bims-moremu 2025-04-13 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2025–04–13
33 papers selected by
Anna Vainshtein, Craft Science Inc.

The emerging role of exercise preconditioning in preventing skeletal muscle atrophy.
Volitional exercise elicits physiological and molecular improvements in the severe D2.mdx mouse model of Duchenne muscular dystrophy.
Complement pathway activation mediates pancreatic cancer-induced muscle wasting and pathological remodeling.
Adipose-derived small extracellular vesicle miR-146a-5p targets Fbx32 to regulate mitochondrial autophagy and delay aging in skeletal muscle.
Effects of aging and resistance exercise on muscle strength, physiological properties, longevity proteins, and telomere length in SAMP8 mice.
Constitutively Active mTORC1 Signaling Modifies the Skeletal Muscle Metabolome and Lipidome Response to Exercise.
Zebrafish genetic model of neuromuscular degeneration associated with Atrogin-1 expression.
Short-term disuse shapes the adaptive response to resistance training.
Excessive exercise elicits poly (ADP-ribose) Polymerase-1 activation and global protein PARylation driving muscle dysfunction and performance impairment.
In vivo self-renewal and expansion of quiescent stem cells from a non-human primate.
Balancing benefits and risks of aerobic exercise for aging and musculoskeletal health.
Proteomic and Metabolomic Profiling Nominates Druggable Targets and Biomarkers for Pulmonary Arterial Hypertension-Associated Myopathy and Exercise Intolerance.
Sarcopenia: an aging perspective and management options.
Protocol for the isolation of mouse fibro/adipogenic progenitors using magnetic-activated cell sorting.
High-resolution analyses of the secretomes from murine C2C12 cells and primary human skeletal muscle cells reveal distinct differences in contraction-regulated myokine secretion.
Resistance training-induced dihydrotestosterone is blunted in aging rat skeletal muscle.
Revisiting insulin-stimulated hydrogen peroxide dynamics reveals a cytosolic reductive shift in skeletal muscle.
Transposon expression and repression in skeletal muscle.
Extracellular Vesicles Released From Skeletal Muscle Post-Chronic Contractile Activity Increase Mitochondrial Biogenesis in Recipient Myoblasts.
The metabolic enzyme GYS1 condenses with NONO/p54nrb in the nucleus and spatiotemporally regulates glycogenesis and myogenic differentiation.
Autoimmune mechanisms elucidated through muscle acetylcholine receptor structures.
The SIRT1 activator SRT2104 exerts exercise mimetic effects and promotes Duchenne muscular dystrophy recovery.
Dietary advanced glycation end-products exacerbate sarcopenia onset by activating apoptosis through PRMT1-mediated CRTC3 arginine methylation.
Decellularized Extracellular Matrix-Derived Hydrogels: a Powerful Class of Biomaterials for Skeletal Muscle Regenerative Engineering Applications.
Endothelial IGF- 1R deficiency disrupts microvascular homeostasis, impairing skeletal muscle perfusion and endurance: implications for age-related sarcopenia.
Activation of SIK1 by phanginin A regulates skeletal muscle glucose uptake by phosphorylating HADC4/5/7 and enhancing GLUT4 expression and translocation.
Preliminary Insights into the Acute Molecular Responses in C2C12 Myotubes to Hyperthermia and Insulin Treatment.
Strategy for drug repurposing in fibroadipogenic replacement during muscle wasting: application to duchenne muscular dystrophy.
Exerkine-mediated organ interactions: A new interpretation of exercise on cardiovascular function improvement.
Placenta-Derived Mesenchymal Stromal-Like Cells Promote 3D-Engineered Muscle Tissue Differentiation and Vessel Network Maturation.
Alternative splicing of the Snap23 microexon is regulated by MBNL, QKI, and RBFOX2 in a tissue-specific manner and is mis-spliced in striated muscle diseases.
Selection of optimal human myoblasts based on patient related factors influencing proliferation and differentiation capacity.
Quantifying Leg Muscle Disuse Atrophy During Bed Rest Using DXA, CT, and MRI.

Front Physiol. 2025 ;16 1559594

The emerging role of exercise preconditioning in preventing skeletal muscle atrophy.

Xu Zhou, Shiming Li, Lu Wang, Jun Wang, Peng Zhang, Xiaoping Chen.

  Skeletal muscle atrophy, characterized by the loss of muscle mass and function, can result from disuse, aging, disease, drug. Exercise preconditioning-a form of exercise training performed before these harmful threats-induces notable remodeling and extensive biochemical adaptations in skeletal muscle, creating a protective phenotype in muscle fibers, and thus serving as an effective intervention for preventing skeletal muscle atrophy. Here, we review the current understanding relating to how exercise preconditioning protects skeletal muscle from damage caused by inactivity, sarcopenia, disease, or pharmacological intervention, with an emphasis on the cellular mechanisms involved. Key mechanisms highlighted as making a significant contribution to the protective effects of exercise on skeletal muscle fibers include mitochondria; the expression of cytoprotective proteins such as HSP72, SOD2, SESN2, PGC-1α and AMPK; and the regulation of oxidative stress. These findings underscore the potential of exercise preconditioning as a non-pharmacological intervention for preserving muscle mass and function, as well as preventing muscular atrophy, ultimately improving the quality of life for at-risk populations.

Keywords:  disuse atrophy; exercise preconditioning; mitochondrial dysfunction; muscular atrophy; sarcopenia

DOI:  https://doi.org/10.3389/fphys.2025.1559594
J Physiol. 2025 Apr 06.

Volitional exercise elicits physiological and molecular improvements in the severe D2.mdx mouse model of Duchenne muscular dystrophy.

Stephanie R Mattina, Sean Y Ng, Andrew I Mikhail, Derek W Stouth, Cora E Jornacion, Irena A Rebalka, Thomas J Hawke, Vladimir Ljubicic.

  Duchenne muscular dystrophy (DMD) is characterized by progressive muscle wasting and weakness. Prescribed moderate exercise in patients is beneficial, but concerns remain due to the vulnerability of dystrophic muscle to damage. Voluntary wheel running (VWR) is a self-regulated form of exercise that improves muscle health in the typical C57.mdx mouse model of DMD. The purpose of the current study was to investigate the impact of VWR in more severe and clinically relevant D2.mdx mice. Male D2.mdx animals were assigned to a sedentary (D2.mdx SED) or VWR group for 8-10 weeks, whereas DBA/2J wild-type mice served as healthy, sedentary controls (WT SED). Selective skeletal muscle mass and ex vivo force generation were elevated in D2.mdx animals that ran a relatively high volume (D2.mdx High VWR; 1.84 ± 0.84 km/day) compared to low-volume runners (D2.mdx Low VWR; 0.46 ± 0.31 km/day) and SED counterparts. VWR did not exacerbate the dystrophy, and instead attenuated the fibrotic profile compared to D2.mdx SED mice. A VWR-induced shift towards a more slow, oxidative phenotype was also observed. Mitochondrial respiration was reduced in D2.mdx SED animals versus WT SED mice but was partially restored following both Low and High VWR. Finally, a dose-dependent increase in the expression of mitochondrial proteins was observed following VWR, whereas markers of mitochondrial fusion were particularly elevated in D2.mdx High VWR mice. Our results indicate that VWR enhances muscle and mitochondrial biology in D2.mdx animals and further supports the therapeutic role of exercise for DMD patients. KEY POINTS: Duchenne muscular dystrophy (DMD) is a life-limiting neuromuscular disorder characterized by muscle weakness and wasting. Skeletal and cardiac muscle quality is compromised in the dystrophic condition. Exercise promotes functional and molecular adaptations in healthy individuals and mild dystrophic mouse models. However, the effects of exercise in more severe and clinically relevant models of DMD require investigation. A relatively high volume of voluntary wheel running (VWR) augmented selective muscle mass and muscle function without exacerbating the dystrophic pathology in D2.mdx mice. Volitional exercise normalized dystrophic skeletal muscle mitochondrial respiration and upregulated mitochondrial content compared to sedentary counterparts. A higher dose of VWR increased organelle fusion protein expression compared to both healthy and dystrophic sedentary animals, as well as D2.mdx mice that ran lower volumes. Our results provide evidence from a severe preclinical model that volitional exercise may be a safe and efficacious lifestyle-based intervention for DMD.

