bims-moremu 2025-10-12 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2025–10–12
thirty-two papers selected by
Anna Vainshtein, Craft Science Inc.

Enlargement of the muscle stem cell pool in linc-MYH-deficient mice does not prevent sarcopenia during aging.
Estrogen-Related Receptor Alpha Promotes Skeletal Muscle Regeneration and Mitigates Muscular Dystrophy.
Markers of mitochondrial function and oxidative metabolism in skeletal muscle do not display intrinsic circadian regulation in female mice.
Glycolytic metabolism and biomass production from glucose in human skeletal muscle growth.
Unravelling the Diversity Observed in Cancer Cachexia.
R-spondin 3 is a myokine that mediates type I fiber determination during skeletal muscle regeneration.
Phosphorylation of RYR1 at Ser2902 decreases Ca2+ leak in skeletal muscle and susceptibility to malignant hyperthermia and heat stroke.
Exercise training-induced extracellular miR-136-3p modulates glucose uptake and myogenesis through targeting of NRDC in human skeletal muscle.
Advances in vascular endothelial cell-mediated regulation of satellite cell repair and regeneration.
Integrated fibre-specific methylome and proteome profiling of human skeletal muscle across males and females with fibre-type deconvolution.
Microenvironment-driven satellite cell regeneration and repair in aging-related sarcopenia: mechanisms and therapeutic frontiers.
Piezo1 activator Yoda1 promotes protein anabolism in cultured murine myotubes.
Skeletal Muscle PGC-1α Remodels Mitochondrial Phospholipidome but Does Not Alter Energy Efficiency for ATP Synthesis.
Metabolic stress and muscle mechanics: Acute response of isolated soleus and EDL muscles to prolonged fasting in mice with distinct muscle phenotypes.
Consequences of plectin ablation on the various intermediate filament systems in skeletal muscle.
CTRP9 as a myokine mitigates sarcopenia via the LAMP-2A/NLRP3 pathway.
Muscle Organoids Reveal Exercise-Like Contractions Rapidly Promote Muscle Health Via Lamtor1's Signaling to Both AMPK and mTOR.
Transcriptomic analysis demonstrates moderators of muscle quality are altered in age-related sarcopenic obesity.
IP3 Receptors Mediate Calcium and Anabolic Signaling Associated with Muscle Atrophy upon 3-Day Hind Limb Unloading in Rats.
Regarding: In Vivo Evaluation of Decellularised Skeletal Muscle Matrices for Skeletal Muscle Repair: A Systematic Review.
Translational progress in the development of pharmacotherapies for Duchenne muscular dystrophy.
Signaling networks governing skeletal muscle growth, atrophy, and cachexia : By.
Muscle Cathepsin B Treatment Improves Behavioral and Neurogenic Deficits in a Mouse Model of Alzheimer's Disease.
Muscle derived BMP4 regulates morphology and function of endplates on extrafusal and intrafusal muscle fibers in adult mice.
Restoration of skeletal muscle function via mesenchymal stem cells: mechanistic insights and therapeutic advances in myasthenia gravis.
Exercise is required to maintain unacylated ghrelin response in adult male rat skeletal muscle, regardless of dietary fat consumption.
Skeletal Muscle Alterations and Functional Repercussions in Patients with Colorectal Cancer-associated Cachexia.
Experimental Evidence Against Taurine Deficiency as a Driver of Aging in Humans.
Integrated transcriptomics unveils mitochondrial oxidative phosphorylation dysfunction as a shared mechanism in sarcopenia and obesity.
Myopathies: Radiologist's Essential Tips for Clinical, Pathologic, and Imaging Findings.
MyomiRs Expression in Limb Girdle Muscular Dystrophy.
Cell therapy for Duchenne muscular dystrophy: promises, challenges, and controversies.

Front Cell Dev Biol. 2025 ;13 1667437

Enlargement of the muscle stem cell pool in linc-MYH-deficient mice does not prevent sarcopenia during aging.

Qing Yin, Christelle Labib, Thomas Boettger, Thomas Braun.

  Loss of skeletal muscle mass and muscle strength during aging (sarcopenia) and reduced skeletal muscle regeneration are often attributed to the age-dependent decline of muscle stem cells (MuSCs). However, it has not been analyzed whether enlargement of the MuSC pool in old animals can attenuate sarcopenia or restore regenerative potential. Here, we directly tested this idea by taking advantage of linc-MYH-mutant mice, which show a substantially increased number of MuSCs in young mice. We found that 24-month-old geriatric linc-MYH knockout mice still maintain a consistently enlarged MuSC pool compared to age-matched controls. MuSCs in geriatric linc-MYH knockout mice were located beneath the basal lamina and remained mostly in a quiescent state. Importantly, enlargement of the MuSC pool did not prevent sarcopenia, or improve muscle function and regeneration. Instead, the larger MuSC pool in geriatric linc-MYH-/- mice resulted in the formation of smaller muscles during regeneration with thicker fibers, characterized by an increased myonuclei content per fiber. Furthermore, we observed shifts of the muscle fiber-type composition in linc-MYH-/- mice during aging, including a reduction of type IIb fibers in the tibialis anterior muscle and a reduction of type IIa fibers in the soleus, combined with an increase of type I fibers.

Keywords:  aging; linc-MYH; mice; muscle stem cells; sarcopenia

DOI:  https://doi.org/10.3389/fcell.2025.1667437
FASEB J. 2025 Oct 15. 39(19): e71094

Estrogen-Related Receptor Alpha Promotes Skeletal Muscle Regeneration and Mitigates Muscular Dystrophy.

Thi Thu Hao Nguyen, Ya Xiang Huang, Svitlana Poliakova, Citu Citu, Eira Mann, Danesh H Sopariwala, Zhongming Zhao, Ashok Kumar, Vihang A Narkar.

