perfusion imaging, muscle contractility, and a 6-min limb function test. Histological analyses were used to assess myofiber area and capillary density. NNMT mRNA and protein levels were significantly elevated in skeletal muscle from patients with PAD and were persistently elevated in MuSCs from BALB/cJ mice after HLI. NNMTi treatment did not affect limb perfusion recovery or capillary density but trended toward reduced necrosis severity (p = 0.08). Muscle mass and myofiber size were unchanged by treatment; however, NNMTi significantly improved muscle strength (p < 0.0001), power (p = 0.0305), and total work (p = 0.0367) in ischemic limbs compared to placebo. Inhibition of NNMT enhanced ischemic muscle strength and performance in a preclinical model of PAD independent of changes in perfusion.

Keywords:  ischemia; metabolism; skeletal muscle; vascular disease

DOI:  https://doi.org/10.14814/phy2.70615
Redox Biol. 2025 Oct 10. pii: S2213-2317(25)00403-3. [Epub ahead of print]87 103890

Gestational low-protein diet impairs mitochondrial function and skeletal muscle development by inducing immune responses in male offspring.

Atilla Emre Altinpinar, Moussira Alameddine, Ufuk Ersoy, Ioannis Kanakis, Vanja Pekovic-Vaughan, Susan E Ozanne, Katarzyna Goljanek-Whysall, Aphrodite Vasilaki.

  Maternal nutrition is essential for proper fetal and postnatal organ maturation and is linked to the future risk of developing metabolic syndrome, cardiovascular disease, and muscle loss. There is still limited understanding how a low-protein intake during gestation influences skeletal muscle development, inflammation, and the related pathways. This study aimed to investigate the impact of gestational low-protein diet in mice on skeletal muscle development and inflammatory responses in male offspring. Pups born from mothers fed a low-protein diet (LPD) were lactated by normal protein diet (NPD)-fed mothers and maintained on NPD post-weaning (LNN group). Offspring born from mothers fed an NPD and maintained on an NPD during lactation and beyond were used as controls (NNN group). In 21-day-old offspring from protein-restricted mothers, RNA-Seq analysis showed upregulation of immune response-related genes, enriching adaptive immunity pathways. Additionally, LNN group exhibited elevated markers of inflammation, along with disruptions in antioxidant defence balance and macrophages infiltration in gastrocnemius muscle at 3 months of age. Energy metabolism was impaired, as indicated by changes in related proteins and enzymes involved in mitochondrial function. We conclude that gestational LPD adversely affects skeletal muscle development in male offspring.

Keywords:  Immune response; Inflammation; Maternal nutrition; Oxidative stress; Protein restriction; Skeletal muscle

DOI:  https://doi.org/10.1016/j.redox.2025.103890
Nat Commun. 2025 Oct 13. 16(1): 9073

Large-scale serum protein biomarkers discovery associated with function and clinical milestones in Duchenne muscular dystrophy.

N A Ikelaar, A M Barnard, S W M Eng, Shahrzad Hosseini Vajargah, K C H Ha, H E Kan, K Vandenborne, E H Niks, G A Walter, P Spitali.

Duchenne muscular dystrophy (DMD) is characterized by progressive muscle wasting and weakness. Serum proteins may offer insight into disease processes and clinical decline. This observational study uses the 7 K SomaScan® assay to discover serum proteins associated with muscle function and disease milestones. In total 702 serum samples from 153 male patients, collected across two centers (2009-2022), are analyzed. Using linear mixed effects modelling, we evaluate age and corticosteroid use as covariates affecting protein levels and assess protein correlations with longitudinal clinical function. Here we show 318 aptamers (294 proteins) significantly associated with motor performance across the two sites, with most associations found with lower limb functional tests (NSAA, 10MRW, and 6MWT). Thirty-six proteins are associated with milestones including RGMA, ART3, ANTXR2, and DLK1. These proteins show promise as prognostic biomarkers, and could potentially be used for patient stratification in clinical trial design and for monitoring interventions.

DOI: https://doi.org/10.1038/s41467-025-64146-y
Curr Opin Clin Nutr Metab Care. 2025 Oct 06.

The mitochondrial side of frailty.

Emanuele Marzetti, Rosa Di Lorenzo, Anna Picca.