Keywords:  exercise; mitochondria; neuromuscular disorders; skeletal muscle

DOI:  https://doi.org/10.1113/JP286768
J Clin Invest. 2025 Apr 08. pii: e178806. [Epub ahead of print]

Complement pathway activation mediates pancreatic cancer-induced muscle wasting and pathological remodeling.

Andrew C D'Lugos, Jeremy B Ducharme, Chandler S Callaway, Jose G Trevino, Carl Atkinson, Sarah M Judge, Andrew R Judge.

  Cancer cachexia is a multifactorial condition characterized by skeletal muscle wasting that impairs quality of life and longevity for many cancer patients. A greater understanding of the molecular etiology of this condition is needed for effective therapies to be developed. We performed a quantitative proteomic analysis of skeletal muscle from cachectic pancreatic ductal adenocarcinoma (PDAC) patients and non-cancer controls, followed by immunohistochemical analyses of muscle cross-sections. These data provide evidence of a local inflammatory response in muscles of cachectic PDAC patients, including an accumulation of plasma proteins and recruitment of immune cells into muscle that may promote the pathological remodeling of muscle. Our data further support the complement system as a potential mediator of these processes, which we tested by injecting murine pancreatic cancer cells into wild type (WT) mice, or mice with genetic deletion of the central complement component 3 (C3-/- mice). Compared to WT mice, C3-/- mice showed attenuated tumor-induced muscle wasting and dysfunction and reduced immune cell recruitment and fibrotic remodeling of muscle. These studies demonstrate that complement activation is contributory to the skeletal muscle pathology and dysfunction in PDAC, suggesting that the complement system may possess therapeutic potential in preserving skeletal muscle mass and function.

Keywords:  Cancer; Muscle; Muscle biology; Oncology; Proteomics

DOI:  https://doi.org/10.1172/JCI178806
J Nanobiotechnology. 2025 Apr 10. 23(1): 287

Adipose-derived small extracellular vesicle miR-146a-5p targets Fbx32 to regulate mitochondrial autophagy and delay aging in skeletal muscle.

Mengran Qin, Yan Wang, Zihan Wang, Benchao Dong, Peichuan Yang, Youyi Liu, Qianyun Xi, Jianxiong Ma.

  This study investigates how miR-146a-5p, found in adipose tissue-derived small extracellular vesicles (sEV), influences mitochondrial autophagy and its impact on delaying skeletal muscle aging through the targeting of Fbx32. The findings highlight miR-146a-5p as crucial in skeletal muscle development and aging, influencing autophagy, apoptosis, differentiation, and proliferation, collectively impacting muscle atrophy. In C2C12 cells, miR-146a-5p mimics decreased apoptosis, autophagy, and reactive oxygen species (ROS) levels, while enhancing ATP production; conversely, miR-146a-5p inhibitors had the opposite effects. Furthermore, miR-146a-5p-enriched sEV from adipose tissue alleviated skeletal muscle atrophy in aged mice and promoted muscle fiber growth and repair by regulating mitochondrial autophagy and apoptosis. Mechanistically, miR-146a-5p modulated mitochondrial autophagy in myoblasts by targeting Fbx32 and impacting the FoxO3 signaling pathway. This led to a notable decrease in apoptosis-related gene expression, reduced ROS production, and elevated ATP levels. In conclusion, miR-146a-5p derived from WAT-sEV modulates myoblast autophagy, apoptosis, ROS, and differentiation through the Fbx32/FoxO3 signaling axis. This work presents a novel molecular target and theoretical framework for delaying skeletal muscle aging and developing therapies for skeletal muscle-related disorders.

Keywords:  Aging; Fbx32; Mitochondrial autophagy; miR-146a-5p; sEV

DOI:  https://doi.org/10.1186/s12951-025-03367-1
Biogerontology. 2025 Apr 04. 26(2): 88

Effects of aging and resistance exercise on muscle strength, physiological properties, longevity proteins, and telomere length in SAMP8 mice.

Hanlin Jiang, Shota Inoue, Junpei Hatakeyama, Peng Liu, Tingrui Zhao, Yifan Zhang, Bin Liu, Chunxiao He, Hideki Moriyama.

  Skeletal muscle aging, characterized by progressive declines in muscle mass and strength, correlates with reduced quality of life and increased mortality. Resistance exercise is known to be critical for maintaining skeletal muscle health. This study investigated the effects of aging and resistance exercise on muscle strength, physiological properties, longevity proteins, and telomere length in mice. Twenty-eight-week-old senescence-accelerated mouse prone 8 (SAMP8) mice were used as a model for muscle aging, with senescence-accelerated mouse resistant 1 (SAMR1) mice serving as healthy controls. The mice underwent a 12-week regimen of ladder-climbing training, a form of resistance exercise, performed three days per week. After the training, muscle strength and muscle weight were measured. Levels of the longevity proteins adenosine monophosphate-activated kinase (AMPK), mammalian target of rapamycin (mTOR), and sirtuin 1 (SIRT1) were assessed via western blotting, and telomere length was evaluated by qPCR. SAMP8 mice exhibited significantly lower muscle mass and strength than SAMR1 mice, while resistance exercise attenuated these deficits in SAMP8 mice. SAMP8 mice showed elevated AMPK phosphorylation and SIRT1 levels compared to SAMR1 mice; resistance exercise normalized AMPK phosphorylation levels to approximate those of SAMR1 mice. mTOR activity was significantly reduced in SAMP8 mice but tended to be restored by resistance exercise. Telomere length remained unchanged in SAMP8 mice after resistance exercise compared to their sedentary controls. In conclusion, aging reduces muscle function and disrupts levels of longevity proteins. Resistance exercise mitigates these effects by improving muscle function and restoring molecular balance.

Keywords:  Longevity proteins; Muscle aging; Resistance exercise; Sarcopenia; Telomere length

DOI:  https://doi.org/10.1007/s10522-025-10234-x
J Appl Physiol (1985). 2025 Apr 11.

Constitutively Active mTORC1 Signaling Modifies the Skeletal Muscle Metabolome and Lipidome Response to Exercise.

Hanna Kalenta, Sean P Kilroe, Trevor B Romsdahl, Erik D Marchant, Rosario Maroto, Jennifer J Linares, William K Russell, Blake B Rasmussen.

  A chronic increase in mTORC1 signaling is implicated in reduced longevity, altered metabolism, and mitochondrial dysfunction. Abnormal mTORC1 signaling may also be involved in the etiology of sarcopenia. To better understand the role of mTORC1 signaling in the regulation of muscle metabolism we developed an inducible muscle specific DEPDC5 knockout model which results in constitutively active mTORC1 signaling. We hypothesized that constitutively active mTORC1 signaling in skeletal muscle would alter the metabolomic and lipidomic response to an acute bout of exercise. Wild-type (WT) and DEPDC5 muscle specific knockout (KO) mice were studied at rest and following a 1 hr bout of treadmill exercise. Acute exercise induced an increased reliance on glycolytic and PPP metabolites in the muscle of mice with hyperactive mTORC1. Lipidomic analysis showed an increase in triacylglycerols (TGs) in KO mice. While exercise had a pronounced effect on muscle metabolism, the genotype effect was larger, indicating that constitutively active mTORC1 signaling exerts a dominant influence on metabolic and lipidomic regulation. We conclude that increased mTORC1 signaling shifts muscle metabolism toward greater reliance on non-oxidative energy sources in response to exercise. Understanding the mechanisms responsible for these effects may lead to the development of strategies for restoring proper mTORC1 signaling in conditions such as aging and sarcopenia.

Keywords:  Metabolomics; exercise; lipidomics; mTORC1; muscle

DOI:  https://doi.org/10.1152/japplphysiol.00987.2024
bioRxiv. 2025 Mar 09. pii: 2025.03.07.642048. [Epub ahead of print]

Zebrafish genetic model of neuromuscular degeneration associated with Atrogin-1 expression.

Romain Menard, Elena Morin, Dexter Morse, Caroline Halluin, Marko Pende, Aissette Baanannou, Janelle Grendler, Heath Fuqua, Jijia Li, Laetitia Lancelot, Jessica Drent, Frédéric Bonnet, Joel H Graber, Prayag Murawala, Cédric Dray, Jean-Philippe Pradère, James A Coffman, Romain Madelaine.