  Skeletal muscle regeneration in chronic muscle diseases such as Duchenne Muscular Dystrophy (DMD) has remained clinically unsurmountable. Estrogen-related receptor alpha (ERRα) plays a critical role in adult skeletal muscle metabolism and exercise fitness. Whether ERRα activation can drive muscle regeneration and mitigate dystrophy in DMD is not known. We have investigated ERRα signaling in pre-clinical models of acute muscle injury and DMD. ERRα is induced in differentiating C2C12 myoblast and regenerating muscle. ERRα silencing suppressed proliferation and differentiation in C2C12 myoblasts. RNA sequencing revealed that angiogenic factor and proliferation genes were downregulated by ERRα knockdown in proliferating cells, whereas oxidative mitochondrial and differentiation regulator genes were downregulated in differentiating cells. In accordance with in vitro findings, transgenic ERRα overexpression in rodent skeletal muscle stimulates muscle regeneration after acute BaCl2 injury, which is accompanied by enhanced angiogenesis and mitochondrial biogenesis. Notably, ERRα and its angiogenic and metabolic target gene expression is suppressed in muscle stem cells (MuSCs) derived from dystrophic muscles in mdx mice, coinciding with proliferation and differentiation defects in these cells. Loss of ERRα and its target gene expression was recapitulated in adult dystrophic mdx muscles. Consequently, muscle specific ERRα overexpression in mdx mice restored angiogenic and metabolic gene expression, induced vascular and oxidative remodeling, alleviated baseline muscle damage, boosted regeneration in dystrophic muscle and improved function. Our studies demonstrate a pro-regenerative role of ERRα and its deficiency in dystrophic muscles and MuSCs. ERRα activation could be a therapeutic strategy for DMD through angio-metabolic gene programming.

Keywords:  angiogenesis; dystrophy; metabolism; regeneration; skeletal muscle

DOI:  https://doi.org/10.1096/fj.202501764R
Am J Physiol Endocrinol Metab. 2025 Oct 08.

Markers of mitochondrial function and oxidative metabolism in skeletal muscle do not display intrinsic circadian regulation in female mice.

Liam S Fitzgerald, Connor Scott Reynoso Spurrier, Nathan Lau, Miles Melamed, Lindsey A Burnett, Gretchen A Meyer, Chang Gui, Andrea L Hevener, James A Sanford, Simon Schenk.

  Mitochondria are key regulators of metabolism and ATP supply in skeletal muscle, while circadian rhythms influence many physiological processes. However, whether mitochondrial function is intrinsically regulated in a circadian manner in mouse skeletal muscle is inadequately understood. Accordingly, we measured post-absorptive transcript abundance of markers of mitochondrial autophagy, dynamics, and metabolism (extensor digitorum longus [EDL], soleus, gastrocnemius), protein abundance of electron transport chain complexes (EDL and soleus), enzymatic activity of SDH (tibialis anterior and plantaris), and maximal mitochondrial respiration (tibialis anterior) in different skeletal muscles from female C57BL/6NJ mice at four zeitgeber times: 1, 7, 13, and 19. Our findings demonstrate that markers of mitochondrial function and oxidative metabolism do not display intrinsic time-of-day regulation at the gene, protein, enzymatic, or functional level. The core-clock genes Bmal1 and Dbp exhibited intrinsic circadian rhythmicity in skeletal muscle (i.e., EDL, soleus, gastrocnemius) and circadian amplitude varied by muscle type. These findings demonstrate that female mouse skeletal muscle does not display circadian regulation of markers of mitochondrial function or oxidative metabolism over 24 hours.

Keywords:  chronobiology; extensor digitorum longus; soleus; tibialis anterior; time-of-day

DOI:  https://doi.org/10.1152/ajpendo.00027.2025
Am J Physiol Cell Physiol. 2025 Oct 10.

Glycolytic metabolism and biomass production from glucose in human skeletal muscle growth.

Sakari Mäntyselkä, Marco Ahvenlammi, Jennika Vartiainen, Eeli J Halonen, Kalle Kolari, Henning Wackerhage, Perttu Permi, Markku Varjosalo, Milla M Kelahaara, Juha P Ahtiainen, Elina Kalenius, Riikka Kivelä, Juha J Hulmi.

  Skeletal muscle is the main consumer of glucose after a mixed meal, and resistance exercise further increases muscle glucose uptake. Emerging evidence suggests that glucose uptake in muscles is not only stored as glycogen or used as a fuel but can also be incorporated into other biomass during growth. We aimed to study the utilization of glucose-derived carbons for protein, RNA, and lipid synthesis during human skeletal muscle (HSkM) cell growth. We also investigated whether muscle growth in vivo by resistance training (RT) affects the abundance of metabolites and enzymes required for these processes in human muscle. We found that differentiated HSkM cells incorporated glucose-derived carbon into proteins, RNA, and lipids, and anabolic stimulation further increased these processes. Liquid chromatography-mass spectrometry metabolomics and proteomics revealed that 10 weeks of RT in humans increased essential metabolites and enzymes for nucleotide, serine, and glycine synthesis, including phosphoglycerate dehydrogenase (PHGDH) in muscle. We also examined whether the PHGDH enzyme, starting the serine synthesis pathway branching from glycolysis, is sufficient and essential for human muscle protein, RNA, and lipid anabolism. We found that PHGDH inhibitors decreased protein synthesis and glucose-derived carbon incorporation into macromolecules, whereas manipulation of PHGDH abundance had mixed effects. Moreover, PHGDH was revealed to be important for myogenesis. The data suggest that glucose is not only used for ATP generation but also as a building block in human muscle cell growth. The results open new avenues for studies investigating the mechanisms of RT and muscle growth in improving muscle glucose metabolism.

Keywords:  Metabolomics; Myogenesis; PHGDH; Proteomics; Resistance training

DOI:  https://doi.org/10.1152/ajpcell.00525.2025
Am J Physiol Cell Physiol. 2025 Oct 06.

Unravelling the Diversity Observed in Cancer Cachexia.

Thomas J Hawke, Tyrone A Washington, Yusuke Nishimura, Nicholas P Greene.



Keywords:  cachexia; fat loss; muscle loss; skeletal muscle; wasting

DOI:  https://doi.org/10.1152/ajpcell.00731.2025
Mol Biol Rep. 2025 Oct 09. 52(1): 995

R-spondin 3 is a myokine that mediates type I fiber determination during skeletal muscle regeneration.

Teng Hu, Yoshitaka Mita, Xinhe Zhu, Yasuro Furuichi, Yoshimi Nakagawa, Yasuko Manabe, Nobuharu L Fujii.