   PURPOSE OF REVIEW: Frailty, a prevalent geriatric condition marked by reduced physiological reserve and greater vulnerability to stressors, is increasingly linked to mitochondrial dysfunction. This review summarizes current evidence on mitochondrial quality control, bioenergetics, and signaling in frailty, with emphasis on biomarker discovery and translational potential.
RECENT FINDINGS: Preclinical and human studies have shown that impaired mitochondrial biogenesis, altered dynamics, and defective mitophagy contribute to frailty, sarcopenia, and immune dysregulation. Frail older adults exhibit reduced mitochondrial DNA content, diminished mitochondrial respiratory capacity, elevated reactive oxygen species generation, and distinctive metabolomic changes. Potential biomarkers include mitochondria-derived vesicles, circulating metabolites, and measures of peripheral blood mononuclear cell respiration, which may enable early detection of functional decline. Multivariate profiling approaches have identified sex-specific and shared molecular signatures converging on mitochondrial pathways. Interventions promoting mitochondrial health, including resistance training and targeted immunomodulation, hold promise in slowing frailty progression.
SUMMARY: Mitochondrial dysfunction lies at the intersection of musculoskeletal, metabolic, and immune changes underpinning frailty. While integrative biomarker panels have defined metabolic signatures, early diagnosis and personalized therapies remain unmet needs. Longitudinal studies are required to establish causality, refine biomarker utility, and guide precision medicine strategies to preserve mitochondrial function, extend healthspan, and improve quality of life in aging populations.

Keywords:  inflammaging; metabolic dysregulation; mitochondrial quality control; oxidative capacity; physical frailty

DOI:  https://doi.org/10.1097/MCO.0000000000001175
Front Pharmacol. 2025 ;16 1669591

Effects of statins on sarcopenia with focus on mechanistic insights and future perspectives.

Xianxu Zhang, Xianghong Wang, Lei Huang, Changlin Zhou, Bin Qian, Zhiqiang Luo, Yanqiang Chen.

  Sarcopenia is an age-related geriatric syndrome characterized by the progressive decline in skeletal muscle mass and function. Its pathogenesis is multifactorial, involving complex interactions between inflammatory responses, oxidative stress, and mitochondrial dysfunction. In recent years, statins, widely used as lipid-lowering agents, have garnered attention for their pleiotropic biological effects, particularly in their potential therapeutic value for anti-inflammatory, antioxidant, microcirculation improvement, and regulation of skeletal muscle metabolism. Statins have demonstrated promising potential in the prevention and treatment of sarcopenia. This review systematically examines the mechanisms through which statins act in sarcopenia, highlighting their pharmacological properties, biological effects, and relevant clinical and preclinical research advancements. Existing studies suggest that moderate statin use may improve the skeletal muscle microenvironment and maintain mitochondrial homeostasis by inhibiting the NF-κB signaling pathway, activating the Nrf2/ARE pathway, and modulating the AMPK/SIRT1/PGC-1α pathways. However, evidence also indicates that high doses or statin use in genetically predisposed individuals may result in mitochondrial dysfunction and muscle toxicity. Based on these findings, this paper proposes a "dose-mechanism-individual background" three-dimensional interaction model and further explores its potential synergistic or antagonistic effects when combined with exercise and nutritional interventions. Future research should prioritize conducting prospective clinical trials with stratified designs to develop individualized, precise intervention strategies, thus advancing the translational application of statins in managing muscle health in aging populations.

Keywords:  drug pleiotropy; inflammation; mitochondrial function; oxidative stress; sarcopenia; statins

DOI:  https://doi.org/10.3389/fphar.2025.1669591
Int J Mol Sci. 2025 Sep 25. pii: 9376. [Epub ahead of print]26(19):

Integrative Transcriptomic and Network-Based Analysis of Neuromuscular Diseases.

Federico García-Criado, Lucia Hurtado-García, Elena Rojano, Álvaro Esteban-Martos, Jesús Pérez-García, Pedro Seoane, Juan A G Ranea.

  Neuromuscular diseases (NMDs) like Duchenne muscular dystrophy (DMD), limb-girdle muscular dystrophy (LGMD), and amyotrophic lateral sclerosis (ALS) are rare, progressive disorders with complex molecular mechanisms. Traditional transcriptomic analyses often struggle to capture systems-level dysregulation, especially given the small sample sizes typical of rare disease studies. Our differential expression analysis of eight public RNA-seq datasets from various cell types in DMD, LGMD, and ALS revealed not only disease-relevant pathways but also unexpected enrichments, such as renal development, suggesting systemic impacts beyond muscle tissue. To address limitations in capturing broader molecular mechanisms, we applied an integrative systems biology approach combining differential expression data, protein-protein interaction (PPI) networks, and network embedding techniques. Comparative functional enrichment revealed shared pathways, including glycosaminoglycan binding in both DMD and FUS-related ALS, implicating extracellular matrix-protein interactions in FUS mutation effects. Mapping DEGs onto the human PPI network and assessing their proximity to causal genes uncovered dysregulated non-coding RNAs, such as PAX8-AS1, SBF2-AS1, and NEAT1, potentially indicating common regulatory roles. We also found candidate genes within disease-proximal clusters, like HS3ST3A1, which may contribute to pathogenesis. Overall, this integrative approach reveals shared transcriptional programs and novel targets, advancing our understanding and potential treatment strategies for NMDs.