The degenerative loss of muscle associated with aging leading to muscular atrophy is called sarcopenia. Currently, practicing regular physical exercise is the only efficient way to delay sarcopenia onset. Identification of therapeutic targets to alleviate the symptoms of aging requires in vivo model organisms of accelerated muscle degeneration and atrophy. The zebrafish undergoes aging, with hallmarks including mitochondrial dysfunction, telomere shortening, and accumulation of senescent cells. However, zebrafish age slowly, and no specific zebrafish models of accelerated muscle atrophy associated with molecular events of aging are currently available. We have developed a new genetic tool to efficiently accelerate muscle-fiber degeneration and muscle-tissue atrophy in zebrafish larvae and adults. We used a gain-of-function strategy with a molecule that has been shown to be necessary and sufficient to induce muscle atrophy and a sarcopenia phenotype in mammals: Atrogin-1 (also named Fbxo32). We report the generation, validation, and characterization of a zebrafish genetic model of accelerated neuromuscular atrophy, the atrofish. We demonstrated that Atrogin-1 expression specifically in skeletal muscle tissue induces a muscle atrophic phenotype associated with locomotion dysfunction in both larvae and adult fish. We identified degradation of the myosin light chain as an event occurring prior to muscle-fiber degeneration. Biological processes associated with muscle aging such as proteolysis, inflammation, stress response, extracellular matrix (ECM) remodeling, and apoptosis are upregulated in the atrofish. Surprisingly, we observed a strong correlation between muscle-fiber degeneration and reduced numbers of neuromuscular junctions in the peripheral nervous system, as well as neuronal cell bodies in the spinal cord, suggesting that muscle atrophy could underly a neurodegenerative phenotype in the central nervous system. Finally, while atrofish larvae can recover locomotive functions, adult atrofish have impaired regenerative capacities, as is observed in mammals during muscle aging. In the future, the atrofish could serve as a platform for testing molecules aimed at treating or alleviating the symptoms of muscle aging, thereby opening new therapeutic avenues in the fight against sarcopenia.

DOI: https://doi.org/10.1101/2025.03.07.642048
J Physiol. 2025 Apr 08.

Short-term disuse shapes the adaptive response to resistance training.

Jacob Andresen.



Keywords:  exercise physiology; muscle adaptation; muscle physiology; muscle plasticity; resistance training

DOI:  https://doi.org/10.1113/JP288530
Mol Metab. 2025 Apr 03. pii: S2212-8778(25)00042-0. [Epub ahead of print] 102135

Excessive exercise elicits poly (ADP-ribose) Polymerase-1 activation and global protein PARylation driving muscle dysfunction and performance impairment.

Barbara M Crisol, Matheus B Rocha, Beatriz Franco, Ana Paula Morelli, Carlos K Katashima, Scylas J A Junior, Fernanda S Carneiro, Renata R Braga, Rafael S Brícola, Graciana de Azambuja, Raul Gobato Costa, Andrea M Esteves, Marcelo A Mori, Maria C G Oliveira, Dennys E Cintra, José R Pauli, Filip J Larsen, Adelino S R da Silva, Eduardo R Ropelle.

Excessive exercise combined with inadequate recovery time may trigger fatigue, performance impairment, and ultimately the overtraining syndrome. The intramyocellular mechanisms involved in the overtraining syndrome remain only partially known. Here, we combined multi-omics analyses from isogenic BXD mouse strains with a mouse model of overtraining and excessive exercise protocol in mice and humans to evaluate the molecular mechanism involved in the performance impairment induced by excessive exercise. We identified that BXD mouse strains with elevated levels of Parp1 gene expression in the skeletal muscle displayed features like overtraining syndrome and abnormal muscle genetic signature. High PARP1 protein content and aberrant PARylation of proteins were detected in the skeletal muscle of overtrained, but not in trained mice. Overtraining syndrome reduced mitochondrial function promoted by exercise training, induced muscle hyperalgesia, reduced muscle fiber size and promoted a similar gene signature of myopathy and atrophy models. Short periods of excessive exercise also increased PARylation in the skeletal muscle of mice and healthy subjects. The pharmacological inhibition of PARP1, using Olaparib, and genetic Parp1 ablation, preserved muscle anatomy and protected against physical performance impairment and other symptoms of the overtraining syndrome in mice. In conclusion, PARP1 excessive activation is related to muscle abnormalities led by long or short periods of excessive exercise, and here we suggest that PARP1 is a potential target in the treatment and prevention of overtraining syndrome.

DOI: https://doi.org/10.1016/j.molmet.2025.102135
bioRxiv. 2025 Mar 28. pii: 2025.03.27.645793. [Epub ahead of print]

In vivo self-renewal and expansion of quiescent stem cells from a non-human primate.

Jengmin Kang, Abhijnya Kanugovi, M Pilar J Stella, Zofija Frimand, Jean Farup, Andoni Urtasun, Shixuan Liu, Anne-Sofie Clausen, Heather Ishak, Summer Bui, Soochi Kim, Camille Ezran, Olga Botvinnik, Ermelinda Porpiglia, Mark Krasnow, Antoine de Morree, Thomas A Rando.

The development of non-human primate models is essential for the fields of developmental and regenerative biology because those models will more closely approximate human biology than do murine models. Based on single cell RNAseq and fluorescence-activated cell sorting, we report the identification and functional characterization of two quiescent stem cell populations (skeletal muscle stem cells (MuSCs) and mesenchymal stem cells termed fibro-adipogenic progenitors (FAPs)) in the non-human primate Microcebus murinus (the gray mouse lemur). We demonstrate in vivo proliferation, differentiation, and self-renewal of both MuSCs and FAPs. By combining cell phenotyping with cross-species molecular profiling and pharmacological interventions, we show that mouse lemur MuSCs and FAPs are more similar to human than to mouse counterparts. We identify unexpected gene targets involved in regulating primate MuSC proliferation and primate FAP adipogenic differentiation. Moreover, we find that the cellular composition of mouse lemur muscle better models human muscle than does macaque ( Macaca fascicularis ) muscle. Finally, we note that our approach presents as a generalizable pipeline for the identification, isolation, and characterization of stem cell populations in new animal models.

DOI: https://doi.org/10.1101/2025.03.27.645793
Exp Gerontol. 2025 Apr 02. pii: S0531-5565(25)00076-2. [Epub ahead of print] 112747

Balancing benefits and risks of aerobic exercise for aging and musculoskeletal health.

Wenduo Liu, Zilin Wang, Yu Gu, Jae Cheol Kim, Sang Hyun Kim.

   BACKGROUND: Long-term exercise is recognized as one of the most effective means of maintaining health after aging, but the relationship between moderate exercise and health in the older population is often overlooked.
OBJECTIVE: The present study was conducted to investigate the effects of excessive endurance exercise on the old mice musculoskeletal system.
RESULTS: The 8 weeks of normal endurance exercise significantly improved skeletal muscle mitochondrial biogenesis and increased femoral osteogenesis in young and old mice. However, the continued accumulation of total exercise volume as the exercise cycle was prolonged resulted in the younger and older mice exhibiting different exercise effects. After 8-16 weeks of moderate-intensity endurance exercise, young mice showed consistent effects of increased mitochondrial biogenesis in skeletal muscle. However, after 12-16 weeks of moderate-intensity endurance exercise, the original effects of exercise-induced mitochondrial biosynthesis were instead impaired in older mice. After 16 weeks of exercise, the aged mice showed a produces consumptive weight loss, an increase inflammation level in adipose tissue, and a decrease in femoral bone mineral density. Interestingly, with an increase in total exercise, the level of skeletal muscle inflammation in old mice did not increase significantly, while a longer exercise cycle reduced the level of skeletal muscle apoptosis, thereby maintaining the state of skeletal muscle.
CONCLUSIONS: Appropriate moderate-intensity endurance exercise has a significant gain in maintaining musculoskeletal health in aged mice. However, excessive endurance impairs the health of the musculoskeletal system in aged mice.

Keywords:  Age-related adaptation; Inflammation; Mitochondria; Moderate-intensity aerobic exercise; Musculoskeletal health

DOI:  https://doi.org/10.1016/j.exger.2025.112747
bioRxiv. 2025 Mar 28. pii: 2025.03.27.644723. [Epub ahead of print]

Proteomic and Metabolomic Profiling Nominates Druggable Targets and Biomarkers for Pulmonary Arterial Hypertension-Associated Myopathy and Exercise Intolerance.

Phablo Abreu, Ryan Moon, Jenna B Mendelson, Todd Markowski, LeeAnn Higgins, Kevin Murray, Candace Guerrero, Jeffrey Blake, Sasha Z Prisco, Kurt W Prins.