   BACKGROUND: In recent years, skeletal muscle has been recognized not only as a locomotor organ but also as a secretory organ. The bioactive molecules it releases, known as myokines, act on distant organs through the circulation and locally on muscle tissue. Previously, we identified R-spondin 3 (Rspo3) as a Type I fiber-specific myokine that promotes myoblast differentiation into Type I fibers in vitro. In this study, we further investigated whether Rspo3 is involved in regulating Type I fiber determination in vivo.
METHODS AND RESULTS: We generated tamoxifen-induced muscle-specific Rspo3-deficient mice and found that Rspo3 deficiency impaired Type I fiber determination during muscle regeneration. In contrast, transient overexpression of Rspo3 through in vivo electroporation enhanced the regeneration of Type I fibers, supporting its functional role in fiber-type specification.
CONCLUSION: This work reveals that Rspo3 as a Type I fiber specific myokine promotes Type I fiber determination during muscle regeneration in vivo.

Keywords:  Muscle regeneration; Myokine; R-spondin 3; Skeletal muscle; Type I fiber

DOI:  https://doi.org/10.1007/s11033-025-11099-6
Sci Signal. 2025 Oct 07. 18(907): eadx3087

Phosphorylation of RYR1 at Ser2902 decreases Ca2+ leak in skeletal muscle and susceptibility to malignant hyperthermia and heat stroke.

Rachel Sue Zhen Yee, Chang Seok Lee, Ting Chang, Sung Yun Jung, Omar Yousif, Courtney Cavazos, John Colyer, Filip Van Petegem, George G Rodney, Susan L Hamilton.

Ryanodine receptor 1 (RYR1) is the sarcoplasmic reticulum (SR) Ca2+ release channel required for both skeletal muscle contraction and Ca2+ leak. Mutations in RYR1 cause malignant hyperthermia susceptibility (MHS) and enhanced sensitivity to heat stroke (ESHS), which can result in death due to excessive skeletal muscle thermogenesis upon exposure to volatile anesthetics or heat. Here, we investigated the molecular and physiological functions of phosphorylation of RYR1 at Ser2902 by the kinase striated muscle preferentially expressed protein (SPEG). Muscle from SPEG-deficient mice expressing RYR1 with a Ser2902→Asp2902 (S2902D) point mutation to mimic phosphorylation by SPEG showed decreased SR Ca2+ sparks. Muscle from mice homozygous for the S2902D point mutation had reduced SR Ca2+ transients and small changes in force generation but overall mild phenotypic changes. YS mice, which are heterozygous for a Tyr524→Ser524 point mutation in RYR1, show increased Ca2+ leak and are a model of MHS and ESHS. Crossing YS mice with S2902D mice led to decreased SR Ca2+ leak and desensitized the mice to both volatile anesthetics and heat. Thus, SPEG inhibits SR Ca2+ leak in skeletal muscle by phosphorylating Ser2902 on RYR1, and mutation of Ser2902 to Asp2902 to mimic this phosphorylation event rescues YS mice from heat-induced death.

DOI: https://doi.org/10.1126/scisignal.adx3087
J Sport Health Sci. 2025 Oct 03. pii: S2095-2546(25)00073-0. [Epub ahead of print] 101091

Exercise training-induced extracellular miR-136-3p modulates glucose uptake and myogenesis through targeting of NRDC in human skeletal muscle.

Mutsumi Katayama, Elena Caria, Dimitri Van Simaeys, Anna Yagüe Sanz, Romain Barrès, Kenneth Caidahl, Oscar Pb Wiklander, Samir El-Andaloussi, Per-Olof Berggren, Juleen R Zierath, Anna Krook.

   BACKGROUND: Regular physical training induces adaptive effects across multiple organ systems, highlighting the existence of inter-organ communication networks. However, the molecular mechanisms underlying both exercise-induced adaptations and organ-to-organ signaling are not fully characterized. Circulating extracellular vesicles (EVs), including exosomes, carry molecules like microRNAs (miRNAs) that may mediate tissue crosstalk. This study aimed to identify specific exercise training-responsive miRNAs that affect skeletal muscle function.
METHODS: miRNA expression profiles of serum-derived EVs were analyzed in healthy young individuals before and after 3 weeks endurance exercise training. Exercise training-responsive miRNAs were then validated for a functional role in cellular metabolic processes in human myotubes.
RESULTS: We identified several exercise training-responsive miRNAs within exosome-rich EVs in serum, including miR-136-3p. In human myotubes, miR-136-3p enhanced glucose uptake and targeted the nardilysin convertase (NRDC) gene. Transfection of miR-136-3p or silencing of NRDC induced a shift towards glycolytic metabolism in mitochondria and modulated gene expressions related to myogenesis. Pancreatic islets were identified as a potential source of miR-136-3p based on in silico analysis of gene expression and a molecular analysis of conditioned media from isolated pancreatic islets.
CONCLUSION: MiR-136-3p is an endurance training-responsive molecular transducer that modulates glucose metabolism and cellular proliferation in myocytes. Associated with EVs, extracellular miR-136-3p may serve as a molecular messenger to communicate islet-skeletal muscle crosstalk after exercise. Extracellular miR-136-3p may serve as a molecular messenger to communicate islet-skeletal muscle crosstalk. Our results highlight a miRNA-mediated mechanism that participates in inter-organ communication to fine tune the metabolic adaptations to exercise.

Keywords:  Endurance training; Extracellular miRNA; Human skeletal muscle; Nardilycin convertase (NRDC); miR-136-3p

DOI:  https://doi.org/10.1016/j.jshs.2025.101091
Inflamm Regen. 2025 Oct 07. 45(1): 30

Advances in vascular endothelial cell-mediated regulation of satellite cell repair and regeneration.

Chunyan Yang, Liting Zhang, Lihua Liu, Lijuan Bai, Yun Liu, Ruiyun Wang, Benling Qi.

  With advancing age, vascular endothelial cells (ECs) exhibit functional decline and reduced angiogenic capacity, adversely affecting muscle homeostasis. Satellite cells (SCs), serving as the primary stem cells in adult skeletal muscle, are responsible for proliferating, differentiating, and repairing damaged tissue post-injury. Notably, ECs regulate skeletal muscle regeneration not only through angiogenesis-mediated oxygen and nutrient supply to injured areas but also via molecular signaling pathways that modulate SC activation, proliferation, and differentiation. Investigating the regulatory mechanisms of ECs on SCs is crucial for understanding muscle regeneration, repair, and therapeutic strategies for related disorders. This review focuses on EC-mediated regulation of SCs during skeletal muscle regeneration, aiming to elucidate their intricate interplay and provide novel perspectives and theoretical frameworks for advancing research in muscle regeneration and muscle-related disease treatment.