Keywords:  differential gene expression; integrative analysis; network-based analysis; neuromuscular diseases

DOI:  https://doi.org/10.3390/ijms26199376
Br J Sports Med. 2025 Oct 13. pii: bjsports-2025-110096. [Epub ahead of print]

Impaired neuromusculoskeletal response to training stimuli associated with low energy availability: a systematic review.

Alexandra F DeJong Lempke, Katherine L Smulligan, Gauri A Desai, Kelsey E Hagan, Jessie R Oldham, Leila Z Islam, Kristin E Whitney.

   OBJECTIVE: Low energy availability (LEA) impairs musculoskeletal health, with emerging evidence of impaired neuromusculoskeletal adaptations to training. We aimed to synthesise the existing evidence examining neuromusculoskeletal responses to training stimuli among individuals with LEA.
DESIGN: Systematic review (PROSPERO 603258).
DATA SOURCES: Six databases were searched on 4 November 2024 (total n=6399; duplicates n=2811; articles to screen n=3388). Search terms included the population and training-related exposures. Two blinded, independent reviewers screened articles using the Covidence web-based tool.
ELIGIBILITY CRITERIA: Original articles written in English with any form of neuromusculoskeletal responses to training stimuli (premeasures and postmeasures) assessed among individuals aged ≥10 years with LEA were included. Study details, methodological quality (Physiotherapy Evidence Database, PEDro scale) and descriptive summaries with change percentages by time point and LEA status were extracted.
RESULTS: 21 studies met inclusion criteria (total participants: 536; 44% males, 56% females; PEDro: 5±2). Inconsistencies in LEA thresholds and criteria, exercise exposures and follow-up time frames precluded pooled analyses. All studies examined changes in lean muscle or fat-free mass (FFM), with seven also examining functional or activity-specific performance, and fewer concurrently examining strength, limb circumference, cellular-level or subjective neuromusculoskeletal measures. 10 studies identified that those with LEA had impaired lean mass/FFM responses (-1% to -5%), and 10 found no substantial changes over time (<1%). Six studies identified functional/sport-specific impairments over time among those with LEA (-4% to -10%). All remaining primary adaptations (strength, limb circumference, cellular-level and subjective measures) were impaired with LEA. These findings are clinically meaningful to consider, particularly for LEA-related impaired responses to rehabilitation targeting muscle hypertrophy and strength.
CONCLUSIONS: Coaches, athletes and clinicians should be aware of the evidence suggesting LEA impairs neuromusculoskeletal training responses.

Keywords:  Muscle; Relative Energy Deficiency in Sport; Strength

DOI:  https://doi.org/10.1136/bjsports-2025-110096
Med Sci Sports Exerc. 2025 Nov 01. 57(11): 2599-2613

Physical Activity and Exercise Intensity Terminology: A Joint American College of Sports Medicine (ACSM) Expert Statement and Exercise and Sport Science Australia (ESSA) Consensus Statement.

David J Bishop, Belinda Beck, Stuart J H Biddle, Keri L Denay, Alessandra Ferri, Martin J Gibala, Samuel Headley, Andrew M Jones, Mary Jung, Matthew J-C Lee, Trine Moholdt, Robert U Newton, Sophia Nimphius, Linda S Pescatello, Nicholas J Saner, Chris Tzarimas.

   ABSTRACT: The evidence supporting the many beneficial effects of physical activity, including exercise, is overwhelming. This has led to numerous publications, statements, and position stands providing evidence-based recommendations to realize the performance-enhancing and therapeutic benefits of exercise. However, one factor hampering research and limiting the adoption of these recommendations is the inconsistent use of terminology associated with different exercise intensities. The goal of this international group of researchers and practitioners, therefore, was to propose standardized physical activity and exercise intensity terminology that has utility across all ages, sexes, genders, physical abilities, conditions, applications, and activities. After much discussion, we propose a standard terminology for physical activity, exercise, and sport and human performance comprising five exercise intensities: very low, low, moderate, high, and very high. We also propose five different descriptors for the perception of effort that align with the five intensities we have suggested: very easy, easy, somewhat hard, hard, and very hard. To enable consistent use of these descriptors with both cardiorespiratory and resistance exercise, we suggest not using descriptors such as light, heavy, weak, or strong (which might be perceived as only being applicable to describing load). We appreciate that some fields have long-established terminology and may be reluctant to change. Nonetheless, at a minimum, the terminology proposed here allows for more clarity when comparing the different exercise intensity descriptors currently used by different fields. Finally, we hope this will be an important "first step" in harmonizing the descriptions of exercise intensity across the fields of physical activity for public health, exercise science, and sport science.

Keywords:  CARDIORESPIRATORY EXERCISE; EXERCISE IS MEDICINE; HEALTH; PRESCRIPTION; PUBLIC HEALTH; RESISTANCE TRAINING; SPORT

DOI:  https://doi.org/10.1249/MSS.0000000000003795