Background: Pulmonary arterial hypertension (PAH) is a rare but debilitating condition that causes exercise intolerance and ultimately death. Skeletal muscle derangements contribute to depressed exercise capacity in PAH, but the mechanisms underlying muscle dysfunction including the changes in muscle biology based on fiber type are understudied.
Methods: We evaluated exercise capacity, muscle histopathology, mitochondrial density, mitochondrial proteomics, and metabolomics/lipidomics of quadriceps ( predominately fast fibers ) and soleus ( predominately slow fibers) muscles in the monocrotaline (MCT) rat model of PAH.
Results: MCT rats exhibited impaired exercise capacity. Surprisingly, there were divergent atrophic and metabolic remodeling in the quadriceps and soleus muscles of MCT rats. In the quadriceps , there was a mild atrophic response only in type II fibers. In contrast, both type I and II fibers atrophied in the soleus . Both muscles exhibited fibrotic infiltration, but mitochondrial density was reduced in the quadriceps only. Mitochondrial proteomics and tissue metabolomics/lipidomics profiling demonstrated the two muscles exhibited distinct responses as the quadriceps had impairments in oxidative phosphorylation/fat metabolism and storage of triacylglycerides. However, the soleus showed signs of proteasome deficiencies and alterations in phosphatidylcholine/phosphatidylethanolamine homeostasis. Finally, profiling of metabolites/lipids in the serum identified potential novel biomarkers of exercise intolerance in PAH including the dimethylarginine pathway, cysteine, and triacylglycerides.
Conclusion: Our data suggests differential cachectic and metabolic responses occur in PAH-induced myopathy. We nominate mitochondrial biogenesis and proteasome activation as potential druggable targets for PAH-myopathy.

DOI: https://doi.org/10.1101/2025.03.27.644723
Int J Sports Med. 2025 Apr 08.

Sarcopenia: an aging perspective and management options.

Ana M Teixeira, Shiva E Nosrani, Mohsen Parvani, João Viola, Shaghayegh Mohammadi.

There is no doubt that sarcopenia is one of the most defining characteristics of aging that negatively impacts people's health and quality of life. The condition is characterized by progressive and generalized loss of muscle mass and strength, affecting physical performance. It is part of aging but can be exacerbated by pathophysiological conditions like cancer, and several factors such as a sedentary lifestyle, poor nutrition, chronic diseases, falls and immobilization. Numerous cellular mechanisms have been implicated in its pathogenesis, including hormonal changes, mitochondrial dysfunction, altered apoptotic and autophagic signalling, muscle fiber composition, as well as inflammatory pathways. To prevent sarcopenia, exercise is one of the most effective strategies, as it has a strong influence on both anabolic and catabolic muscle pathways and helps improve skeletal muscle function. A well-rounded, multicomponent exercise program that targets muscle strength, aerobic capacity, and balance is recommended for optimal results. While nutrition is essential for muscle maintenance, relying solely on dietary interventions is unlikely to fully address sarcopenia. Therefore, a combination of adequate nutrition and regular exercise, is recommended to promote muscle health and function. The purpose of this paper is to review sarcopenia from an aging viewpoint and discuss the role of exercise and nutrition as prevention and management options.

DOI: https://doi.org/10.1055/a-2577-2577
STAR Protoc. 2025 Apr 08. pii: S2666-1667(25)00147-9. [Epub ahead of print]6(2): 103741

Protocol for the isolation of mouse fibro/adipogenic progenitors using magnetic-activated cell sorting.

Jinghui Gao, Yaochao Zheng, Aria Sikal, Elijah Sterling, Rachel Hankin, Yao Yao.

  Fibro/adipogenic progenitors (FAPs) are mesenchymal progenitors that support muscle stem cell activation and modulate the extracellular matrix to facilitate muscle regeneration. Here, we present a protocol for the isolation of FAPs from mouse skeletal muscle. We describe steps for performing enzymatic digestion, mechanical dissociation, and magnetic-activated cell sorting (MACS). This protocol enables the isolation of FAPs with high yield and purity, facilitating research on muscle disorders and advancing muscle regeneration strategies.

Keywords:  Cell Biology; Developmental biology; Genetics; Molecular Biology

DOI:  https://doi.org/10.1016/j.xpro.2025.103741
Front Physiol. 2025 ;16 1549316

High-resolution analyses of the secretomes from murine C2C12 cells and primary human skeletal muscle cells reveal distinct differences in contraction-regulated myokine secretion.

Pia Marlene Förster, Julian Hogenkamp, Moira Fee Pottgießer, Christian Binsch, Awovi Didi Humpert, Carolin Laura Brügge, Michelle Isabel Deatc, Regina Ensenauer, Alexandra Chadt, G Hege Thoresen, D Margriet Ouwens, Sonja Hartwig, Stefan Lehr, Hadi Al-Hasani.

  Myokines released by skeletal muscle in response to contraction may contribute to the health-promoting effects of exercise. Previous studies with cultured rodent and human myotubes have revealed highly complex patterns of myokine secretion. However, the commonalities and differences in the secretory response of the different cell models have not been explored, limiting the interpretation of these results. In the present study, we performed a comprehensive analysis of contraction-regulated secretomes using the most commonly used skeletal muscle cell models, cultured murine C2C12 myotubes and satellite cell-derived primary human myotubes (HSkMC). The cells were subjected to low-frequency electrical pulse stimulation (EPS) for 6 h followed by high-resolution mass spectrometry analysis of secreted proteins in the culture medium. We identified 5,710 and 3,285 proteins in the secretomes of C2C12 myotubes and HSkMC, with 80% of human myokines also detected in the murine secretome. Additionally, we found 518 and 336 secreted proteins that were differentially regulated during contraction in murine and human cells, respectively, along with 1,440 and 385 previously unknown potential myokines secreted by murine and human myotubes. Bioinformatic prediction analyses revealed that the majority of the newly identified myokines were secreted via unconventional protein secretion pathways (UPS) in the murine secretome, whereas most novel proteins in the human secretome were secreted via the classical endoplasmic reticulum (ER)-to-Golgi pathway. Moreover, ontology analysis indicates cell type-specific differences in cellular compartments involved in myokine secretion. Collectively, our results provide a comprehensive overview of the secretomes of two of the most commonly used cell models and may provide guidance for further studies of myokines.

Keywords:  C2C12; EPS; HSkMCs; mass spectrometry; muscle contraction; myokines; secretomes

DOI:  https://doi.org/10.3389/fphys.2025.1549316
J Physiol Sci. 2025 Mar 27. pii: S1880-6546(25)00074-5. [Epub ahead of print]75(2): 100019

Resistance training-induced dihydrotestosterone is blunted in aging rat skeletal muscle.

Yung-Li Hung, Akihito Ishigami, Shuichi Machida.

  This study aimed to investigate the influence of aging on steroid hormone production in skeletal muscles in response to resistance training. Male F344 rats, aged 4 months (young) and 22 months (old), were randomized into the sedentary and training groups. The training group performed resistance training by climbing a ladder with a load every three days for eight weeks. After the training period, the flexor hallucis longus muscle was dissection, and muscle steroid hormone levels were analyzed using liquid chromatography-tandem mass spectrometry. We found that resistance training significantly increased muscle mass in young and old rats, although the increase was less pronounced in the latter. In young, trained rats, muscle dihydrotestosterone levels were approximately 35-fold higher compared to sedentary controls (p < 0.01); dihydrotestosterone levels did not differ significantly between sedentary and trained old rats. These findings indicate that resistance training-induced dihydrotestosterone production is blunted in aging rat skeletal muscle.

Keywords:  Aging; Muscle hypertrophy; Resistance training; Steroidogenesis

DOI:  https://doi.org/10.1016/j.jphyss.2025.100019
Redox Biol. 2025 Mar 25. pii: S2213-2317(25)00120-X. [Epub ahead of print]82 103607

Revisiting insulin-stimulated hydrogen peroxide dynamics reveals a cytosolic reductive shift in skeletal muscle.

Carlos Henríquez-Olguín, Samantha Gallero, Anita Reddy, Kaspar W Persson, Farina L Schlabs, Christian T Voldstedlund, Gintare Valentinaviciute, Roberto Meneses-Valdés, Casper M Sigvardsen, Bente Kiens, Edward T Chouchani, Erik A Richter, Thomas E Jensen.