Keywords:  Molecular Mechanisms; Satellite Cells; Satellite Cells Niche; Vascular Endothelial Cells

DOI:  https://doi.org/10.1186/s41232-025-00394-1
Skelet Muscle. 2025 Oct 10. 15(1): 28

Integrated fibre-specific methylome and proteome profiling of human skeletal muscle across males and females with fibre-type deconvolution.

Andrew S Palmer, Esther García-Domínguez, Megan F Taylor, Andrew Garnham, Kirsten Seale, Joel R Steele, Han-Chung Lee, Ralf B Schittenhelm, Nir Eynon.

   BACKGROUND: Skeletal muscle is an important organ for health and movement, largely driven by specific muscle fibres. However, the comparison of fibre-type-specific DNA methylation and protein abundance from the same sample presents challenges. By combining previous methodological approaches we were able to directly compare the methylome and proteome in Type I and Type II human skeletal muscle fibres in males and females.
METHODS: We assessed the methylome using the EPICv2 Infinium array and the proteome using liquid chromatography tandem mass spectrometry (LC-MS/MS) from Type I and Type II fibre pools from both males ( n=7 ) and females ( n=5 ).
RESULTS: We identified 5,689 robust differentially methylated regions (Fisher P-value <0.001 ) and found strong relationships between methylation and protein abundance in key contractile and metabolic genes. Further, we generated a reference matrix of Type I and Type II fibres and leveraged deconvolution algorithms to accurately estimate fibre-type proportions using whole-muscle DNA methylation data, providing a method to correct for fibre-type in future studies. These results are presented primarily as a resource for others to utilise.
CONCLUSION: We provide integrated methylome and proteome profiles of human muscle fibre-types generalisable to both male and females as a freely accessible interactive repository, MyoMETH ( https://myometh.net ), allowing further investigation into fibre regulation. Data are available via ProteomeXchange with identifier PXD066393 and the Gene Expression Omnibus at GSE304045 .

Keywords:  Deconvolution; Human-skeletal-muscle; Methylome; Muscle-fibres; Proteome

DOI:  https://doi.org/10.1186/s13395-025-00396-0
Stem Cell Res Ther. 2025 Oct 07. 16(1): 545

Microenvironment-driven satellite cell regeneration and repair in aging-related sarcopenia: mechanisms and therapeutic frontiers.

Na Li, Yushu Chen, Qiong Wang, Xiaoqin Liu, Chao Han, Chao Qu, Xin Guan, Wei Zou, Xiaomin Wang, Ang Li, Jing Liu, Yanfu Wang.

  Sarcopenia, a progressive age-related decline in skeletal muscle mass and function, is closely linked to impaired regenerative capacity of satellite cells (SCs), also known as satellite cells. Age-dependent SCs dysfunction, driven by intrinsic senescence and niche dysregulation, disrupts activation, proliferation, and differentiation, thereby exacerbating regenerative deficits in sarcopenia. The SCs niche undergoes age-related remodeling, characterized by immune cell infiltration, ECM stiffening, and aberrant FAPs differentiation toward Fibro-Adipogenic lineages. Immune subsets orchestrate inflammation resolution and SCs activation during regeneration, while FAPs exhibit dual roles: transient pro-regenerative WISP1 secretion and chronic fibrotic conversion. Concurrently, vascular-neural networks sustain SCs quiescence and neuromuscular junction integrity, with age-related degradation of these systems exacerbating regenerative decline. Single-cell omics and 3D genomic studies have revealed heterotypic interactions and chromatin structural changes underlying SCs dysfunction in aging. Emerging therapeutic strategies targeting SCs rejuvenation and niche restoration-including metabolic regulation, endocrine interventions, and cell-based therapies-are complemented by advances in single-cell omics and 3D modeling technologies, which offer unprecedented opportunities to dissect niche complexity and identify novel therapeutic targets for sarcopenia. This review synthesizes recent advancements in understanding the role of SCs and their dynamic niche microenvironment in sarcopenia pathogenesis, exploring novel therapeutic strategies while underscoring the critical importance of deciphering their bidirectional interplay for developing effective interventions against age-related muscle loss.

Keywords:  Extracellular matrix (ECM); Fibro adipogenic precursors (FAPs); Muscle stem cells (MuSCs); Satellite cell niche; Satellite cells (SCs)

DOI:  https://doi.org/10.1186/s13287-025-04481-5
Mol Biol Rep. 2025 Oct 09. 52(1): 1003

Piezo1 activator Yoda1 promotes protein anabolism in cultured murine myotubes.

Anastasia R Babkova, Natalia A Vilchinskaya, Ksenia V Sergeeva, Boris S Shenkman, Timur M Mirzoev.

   BACKGROUND: In response to physical forces, skeletal muscles undergo a significant increase in protein anabolism. Piezo1 channels have emerged as key membrane mechanosensors in various tissues, including mammalian skeletal muscle. However, the potential role of Piezo1 channels in activating anabolic processes in muscle cells remains understudied. This study aimed to determine whether Yoda1, a specific Piezo1 activator, is able to promote protein anabolism in cultured skeletal muscle cells.
METHODS AND RESULTS: C2C12 myotubes were treated with Yoda1 (a specific activator of Piezo1), gadolinium (Gd3+) (a non-specific inhibitor of mechanically activated channels), or a combination of Yoda1 and Gd3+. After treatment, the myotubes were collected for Western blot or PCR analysis. Treatment with Yoda1 increased protein synthesis (PS) rates in parallel with enhanced AKT (Ser473), p70S6K (Thr389/Thr412), rpS6 (Ser 240/244) and GSK-3β (Ser9) phosphorylation. Incubation with Gd3+ alone did not induce significant changes in PS rates or intracellular anabolic markers. Treating myotubes with both Yoda1 and Gd3+ abolished the effects of Yoda1 on phosphorylation of p70S6K, rpS6 and PS rates.
CONCLUSION: Our findings show that Piezo1 activator Yoda1 is able to promote anabolic signaling and enhance PS rates in cultured mouse myotubes.