The intracellular redox state is crucial for insulin responses in peripheral tissues. Despite the longstanding belief that insulin signaling increases hydrogen peroxide (H2O2) production leading to reversible oxidation of cysteine thiols, evidence is inconsistent and rarely involves human tissues. In this study, we systematically investigated insulin-dependent changes in subcellular H2O2 levels and reversible cysteine modifications across mouse and human skeletal muscle models. Utilizing advanced redox tools-including genetically encoded H2O2 sensors and non-reducing immunoblotting-we consistently observed no increase in subcellular H2O2 levels following insulin stimulation. Instead, stoichiometric cysteine proteome analyses revealed a selective pro-reductive shift in cysteine modifications affecting insulin transduction related proteins, including Cys179 on GSK3β and Cys416 on Ras and Rab Interactor 2 (RIN2). Our findings challenge the prevailing notion that insulin promotes H2O2 generation in skeletal muscle and suggest that an insulin-stimulated pro-reductive shift modulates certain aspects of insulin signal transduction.

DOI: https://doi.org/10.1016/j.redox.2025.103607
Mob DNA. 2025 Apr 11. 16(1): 18

Transposon expression and repression in skeletal muscle.

Matthew J Borok, Louai Zaidan, Frederic Relaix.

  Transposons and their derivatives make up a major proportion of the human genome, but they are not just relics of ancient genomes. They can still be expressed, potentially affecting the transcription of adjacent genes, and can sometimes even contribute to their coding sequence. Active transposons can integrate into new sites in the genome, potentially modifying the expression of nearby loci and leading to genetic disorders. In this review, we highlight work exploring the expression of transposons in skeletal muscles and transcriptional regulation by the KRAB-ZFP/KAP1/SETDB1 complex. We next focus on specific cases of transposon insertion causing phenotypic variation and distinct muscular dystrophies, as well as the implication of transposon expression in immune myopathies. Finally, we discuss the dysregulation of transposons in facioscapulohumeral dystrophy and aging.

Keywords:  Muscular dystrophy; Skeletal muscle; Transposable elements

DOI:  https://doi.org/10.1186/s13100-025-00352-1
J Extracell Vesicles. 2025 Apr;14(4): e70045

Extracellular Vesicles Released From Skeletal Muscle Post-Chronic Contractile Activity Increase Mitochondrial Biogenesis in Recipient Myoblasts.

Patience O Obi, Tamiris F G Souza, Berkay Özerkliğ, Samira Seif, Benjamin Bydak, Nicholas Klassen, Todd A Duhamel, Adrian R West, Joseph W Gordon, Ayesha Saleem.

  The effect of chronic contractile activity (CCA) on the biophysical properties and functional activity of skeletal muscle extracellular vesicles (Skm-EVs) is poorly understood due to challenges in distinguishing Skm-EVs originating from exercising muscle in vivo. To address this, myoblasts were differentiated into myotubes, and electrically paced (3 h/day, 4 days @ 14 V). CCA evoked an increase in mitochondrial biogenesis in stimulated versus non-stimulated (CON) myotubes as expected. EVs were isolated from conditioned media (CM) from control and stimulated myotubes using differential ultracentrifugation (dUC) and characterised biophysically using tunable resistive pulse sensing (TRPS, Exoid), TEM and western blotting. TEM images confirmed isolated round-shaped vesicles of about 30-150 nm with an intact lipid bilayer. EVs ranged from 98 to 138 nm in diameter, and the mean size was not altered by CCA. Zeta potential and total EV protein yield remained unchanged between groups, and total EV secretion increased after 4 days of CCA. Concomitant analysis of EVs after each day of CCA also demonstrated a progressive increase in CCA-EV concentration, whilst size and zeta potential remained unaltered, and EV protein yield increased in both CON-EVs and CCA groups. CCA-EVs were enriched with small-EVs versus CON-EVs, concomitant with higher expression of small-EV markers CD81, Tsg101 and HSP70. In whole cell lysates, CD63 and ApoA1 were reduced with CCA in myotubes, whereas CD81, Tsg101, Flotillin-1 and HSP70 levels remained unchanged. To evaluate the functional effect of EVs secreted post-CCA, we treated C2C12 myoblasts with all EVs isolated from CON or CCA myotubes after each day of stimulation, and measured cell count, cell viability, protein yield and mitochondrial biogenesis in recipient cells. There was no effect on cell count, viability and protein yield. Myoblasts treated with CCA-EVs exhibited increased mitochondrial biogenesis as indicated by enhanced MitoTracker Red staining, cytochrome c oxidase (COX) activity and protein expression of electron transport chain subunit, CIV-MTCO1. Further, CCA-EV treatment enhanced maximal oxygen consumption rates (OCR) in a dose-dependent manner, and ATP production in treated myoblasts. This increase in maximal OCR was abrogated when CCA-EVs pre-treated with proteinase K were co-cultured with myoblasts, indicating the pro-metabolic effect was likely mediated by transmembrane or peripheral membrane proteins in CCA-EVs. Our data highlight the novel effect of Skm-EVs isolated post-CCA in mediating pro-metabolic effects in recipient cells and thereby transmitting the effects associated with traditional exercise. Further investigation to interrogate the underlying mechanisms involved in downstream cellular metabolic adaptations is warranted.

Keywords:  chronic contractile activity; differential ultracentrifugation; extracellular vesicles; mitochondrial biogenesis; myoblasts; myotubes; skeletal muscle cells

DOI:  https://doi.org/10.1002/jev2.70045
Cell Death Differ. 2025 Apr 08.

The metabolic enzyme GYS1 condenses with NONO/p54nrb in the nucleus and spatiotemporally regulates glycogenesis and myogenic differentiation.

Shujun Peng, Canrong Li, Yifan Wang, Yuguo Yi, Xinyu Chen, Yujing Yin, Fan Yang, Fengzhi Chen, Yingyi Ouyang, Haolun Xu, Baicheng Chen, Haowen Shi, Qingrun Li, Yu Zhao, Lin Feng, Zhenji Gan, Xiaoduo Xie.

Accumulating evidence indicates that metabolic enzymes can directly couple metabolic signals to transcriptional adaptation and cell differentiation. Glycogen synthase 1 (GYS1), the key metabolic enzyme for glycogenesis, is a nucleocytoplasmic shuttling protein compartmentalized in the cytosol and nucleus. However, the spatiotemporal regulation and biological function of nuclear GYS1 (nGYS1) microcompartments remain unclear. Here, we show that GYS1 dynamically reorganizes into nuclear condensates under conditions of glycogen depletion or transcription inhibition. nGYS1 complexes with the transcription factor NONO/p54nrb and undergoes liquid-liquid phase separation to form biomolecular condensates, leading to its nuclear retention and inhibition of glycogen biosynthesis. Compared to their wild-type littermates, Nono-deficient mice exhibit exercise intolerance, higher muscle glycogen content, and smaller myofibers. Additionally, Gys1 or Nono deficiency prevents C2C12 differentiation and cardiotoxin-induced muscle regeneration in mice. Mechanistically, nGYS1 and NONO co-condense with the myogenic transcription factor MyoD and preinitiation complex (PIC) proteins to form transcriptional condensates, driving myogenic gene expression during myoblast differentiation. These results reveal the spatiotemporal regulation and subcellular function of nuclear GYS1 condensates in glycogenesis and myogenesis, providing mechanistic insights into glycogenoses and muscular dystrophy.

DOI: https://doi.org/10.1038/s41418-025-01509-4
Cell. 2025 Apr 02. pii: S0092-8674(25)00277-6. [Epub ahead of print]

Autoimmune mechanisms elucidated through muscle acetylcholine receptor structures.

Huanhuan Li, Minh C Pham, Jinfeng Teng, Kevin C O'Connor, Colleen M Noviello, Ryan E Hibbs.

  Skeletal muscle contraction is triggered by acetylcholine (ACh) binding to its ionotropic receptors (AChRs) at neuromuscular junctions. In myasthenia gravis (MG), autoantibodies target AChRs, disrupting neurotransmission and causing muscle weakness. While treatments exist, variable patient responses suggest pathogenic heterogeneity. Progress in understanding the molecular basis of MG has been limited by the absence of structures of intact human muscle AChRs. Here, we present high-resolution cryoelectron microscopy (cryo-EM) structures of the human adult AChR in different functional states. Using six MG patient-derived monoclonal antibodies, we mapped distinct epitopes involved in diverse pathogenic mechanisms, including receptor blockade, internalization, and complement activation. Electrophysiological and binding assays revealed how these autoantibodies directly inhibit AChR channel activation. These findings provide critical insights into MG immunopathogenesis, uncovering unrecognized antibody epitope diversity and modes of receptor inhibition, and provide a framework for developing personalized therapies targeting antibody-mediated autoimmune disorders.