Keywords:  C2C12 myotubes; GSK-3β; Gadolinium; P70S6K; Piezo1; Protein synthesis; Yoda1

DOI:  https://doi.org/10.1007/s11033-025-11115-9
J Cachexia Sarcopenia Muscle. 2025 Oct;16(5): e70090

Skeletal Muscle PGC-1α Remodels Mitochondrial Phospholipidome but Does Not Alter Energy Efficiency for ATP Synthesis.

Takuya Karasawa, Ran Hee Choi, Cesar A Meza, Shinya Watanabe, J Alan Maschek, Linda S Nikolova, James E Cox, Katsuhiko Funai.

   BACKGROUND: The coupling of oxygen consumption to ATP synthesis via oxidative phosphorylation (OXPHOS) is central for cellular energy homeostasis. Some studies suggest exercise training increases the efficiency of ATP synthesis, but the molecular mechanisms are unclear. We have previously shown that exercise remodels the lipid composition of mitochondrial membranes, and some of these changes in mitochondrial lipids might influence OXPHOS efficiency (ATP produced per O2 consumed, referred to as P/O). Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) is a transcriptional co-activator that coordinately regulates exercise-induced adaptations, including mitochondria. We hypothesized that increased PGC-1α activity might remodel mitochondrial membrane lipids and promote energy efficiency.
METHODS: Mice with skeletal muscle-specific overexpression of PGC-1α (MCK-PGC-1α) and their wildtype littermates were used for this study. Lipid mass spectrometry and quantitative PCR were used to assess muscle mitochondrial lipid composition and their biosynthesis pathway. The abundance of OXPHOS enzymes was determined by Western blotting. High-resolution respirometry and fluorometry analyses were performed to characterize mitochondrial bioenergetics (ATP production, O2 consumption and P/O) for permeabilized fibres and isolated mitochondria. Respiratory supercomplexes were assessed by blue native PAGE.
RESULTS: Lipidomic analyses of skeletal muscle mitochondria from wildtype and MCK-PGC-1α mice revealed that PGC-1α increases the concentrations of cone-shaped lipids such as phosphatidylethanolamine (PE; +25%, p < 0.0001), cardiolipin (CL; +184%, p < 0.0001) and lysophospholipids (+34%-94%, all p < 0.01), while decreasing the concentrations of phosphatidylcholine (PC; -4%, p = 0.0020), phosphatidylinositol (PI; -17%, p < 0.0001) and phosphatidic acid (PA; -35%, p < 0.0001). However, while PGC-1α overexpression increased the abundance of OXPHOS enzymes (two- to fourfold, p < 0.0001), the rate of O2 consumption (1.5-fold, p = 0.0030), or the respiratory supercomplexes (~1.5-fold, p < 0.01), P/O values were unaffected by PGC-1α overexpression in permeabilized fibres or isolated mitochondria.
CONCLUSIONS: Collectively, overexpression of PGC-1α promotes the biosynthesis of mitochondrial PE and CL, but neither PGC-1α nor the mitochondrial membrane lipid remodelling induced in MCK-PGC-1α mice is sufficient to increase the efficiency of mitochondrial ATP synthesis. These findings indicate that PGC-1α-dependent mechanisms or changes in mitochondrial membrane lipids may be insufficient to alter P/O. While muscles from MCK-PGC-1α mice are known not to completely phenocopy adaptations with exercise training, our findings also highlight that there is a need to examine whether exercise training indeed improves P/O in mouse skeletal muscle.

Keywords:  exercise; mitochondria; phospholipids; skeletal muscle

DOI:  https://doi.org/10.1002/jcsm.70090
Biol Open. 2025 Oct 06. pii: bio.062245. [Epub ahead of print]

Metabolic stress and muscle mechanics: Acute response of isolated soleus and EDL muscles to prolonged fasting in mice with distinct muscle phenotypes.

L Cesanelli, B Ylaite, M Brazaitis, N Eimantas, A Ratkevicius, D Satkunskiene, P Minderis.

  Prolonged fasting impacts skeletal muscle by inducing atrophy, thereby limiting contractile capacity and altering tissue mechanical behavior. This study investigated the effects of 48 h of fasting (FAS) versus ad libitum food consumption (CON) on the mechanical properties of fast-twitch (extensor digitorum longus, EDL) and slow-twitch (soleus, SOL) muscles in three mouse strains with distinct muscle phenotypes: C57BL/6J (normal-sized), BEH+/+ (larger muscles), and BEH (myostatin-deficient with markedly larger muscles). Isolated SOL and EDL were subjected to 100 isometric-eccentric contraction cycles, and peak and specific force, rate of force development, fatigue, stiffness, and tangent modulus were assessed. Fasting significantly reduced muscle size and force production capacity (isometric and eccentric) across all strains (p<0.05). SOL muscles showed a greater decline in tetanic force (fatigue index: SOL 67% vs. EDL 33%, p<0.05), while BEH mice exhibited the steepest contractile impairment (p<0.05). Fasting also reduced stiffness and tangent modulus across all strains and muscle types (p<0.05). These findings demonstrate that fasting consistently impairs contractile and mechanical properties of skeletal muscle, with slow-twitch muscles and larger muscles phenotypes being particularly vulnerable. Muscle type and genetic background thus play key roles in determining the extent of functional decline under metabolic stress.

Keywords:  Contractility; Fasting; Mechanobiology; Muscle atrophy; Muscle mechanics

DOI:  https://doi.org/10.1242/bio.062245
Eur J Cell Biol. 2025 Oct 03. pii: S0171-9335(25)00047-0. [Epub ahead of print]104(4): 151522

Consequences of plectin ablation on the various intermediate filament systems in skeletal muscle.

Marta Rocha, Jonas Petsch, Dorothea Schultheis, Michaela M Zrelski, Petra Fichtinger, Inga Koneczny, Samuel Meier-Menches, Gerhard Wiche, Rolf Schröder, Lilli Winter.