Keywords:  acetylcholine receptor; autoantibodies; autoimmune disease; cryoelectron microscopy; electrophysiology; ion channels; muscle weakness; myasthenia gravis; structural biology

DOI:  https://doi.org/10.1016/j.cell.2025.03.004
Cell Death Dis. 2025 Apr 07. 16(1): 259

The SIRT1 activator SRT2104 exerts exercise mimetic effects and promotes Duchenne muscular dystrophy recovery.

Matteo Giovarelli, Silvia Zecchini, Silvia Rosanna Casati, Laura Lociuro, Oriola Gjana, Luca Mollica, Elena Pisanu, Harcel Djaya Mbissam, Ornella Cappellari, Chiara De Santis, Alessandro Arcari, Anne Bigot, Giuditta Clerici, Elisabetta Catalani, Simona Del Quondam, Annapaola Andolfo, Clarissa Braccia, Maria Grazia Cattaneo, Cristina Banfi, Dario Brunetti, Emanuele Mocciaro, Annamaria De Luca, Emilio Clementi, Davide Cervia, Cristiana Perrotta, Clara De Palma.

Duchenne muscular dystrophy (DMD) is a devastating genetic disorder, whose management is still a major challenge, despite progress in genetic and pharmacological disease-modifying treatments have been made. Mitochondrial dysfunctions contribute to DMD, however, there are no effective mitochondrial therapies for DMD. SIRT1 is a NAD+-dependent deacetylase that controls several key processes and whose impairment is involved in determining mitochondrial dysfunction in DMD. In addition to well-known resveratrol, other potent selective activators of SIRT1 exist, with better pharmacokinetics properties and a safer profile. Among these, SRT2104 is the most promising and advanced in clinical studies. Here we unveil the beneficial effects of SRT2104 in flies, mice, and patient-derived myoblasts as different models of DMD, demonstrating an anti-inflammatory, anti-fibrotic, and pro-regenerative action of the drug. We elucidate, by molecular dynamics simulations, that a conformational selection mechanism is responsible for the activation of SIRT1. Further, the impact of SRT2104 in reshaping muscle proteome and acetylome profiles has been investigated, highlighting effects that mimic those induced by exercise. Overall, our data suggest SRT2104 as a possible therapeutic candidate to successfully counteract DMD progression.

DOI: https://doi.org/10.1038/s41419-025-07595-z
Cell Mol Life Sci. 2025 Apr 07. 82(1): 142

Dietary advanced glycation end-products exacerbate sarcopenia onset by activating apoptosis through PRMT1-mediated CRTC3 arginine methylation.

Tian-Jin Huang, Shu Shang, Qin Wan, Qiang Li, Yang-Jingsi Li, Jin-Na Zheng, Fa-Xiu Chen.

   BACKGROUND: Sarcopenia, the age-related decline in muscle mass and function, poses a major health risk to the elderly population. Although dietary advanced glycation end-products (AGEs) have been implicated in worsening sarcopenia, the precise molecular mechanisms remain unclear.
METHODS: A sarcopenia animal model was established by feeding a high AGE diet to C57BL/6 mice. Muscle function and mass were assessed using grip strength tests, and rotarod tests. Proteomic analysis was used to identify differentially expressed proteins. Immunoprecipitation, mass spectrometry, and co-immunoprecipitation were employed to investigate protein interactions both in vivo and in vitro. Quantitative reverse transcription PCR and Western blotting were conducted to measure gene and protein expression levels.
RESULTS: Our results revealed that dietary AGEs accelerated the onset of sarcopenia in mice by triggering apoptosis. Proteomic analysis showed a marked upregulation of protein arginine methyltransferase 1 (PRMT1) in the muscle tissues of mice fed a high AGE diet. PRMT1 mediated the arginine methylation of CREB-regulated transcription coactivator 3 (CRTC3) at the R534 site within its transactivation domain, leading to CRTC3 activation. The activated CRTC3, together with Forkhead box O3a (FOXO3a), transactivated the BAX (BCL2 associated X) gene, initiating Bax downstream signaling, promoting apoptosis in muscle cells, and contributing to muscle atrophy. Inhibition of PRMT1 prevented CRTC3 methylation and suppressed Bax-mediated apoptotic signaling in vitro. Moreover, in vivo treatment with PRMT1 and Bax inhibitors significantly attenuated AGE-induced sarcopenia in mice.
CONCLUSION: PRMT1-mediated CRTC3 arginine methylation plays a critical role in AGE-induced sarcopenia and suggests potential therapeutic targets for preventing sarcopenia progression.

Keywords:  Apoptosis; Arginine methylation; Bax; CRTC3; FOXO3a; PRMT1; Sarcopenia

DOI:  https://doi.org/10.1007/s00018-025-05657-1
Regen Eng Transl Med. 2025 Mar;11(1): 39-63

Decellularized Extracellular Matrix-Derived Hydrogels: a Powerful Class of Biomaterials for Skeletal Muscle Regenerative Engineering Applications.

Mohammed A Barajaa, Debolina Ghosh, Cato T Laurencin.

   Purpose: The extracellular matrix (ECM) is a complicated milieu consisting of structural and functional molecules secreted by the resident cells that provides an optimal microenvironmental niche for enhanced cell adhesion, growth, differentiation, and tissue formation and maturation. For decades, ECM bio-scaffolds prepared from decellularized tissues have been used to promote skeletal muscle regeneration; however, it was recently discovered that these decellularized ECM (dECM) materials can be further processed into hydrogels, thus expanding the potential applications of dECM materials in skeletal muscle regenerative engineerisng (SMRE). This review article highlights the recent advances in dECM-derived hydrogels toward skeletal muscle regeneration and repair.
Method: We screened articles in PubMed and bibliographic search using a combination of keywords. Relevant and high-cited articles were chosen for inclusion in this narrative review.
Results: Here, we discuss the skeletal muscle ECM's structure, function, and biochemical composition with emphasis on the role of the ECM during skeletal muscle embryogenesis, growth, development, and repair. Furthermore, we review various hydrogels used to promote skeletal muscle regeneration. We also review the current applications of dECM-derived hydrogels toward SMRE. Finally, we discuss the clinical translation potential of dECM-derived hydrogels for skeletal muscle regeneration and repair and their potential clinical considerations in the future.
Conclusion: Although much progress has been made in the field of dECM-derived hydrogels toward SMRE, it is still in its nascent stage. We believe improving and standardizing the methods of decellularization, lowering the immunogenicity of dECMs, and carrying out in vivo investigations in large animal models would advance their future clinical applications.
Lay Summary: Researchers have discovered an effective way to turn tissue materials into jelly-like substances known as extracellular matrix (ECM)-derived hydrogels. These ECM-derived hydrogels can help muscles heal better after serious injuries. They can be injected into gaps or used to guide muscle growth in the lab or body. This review article explains how these ECM-derived hydrogels are made and how they can be used to improve muscle healing. It also discusses their possible use in clinics and what needs to be considered before using them for medical treatments.

Keywords:  Decellularization; ECM-derived hydrogels; Injectable hydrogels; Muscle regeneration; Volumetric muscle loss

DOI:  https://doi.org/10.1007/s40883-023-00328-8
Geroscience. 2025 Apr 08.

Endothelial IGF- 1R deficiency disrupts microvascular homeostasis, impairing skeletal muscle perfusion and endurance: implications for age-related sarcopenia.

Adam Nyul-Toth, Santny Shanmugarama, Roland Patai, Rafal Gulej, Janet Faakye, Dorina Nagy, Mark Nagykaldi, Tamas Kiss, Tamas Csipo, Madison Milan, Shoba Ekambaram, Sharon Negri, Raghavendra Y Nagaraja, Anna Csiszar, Jacob L Brown, Holly Van Remmen, Anna Ungvari, Andriy Yabluchanskiy, Stefano Tarantini, Zoltan Ungvari.