  Plectin, a highly versatile and multifunctional cytolinker, acts as a central connector of the intermediate filament (IF) and other cytoskeletal systems. In skeletal muscle, plectin orchestrates and anchors the extrasarcomeric desmin filament network to sites of strategic importance and thereby substantially contributes to its fundamental biomechanical properties. Lack of plectin in skeletal muscle leads to a faulty organization of the desmin IFs, thereby inflicting a reduced mechanical stress tolerance and a progressive myopathic process. Accordingly, the morphological hallmark of the skeletal muscle pathology in most plectinopathies, including epidermolysis bullosa simplex with muscular dystrophy (EBS-MD), is the accumulation of desmin-positive protein aggregates. To address the consequences of plectin-deficiency on other types of IFs, RNA and protein expression as well as localization of various IF subtypes was evaluated in muscle tissue from wild-type and muscle-specific conditional plectin knockout (MCK-Cre/cKO) mice. Notably, vimentin and syncoilin, as well as several other IF subtypes, were significantly upregulated in MCK-Cre/cKO muscles and accumulated in subsarcolemmal and sarcoplasmic areas. In plectin-deficient mouse myoblasts, increased expression levels of vimentin were accompanied by the formation of thickened IF bundles. Primary human myoblasts, treated with the plectin inhibitor plecstatin-1, displayed increased bundling of desmin and vimentin, thus supporting the notion of drastic structural and organizational changes in the network. Finally, we were able to demonstrate the presence of vimentin-positive protein aggregates in skeletal muscle specimens from EBS-MD patients. Together, these data indicate that the depletion of plectin in muscle unequivocally affected the expression and localization of various types of IFs.

Keywords:  Cytoskeleton; Desmin; Intermediate filaments; Plectin; Plectinopathies; Skeletal muscle; Vimentin

DOI:  https://doi.org/10.1016/j.ejcb.2025.151522
Cell Death Dis. 2025 Oct 07. 16(1): 710

CTRP9 as a myokine mitigates sarcopenia via the LAMP-2A/NLRP3 pathway.

Linxi Li, Anju Zuo, Ruoyu Yin, Qiangqiang Liu, Chen Liu, Na Li, Dan Xu, Shaomeng Zhang, Jiarui Li, Shengyun Lei, Shiyan Ruan, Tingting Li, Yuan Guo.

Sarcopenia, a degenerative condition marked by progressive skeletal muscle atrophy and impaired regeneration, is closely associated with aging, chronic inflammation, and disrupted proteostasis. While macroautophagy has been extensively studied in this context, little of the role of chaperone-mediated autophagy (CMA) has been known. In this study, we identified C1q/TNF-related protein 9 (CTRP9) as a novel autocrine myokine secreted by skeletal muscle that exerts dual protective functions-pro-differentiative and anti-atrophic. By using a replicative senescence model in C2C12 myoblasts, we observed that CTRP9 expression declined with cellular aging, accompanied by reduced levels of lysosome-associated membrane protein type 2A (LAMP2A), increased nucleotide-binding domain, leucine-rich-containing family, and pyrin domain-containing-3 (NLRP3) accumulation, and elevated interleukin-1β (IL-1β) secretion. Similar molecular signatures were detected in skeletal muscle tissues of CTRP9 knockout (KO) mice, further validating its role in vivo. Treatment with the biologically active globular domain of CTRP9 (gCTRP9) restored LAMP2A expression, enhanced CMA activity, and promoted selective degradation of NLRP3, thereby alleviating inflammatory stress and cellular senescence. Functionally, gCTRP9 restored myogenic differentiation markers (e.g., MYOD1) while suppressing atrophy-related genes (e.g., Fbxo32) and improving fusion potential and myotube integrity. In primary human myoblasts isolated from elderly individuals, CTRP9 and LAMP2A were significantly downregulated, and NLRP3 expression was increased-changes that were partially reversed upon gCTRP9 treatment. These findings collectively demonstrate that the CTRP9-LAMP2A-NLRP3 axis plays a pivotal role in regulating both muscle regeneration and maintenance. By targeting CMA-mediated NLRP3 degradation, CTRP9 offers a promising therapeutic strategy for combating sarcopenia through coordinated modulation of differentiation pathways and muscle atrophy.

DOI: https://doi.org/10.1038/s41419-025-08025-w
Adv Sci (Weinh). 2025 Oct 07. e05989

Muscle Organoids Reveal Exercise-Like Contractions Rapidly Promote Muscle Health Via Lamtor1's Signaling to Both AMPK and mTOR.

Ziyue Yao, Zongmin Jiang, Xupeng Liu, Liping Zhang, Siyu Guo, Yu Chen, Lanfang Luo, Shilin Ma, Peng Wang, Ng Shyh-Chang.

  Exercise triggers molecular changes in skeletal muscles, but distinguishing immediate responses from secondary inter-organ interactions in muscle biopsies remains challenging. Here, this study differentiates human embryonic stem cells (hESCs) into induced skeletal muscle (iMusc) cells to identify hypertrophic factors and generates a novel 3D human iMusc organoid model for studying the direct effects of exercise-like contractions. Transcriptomics profiling reveals iMusc organoids rapidly induced genes associated with calcium signaling, p38/MAPK, EGF/ErbB, and NGF pathways within 1 h, mimicking exercise responses in vivo. Proteomics profiling and in vivo validation reveal rapid activation of both AMPK and mTORC1 signaling, partly through increased Lamtor1 levels, resolving a paradox in exercise biology. Human muscle biopsy analyses reveal Lamtor1 decreases with aging, and increases with exercise. In vivo and organoid experiments both confirm Lamtor1's role in mTORC1-induced strength and AMPK-induced lipid metabolism. Overall, this 3D iMusc organoid model provides insights into primary contraction-induced changes and identifies Lamtor1 as a novel therapeutic target for exercise mimicry.

Keywords:  3D organoid; AMPK; Lamtor1; exercise mimicry; mTOR; mouse models; skeletal muscle

DOI:  https://doi.org/10.1002/advs.202505989
BMC Genomics. 2025 Oct 09. 26(1): 898

Transcriptomic analysis demonstrates moderators of muscle quality are altered in age-related sarcopenic obesity.

Eleanor R Schrems, Ana Regina Cabrera, Ronald G Jones, Francielly Morena, Kevin A Murach, Nicholas P Greene, Tyrone A Washington.