  Aging is associated with a progressive decline in circulating insulin-like growth factor- 1 (IGF- 1) levels in humans, which has been implicated in the pathogenesis of sarcopenia. IGF- 1 is an anabolic hormone that plays a dual role in maintaining skeletal muscle health, acting both directly on muscle fibers to promote growth and indirectly by supporting the vascular network that sustains muscle perfusion. However, the microvascular consequences of IGF- 1 deficiency in aging muscle remain poorly understood. To elucidate how impaired IGF- 1 input affects skeletal muscle vasculature, we examined the effects of endothelial-specific IGF- 1 receptor (IGF- 1R) deficiency using a mouse model of endothelial IGF- 1R knockdown (VE-Cadherin-CreERT2/Igf1rf/f mice). These mice exhibited significantly reduced skeletal muscle endurance and attenuated hyperemic response to acetylcholine, an endothelium-dependent vasodilator. Additionally, they displayed microvascular rarefaction and impaired nitric oxide-dependent vasorelaxation, indicating a significant decline in microvascular health in skeletal muscle. These findings suggest that endothelial IGF- 1R signaling is critical for maintaining microvascular integrity, muscle perfusion, and function. Impaired IGF- 1 input to the microvascular endothelium may contribute to reduced muscle blood flow and exacerbate age-related sarcopenia. Enhancing vascular health by modulating IGF- 1 signaling could represent a potential therapeutic strategy to counteract age-related muscle decline.

Keywords:  Aging; Claudication; Endothelial dysfunction; IGF- 1; IGF- 1R; Insulin-like growth factor- 1; Microvasculature; Sarcopenia; Skeletal muscle; Vascular function

DOI:  https://doi.org/10.1007/s11357-025-01653-2
Nat Prod Bioprospect. 2025 Apr 07. 15(1): 24

Activation of SIK1 by phanginin A regulates skeletal muscle glucose uptake by phosphorylating HADC4/5/7 and enhancing GLUT4 expression and translocation.

Yu Shi, Xing-de Wu, Yanli Liu, Yu Shen, Hui Qu, Qin-Shi Zhao, Ying Leng, Suling Huang.

  Salt-inducible kinase 1 (SIK1) participates in various physiological processes, yet its involvement in regulating skeletal muscle glucose uptake remains unclear. Previously, we showed that phanginin A, a natural compound isolated from Caesalpinia sappan Linn, activated SIK1 to suppress gluconeogenesis in hepatocytes. Here, we aimed to elucidate the effects of SIK1 on skeletal muscle glucose uptake by using phanginin A. The C2C12 myotubes were incubated with phanginin A and then glucose uptake, mRNA levels, membrane GLUT4 content, phosphorylation levels of proteins in SIK1/HDACs and Akt/AS160 signaling pathways were determined. Phanginin A significantly promoted glucose uptake, while the pan-SIK inhibitor or knocking down SIK1 expression abolished the promotion. Further exploration showed that phanginin A enhanced GLUT4 mRNA levels by increasing histone deacetylase (HDAC) 4/5 phosphorylation and MEF2a mRNA and protein level, and knocking down SIK1 blocked these effects. Additionally, phanginin A induced HDAC7 phosphorylation, upregulated the junction plakoglobin (JUP) expression and Akt/AS160 phosphorylation. Knocking down JUP or SIK1 both attenuated the phanginin A-induced Akt/AS160 signaling and glucose uptake, suggesting that activation of SIK1 by phanginin A inactivated HDAC7 to increase JUP expression and Akt/AS160 phosphorylation, led to upregulation of GLUT4 translocation and glucose uptake. In vivo study showed that phanginin A increased phosphorylation levels of SIK1, HDAC4/5/7, Akt/AS160, and gene expression of MEF2a, GLUT4 and JUP, accompanied by elevated membrane GLUT4 and glycogen content in gastrocnemius muscle of C57BL/6 J mice, indicating enhanced glucose utilization. These findings reveal a novel mechanism that SIK1 activation by phanginin A stimulates skeletal muscle glucose uptake through phosphorylating HADC4/5/7 and the subsequent enhancement of GLUT4 expression and translocation.

Keywords:  Class IIa HDACs; GLUT4; Glucose uptake; Phanginin A; SIK1; Skeletal muscle

DOI:  https://doi.org/10.1007/s13659-025-00504-z
bioRxiv. 2025 Mar 28. pii: 2025.03.26.644592. [Epub ahead of print]

Preliminary Insights into the Acute Molecular Responses in C2C12 Myotubes to Hyperthermia and Insulin Treatment.

Irene C Turnbull, Ross Gillette, Venugopalan D Nair, Angelo D Gaitas.

This study investigates the differential gene expression in an immortalized cell line of mouse skeletal myoblasts (C2C12) derived myotube cells subjected to hyperthermia (40C) with and without insulin treatment to elucidate the impact of thermal stress on skeletal muscle physiology. Hyperthermia, which occurs during intense physical activity or environmental heat exposure, is known to challenge muscle homeostasis and influence metabolic function. mRNA sequencing revealed that hyperthermia robustly altered gene expression upregulating key genes involved in glycolysis, oxidative phosphorylation, heat shock response, and apoptosis. These changes are suggestive of an elevated metabolic state and enhanced cellular stress; however, these results remain preliminary without complementary protein or metabolic assays. Notably, insulin treatment moderated many of the hyperthermia induced transcriptional alterations, particularly affecting genes linked to glucose uptake and metabolism. Together, these findings provide hypothesis generating insights into the interplay between thermal stress and insulin signaling in C2C12 myotubes, and they underscore potential targets for future mechanistic studies.

DOI: https://doi.org/10.1101/2025.03.26.644592
Front Cell Dev Biol. 2025 ;13 1505697

Strategy for drug repurposing in fibroadipogenic replacement during muscle wasting: application to duchenne muscular dystrophy.

Izzy Matthews, Priyanka Mehra, Xavier Suárez-Calvet, Patricia Piñol-Jurado, Dan Cox, Vellia Justian, Ana Carrasco-Rozas, Zoe Laidler, Andrew Bowey, Paul Rushton, Susana López-Fernández, Jordi Díaz-Manera, Esther Fernández-Simón.

   Background: Understanding the cell functionality during disease progression or drugs' mechanism are major challenges for precision medicine. Predictive models describing biological phenotypes can be challenging to obtain, particularly in scenarios where sample availability is limited, such as in the case of rare diseases. Here we propose a new method that reproduces the fibroadipogenic expansion that occurs in muscle wasting.
Methods: We used immortalized fibroadipogenic progenitor cells (FAPs) and differentiated them into fibroblasts or adipocytes. The method successfully identified FAPs cell differentiation fate using accurate measurements of changes in specific proteins, which ultimately constitute a valid cellular in vitro platform for drug screening. Results were confirmed using primary FAPs differentiation as well as comparison with omics data from proteomics and genomic studies.
Results: Our method allowed us to screen 508 different drugs from 2 compounds libraries. Out of these 508, we identified 4 compounds that reduced fibrogenesis and adipogenesis of ≥30% of fibrogenesis and adipogenesis using immortalized cells. After selecting the optimal dose of each compound, the inhibitory effect on FAP differentiation was confirmed by using primary FAPs from healthy subjects (n = 3) and DMD patients (n = 3). The final 4 selected hits reduced fibrogenic differentiation in healthy and DMD samples. The inhibition of adipogenesis was more evident in DMD samples than healthy samples. After creating an inhibitory map of the tested drugs, we validated the signalling pathways more involved in FAPs differentiation analysing data from proteomic and genomic studies.
Conclusion: We present a map of molecular targets of approved drugs that helps in predicting which therapeutic option may affect FAP differentiation. This method allows to study the potential effect of signalling circuits on FAP differentiation after drug treatment providing insights into molecular mechanism of action of muscle degeneration. The accuracy of the method is demonstrated by comparing the signal pathway activity obtained after drug treatment with proteomic and genomic data from patient-derived cells.

Keywords:  adipogenesis; cachexia; fibro-adipogenic progenitor cells; fibrosis; muscle dystrophies; sarcopenia

DOI:  https://doi.org/10.3389/fcell.2025.1505697
Life Sci. 2025 Apr 08. pii: S0024-3205(25)00262-0. [Epub ahead of print]371 123628

Exerkine-mediated organ interactions: A new interpretation of exercise on cardiovascular function improvement.

Renhan Liu, Yue Xi, Xinyan Duan, Yifei Zhao, Zhenjun Tian.