   BACKGROUND: Sarcopenic obesity (SO) is the combined condition of sarcopenia and obesity, which commonly occurs in the older adult population. SO is associated with poor physical function, increased risk of musculoskeletal injury, and reduced quality of life and independence. Information on the molecular underpinnings of this condition is limited. The aim of this study was to provide a transcriptomic analysis characterizing SO induced by lifelong obesity and to provide a deeper understanding of the etiology of the condition.
RESULTS: Young (Y) (6 mo) and aged (A) (21-24 mo) mice were fed either normal chow (L) (12% kcal from fat) or high-fat (O) (60% kcal from fat) diets ad libitum. Through multiple analyses, we observed that genes related to ECM remodeling were downregulated in AO compared with YO, providing insight into the effects of age in a life-long obese condition. Furthermore, we observed that genes related to contraction in slow-twitch muscle fibers and fast-to-slow muscle fiber type transitions were upregulated with obesity in the aged condition.
CONCLUSION: Taken together, our findings reveal specific pathways of dysregulation in SO skeletal muscle, offering molecular insights that enhance our understanding of the underlying mechanisms contributing to impaired muscle function in this condition. Further exploration of these dysregulations is critical to identifying therapeutic treatments targeting the source of muscle functional impairment in SO.

Keywords:  Extracellular matrix; Fibrosis; Muscle contraction; Sarcopenic obesity; Slow-twitch fiber type transition

DOI:  https://doi.org/10.1186/s12864-025-12080-0
Biochemistry (Mosc). 2025 Sep;90(9): 1214-1226

IP3 Receptors Mediate Calcium and Anabolic Signaling Associated with Muscle Atrophy upon 3-Day Hind Limb Unloading in Rats.

Ksenia A Zaripova, Roman O Bokov, Kristina A Sharlo, Svetlana P Belova, Tatiana L Nemirovskaya.

  Skeletal muscle unloading results in muscle atrophy associated with the upregulation of proteolytic genes and suppression of protein synthesis, often accompanied by altered calcium signaling. Here, we used the inositol trisphosphate receptor (IP3R) inhibitor aminoethoxydiphenyl borate (2-APB) to explore the hypothesis that these changes are mediated by IP3Rs. Male Wistar rats were divided into 4 groups: (i) control, (ii) control with daily injections of 2-APB, (iii) 3 days of hind limb suspension, (iv) 3 days of hind limb suspension with daily administration of 2-APB. At the end-point, soleus muscles from the animals were analyzed by Western blotting for the markers of calcium, anabolic, and catabolic signaling. The 3-day hind limb unloading resulted in a decreased muscle weight index, upregulation of the anabolic suppressor pThr56-eEF2, downregulation of anabolic signaling via the mTOR pathway and rRNA expression, as well as the increase in the content of nuclear pThr286-CaMKII (p < 0.05) and cytosolic calcineurin A. While 2-APB did not affect the mTOR-governed changes in anabolism and catabolism, it significantly attenuated alterations in the calcium-dependent targets, such as CaMKII, calcineurin, and eEF2. By contrast, proteolytic signaling (expression of MuRF1, atrogin-1, Ulk1, and ubiquitin mRNAs) after 3-day hind limb unloading was equally upregulated in the control and 2-APB-treated animals. These results suggest that IP3Rs are involved in the unloading-induced muscle atrophy by controlling the nuclear content of calcium; however, they are dispensable for reduced mTOR activity and altered metabolism.

Keywords:  IP3 receptors; atrophy; m soleus; rRNA; unloading

DOI:  https://doi.org/10.1134/S0006297925602497
J Cell Mol Med. 2025 Oct;29(19): e70888

Regarding: In Vivo Evaluation of Decellularised Skeletal Muscle Matrices for Skeletal Muscle Repair: A Systematic Review.

DuJiang Yang, Lin Yang, Shuang Wang, GuoYou Wang.

DOI: https://doi.org/10.1111/jcmm.70888
Regen Med. 2025 Oct 08. 1-12

Translational progress in the development of pharmacotherapies for Duchenne muscular dystrophy.

Kristy Swiderski, Gordon S Lynch.

  Despite the discovery, nearly 40 years ago, that mutations in the dystrophin gene were responsible for Duchenne muscular dystrophy (DMD), a cure for this devastating disease remains elusive. Considerable effort worldwide is focused on understanding DMD and devising treatments, including gene-, cell-, and pharmacologic-based therapies. More than 400 clinical trials for DMD and/or the related Becker muscular dystrophy (BMD) have been registered with clinicaltrials.gov, with many in various stages of completion, and more than 40 having been terminated or withdrawn. The failure of interventions in clinical trials represents a significant emotional burden for the entire DMD community. While some gene-based therapies are being approved, these can be expensive, and currently tend to target specific mutations. Several cell-based therapies and tissue engineering strategies are also currently in development. Of the many pharmacotherapies to address aspects of the pathophysiology of DMD, like preserving muscle fibers, enhancing regeneration, and increasing strength, glucocorticoids remain the most efficacious for attenuating the disease progression. Successful pharmacotherapies may enable patients to take advantage of perfected gene therapies when they eventually become available. Here, we explore the therapeutic merit of different pharmacotherapies currently under consideration and provide an update on recent advances in gene therapies for DMD.

Keywords:  AMPK; gene therapy; inflammation; muscle function; muscle metabolism; muscle regeneration; muscular dystrophy; pharmacotherapy; skeletal muscle

DOI:  https://doi.org/10.1080/17460751.2025.2571355
Skelet Muscle. 2025 Oct 10. 15(1): 29

Signaling networks governing skeletal muscle growth, atrophy, and cachexia : By.

Aniket S Joshi, Meiricris Tomaz da Silva, Savita Kumar, Ashok Kumar.



Keywords:  Cachexia; Hypertrophy; Protein degradation; Protein synthesis; Signaling; Skeletal muscle atrophy

DOI:  https://doi.org/10.1186/s13395-025-00397-z
Aging Cell. 2025 Oct 05. e70242

Muscle Cathepsin B Treatment Improves Behavioral and Neurogenic Deficits in a Mouse Model of Alzheimer's Disease.

Alejandro Pinto, Hazal Haytural, Cássio Morais Loss, Claudia Alvarez, Asude Ertas, Olivia Curtis, Alyssa R Williams, Grayson Murphy, Kenneth J Salleng, Sylvia Gografe, Nishant P Visavadiya, Andy V Khamoui, Ali Altıntaş, Tal Kafri, Romain Barres, Atul S Deshmukh, Henriette van Praag.