  Cardiovascular diseases impair the structure and function of distal organs, including the liver, skeletal muscle, kidney, and adipose tissue. Exercise stimulates the interaction between the cardiovascular system and distal organs that is important for disease rehabilitation and organ health. However, the mechanisms by which exercise improves cardiovascular function through exerkine-mediated organ crosstalk remain incompletely elucidated. We used cardiovascular, exercise, exerkines, skeletal muscle, liver, kidney, and adipose tissue as keywords to search for the relevant articles, sorted out the differences between different exercise types, summarized the functions of 17 exerkines, focused on reviewing and categorizing the molecular mechanisms of interactions between the cardiovascular system and remote organs. We also look forward to future research perspectives on exercise prevention and control of chronic metabolic diseases. The aim of this review is to provide a new theoretical basis for establishing clinical rehabilitation and exercise prescriptions for cardiovascular system diseases.

Keywords:  Cardiovascular; Exercise; Exerkines; Function improvement; Organ interactions

DOI:  https://doi.org/10.1016/j.lfs.2025.123628
Small Sci. 2024 Nov;4(11): 2400228

Placenta-Derived Mesenchymal Stromal-Like Cells Promote 3D-Engineered Muscle Tissue Differentiation and Vessel Network Maturation.

Anna Tsukerman, Majd Machour, Margarita Shuhmaher, Eliana O Fischer, Hagit Shoyhet, Orit Bar-Am, Gali Guterman Ram, Lior Debbi, Dina Safina, Shulamit Levenberg.

  Placental-derived stromal-like cells (PLX-PAD) have been shown to facilitate muscle tissue recovery after injury and stimulate angiogenesis. This work assesses the impact of PLX-PAD cells on the vascularization and maturation of engineered skeletal muscle tissue. Specifically, their effects in direct co-culture with endothelial cells, pericytes, and myoblasts seeded within microporous 3D scaffolds are characterized. Additionally, the impact of hypoxic PLX-PAD cell-conditioned medium (CM) on vascularization and muscle differentiation of engineered tissue is monitored. Co-culture of PLX-PAD with myocytes stimulated myocyte differentiation while PLX-PAD CM promoted the formation of vascular networks. Implantation of a multi-culture system of vascularized human skeletal muscle tissue and PLX-PAD into a rectus abdominal defect in nude mice promoted myocyte differentiation, host vessel penetration, and tissue integration. These findings indicate the ability of placenta-derived cells to induce the formation of vascularized engineered muscle constructs with potential therapeutic applications.

Keywords:  muscle implantation; placenta‐derived mesenchymal stromal cells; regenerative medicine; skeletal muscle; tissue engineering; vascularization

DOI:  https://doi.org/10.1002/smsc.202400228
RNA Biol. 2025 Apr 10.

Alternative splicing of the Snap23 microexon is regulated by MBNL, QKI, and RBFOX2 in a tissue-specific manner and is mis-spliced in striated muscle diseases.

Gabrielle M Gentile, R Eric Blue, Grant A Goda, Bryan B Guzman, Rachel A Szymanski, Eunice Y Lee, Nichlas M Engels, Emma R Hinkle, Hannah J Wiedner, Aubriana N Bishop, Jonathan T Harrison, Hua Zhang, Xander H T Wehrens, Daniel Dominguez, Jimena Giudice.

  The reprogramming of alternative splicing networks during development is a hallmark of tissue maturation and identity. Alternative splicing of microexons (small, genomic regions ≤ 51 nucleotides) functionally regulate protein-protein interactions in the brain and are mis-spliced in neuronal diseases. However, little is known about the regulation and function of alternatively spliced microexons in striated muscle. Here, we investigated alternative splicing of a microexon in the synaptosome-associated protein 23 (Snap23) encoded gene. We found that inclusion of this microexon is developmentally regulated and tissue-specific, as it occurs exclusively in adult heart and skeletal muscle. The alternative region is highly conserved in mammalian species and encodes an in-frame sequence of 11 amino acids. Furthermore, we showed that alternative splicing of this microexon is mis-regulated in mouse models of heart and skeletal muscle diseases. We identified the RNA-binding proteins (RBPs) quaking (QKI) and RNA binding fox-1 homolog 2 (RBFOX2) as the primary splicing regulators of the Snap23 microexon. We found that QKI and RBFOX2 bind downstream of the Snap23 microexon to promote its inclusion, and this regulation can be escaped when the weak splice donor is mutated to the consensus 5' splice site. Finally, we uncovered the interplay between QKI and muscleblind-like splicing regulator (MBNL) as an additional, but minor layer of Snap23 microexon splicing control. Our results are one of the few reports detailing microexon alternative splicing regulation during mammalian striated muscle development.

Keywords:  Microexon; RNA-binding proteins; Snap23; alternative splicing; striated muscle

DOI:  https://doi.org/10.1080/15476286.2025.2491160
Sci Rep. 2025 Apr 05. 15(1): 11714

Selection of optimal human myoblasts based on patient related factors influencing proliferation and differentiation capacity.

Moritz Englich, Andreas Arkudas, Lilly Mengen, Raymund E Horch, Aijia Cai.

  Human myoblasts (hMb) are a promising source for engineering skeletal muscle tissue. But sample-specific variabilities make research with human cells challenging. For the purpose of selecting hMb with adequate proliferation and differentiation properties, the influence of various patient related factors, including age, gender, BMI, anatomical sampling site and previous radio-/chemotherapy on hMb behavior was investigated in this study. Immunofluorescence staining and proliferation periods were analysed for proliferation capacity, while creatine kinase and cell viability assay, immunofluorescence staining and PCR were used to determine differentiation capacity. Using desmin expression, a multiple linear regression (MLR) model was established based on the above-mentioned patient related factors. Higher age and BMI, female gender and chemotherapy had a negative impact on desmin expression. Muscle type specific differences could also be seen. Previous radiotherapy led to senescence of hMb in large parts. Differentiation was mainly influenced by gender in a time-dependent manner, as well as by the anatomical collecting site. We were able to demonstrate the importance of analyzing patient characteristics for the purpose of hMb isolation. Using MLR, these patient characteristics can be used to predict the proliferation capacity of hMb as a step further towards translational application of skeletal muscle engineering and regeneration.

Keywords:  Multiple linear regression; Myoblast proliferation; Myoblasts; Myogenic differentiation; Skeletal muscle; Tissue engineering

DOI:  https://doi.org/10.1038/s41598-025-96108-1
Eur J Sport Sci. 2025 May;25(5): e12299

Quantifying Leg Muscle Disuse Atrophy During Bed Rest Using DXA, CT, and MRI.

Cas J Fuchs, Wesley J H Hermans, Job van den Hurk, Christopher J Wiggins, Per Widholm, Olof Dahlqvist Leinhard, Pandichelvam Veeraiah, Joachim E Wildberger, Jeanine J Prompers, Luc J C van Loon.

  This study evaluated whether dual-energy X-ray absorptiometry (DXA), computed tomography (CT), and magnetic resonance imaging (MRI) provide comparable outcomes in quantifying disuse-induced skeletal muscle atrophy. Although the calculation of muscle volume using MRI analysis may be considered the gold standard, the method remains labor intense and, as such, less practical and more costly. In this context, we also evaluated the efficacy of a commercially available automated MRI analysis method to measure changes in leg muscle volume after two weeks of bed rest. Twelve healthy, male adults (age: 24 ± 3 years, BMI: 23.7 ± 3.1 kg/m2) were subjected to 2 weeks of strict bed rest. Leg muscle assessments were performed before and after bed rest using DXA, single slice (thigh) CT, and MRI. MRI data analyses were performed using both a manual and automated (AMRA) method. Leg lean mass, as assessed with DXA, declined by 5% following bed rest (from 10.2 ± 1.6 to 9.7 ± 1.6 kg; p < 0.001). The thigh muscle cross-sectional area, as assessed with CT, declined by 6% following bed rest (from 155 ± 26 to 146 ± 24 cm2; p < 0.001). Muscle volume, as assessed using MRI, declined by 5% following bed rest, both when assessed manually (from 7.1 ± 1.1 to 6.7 ± 1.0 L; p < 0.001) and automatically (from 7.2 ± 1.1 to 6.8 ± 1.0 L; p < 0.001). A very strong correlation (r = 0.96; p < 0.001) with a low bias (-0.11 ± 0.29 L) was observed between manual and automated muscle volume analysis. DXA, CT, and MRI all show a ∼5% decline in leg muscle quantity following two weeks of bed rest in healthy adults. When using MRI, disuse muscle atrophy can be accurately quantified using an automated approach, rendering time-consuming manual analysis obsolete.

Keywords:  computed tomography; dual‐energy x‐ray absorptiometry; magnetic resonance imaging; muscle mass; muscle volume; skeletal muscle

DOI:  https://doi.org/10.1002/ejsc.12299