  Increasing evidence indicates skeletal muscle function is associated with cognition. Muscle-secreted protease Cathepsin B (Ctsb) is linked to memory in animals and humans, but has an unclear role in neurodegenerative diseases. To address this question, we utilized an AAV-vector-mediated approach to express Ctsb in skeletal muscle of APP/PS1 Alzheimer's disease (AD) model mice. Mice were treated with Ctsb at 4 months of age, followed by behavioral analyses 6 months thereafter. Here we show that muscle-targeted Ctsb treatment results in long-term improvements in motor coordination, memory function, and adult hippocampal neurogenesis, while plaque pathology and neuroinflammation remain unchanged. Additionally, in AD mice, Ctsb treatment normalizes hippocampal, muscle, and plasma proteomic profiles to resemble that of wildtype (WT) controls. In AD mice, Ctsb increases the abundance of hippocampal proteins involved in mRNA metabolism and protein synthesis, including those relevant to adult neurogenesis and memory function. Furthermore, Ctsb treatment enhances plasma metabolic and mitochondrial processes. In muscle, Ctsb treatment elevates protein translation in AD mice, whereas in WT mice mitochondrial proteins decrease. In WT mice, Ctsb treatment causes memory deficits and results in protein profiles across tissues that are comparable to AD control mice. Overall, the biological changes in the treatment groups are consistent with effects on memory function. Thus, skeletal muscle Ctsb application has potential as an AD therapeutic intervention.

Keywords:  Alzheimer's disease; cathepsin B; memory; muscle; neurogenesis; proteomics

DOI:  https://doi.org/10.1111/acel.70242
J Neurosci. 2025 Oct 09. pii: e0707252025. [Epub ahead of print]

Muscle derived BMP4 regulates morphology and function of endplates on extrafusal and intrafusal muscle fibers in adult mice.

Julia M Harrison, Borbala Podor, Asal Yans, Victor F Rafuse.

Understanding factors contributing to neuromuscular junction (NMJ) stability post-development will shed light on how this stability is lost during aging and in neuromuscular diseases. Previous work in Drosophila suggests that morphogens within the bone morphogenetic protein (BMP) family are potential candidates because the BMP homolog, gbb, along with its receptor, wit, have key roles in NMJ structure, stability, and function. Whether BMPs have similar roles at vertebrate NMJs is currently unknown. To examine this question, we generated doxycycline-inducible, muscle specific BMP4 null mice, referred to here as HSACreBMP4fl/fl mice. Motor behavior tasks were examined pre- and post-induction while electrophysiological and morphological characteristics were examined 4 months later in mice of both sexes. Soleus muscles from HSACreBMP4fl/fl mice had significantly reduced contractile force compared to wild-type (WT) littermates. Cross-sectional areas of type I, but not type IIa, muscle fibers were reduced. NMJs were also larger in HSACreBMP4fl/fl muscles compared to controls due to a significant increase in acetylcholine receptor fragment number and distribution. HSACreBMP4fl/fl NMJs displayed reduced amplitude and frequency of miniature endplate potentials (mEPPs), evoked EPP amplitude, quantal content, and had increased failure rates when stimulating at high frequencies. Behaviorally, HSACreBMP4fl/fl mice performed increasingly worse over time on the rotarod after doxycycline administration compared to their WT littermates. Finally, muscle spindle structure and proprioceptive function were significantly compromised in HSACreBMP4fl/fl mice. These results indicate that muscle derived BMP4 regulates morphological and electrophysiological attributes of the NMJ in adult mice as well as the structure and function of muscle spindles.Significance statement Understanding the cellular mechanisms underlying neuromuscular junction (NMJ) stability is critically important in understanding why it is compromised during aging and in motoneuron diseases. Studies in Drosophila larvae have shown that gbb and wit, a ligand and receptor in the BMP signaling pathway, are critical for the stability and function of the NMJ. This paper uses a novel doxycycline-inducible, muscle-specific BMP4 knockdown approach to eliminate muscular BMP4 expression in adult mice. When BMP4 was excised in the adult, we found that muscle strength and neurotransmission were attenuated, endplates fragmented, and mice had locomotor deficits. Furthermore, muscle spindle innervation and proprioceptive function were impaired. Therefore, as in Drosophila larvae, BMP4 is required for normal function and morphology of adult vertebrate NMJs.

DOI: https://doi.org/10.1523/JNEUROSCI.0707-25.2025
Front Cell Dev Biol. 2025 ;13 1658062

Restoration of skeletal muscle function via mesenchymal stem cells: mechanistic insights and therapeutic advances in myasthenia gravis.

Xinyi Zhang, Dongmei Zhang, Ying Zhang, Jian Wang, Jing Lu.

  Mesenchymal stem cells (MSCs) have demonstrated distinct advantages in skeletal muscle repair owing to their self-renewal capacity, multidirectional differentiation potential, and immunomodulatory functions. As a critical regulator of skeletal muscle regeneration, MSCs have been shown to ameliorate skeletal muscle injury induced by factors such as wasting and metabolic disorders through the activation of satellite cell function, inhibition of myofiber atrophy, and regulation of protein metabolic balance. In the treatment of myasthenia gravis (MG), the therapeutic effects of MSCs are exerted through dual mechanisms: first, autoantibody production is reduced via immunomodulation, thereby alleviating immune-mediated attacks at neuromuscular junctions; second, secondary muscle atrophy is delayed by preserving the integrity of neuromuscular signaling. Notably, MSC function is closely associated with acetylcholine metabolism, neuromuscular junction stability, and the aging microenvironment, in which aging-induced MSC decline may exacerbate intramuscular fat infiltration and impair regenerative capacity. In this paper, the biological properties of mesenchymal stem cells (MSCs) and their regulatory roles in skeletal muscle metabolic and injury-related abnormalities are systematically reviewed, and the fundamental significance of MSCs in skeletal muscle repair and myasthenia gravis (MG) therapy is elucidated through multiple mechanisms, including immunomodulation, neuroprotection, and muscle fiber regeneration. Furthermore, the bottlenecks of clinical translation (including cell source selection, phenotypic stability, and efficacy heterogeneity) are analyzed, and the challenges and optimization strategies for clinical application are discussed, with the aim of providing theoretical references for regenerative medicine research in neuromuscular diseases. However, clinical translation studies have indicated that the actual efficacy of most MSC-based therapies is considerably lower than that observed in in vitro experiments. This discrepancy may be attributed to low post-transplantation cell survival, inadequate homing efficiency, and the adverse influence of a senescent microenvironment that impairs cellular function. It has been indicated by recent studies that strategies, including optimization of cell sources and preparation protocols (e.g., the use of allogeneic MSCs derived from adipose tissue or umbilical cord with standardized production), incorporation of biomaterial supports (such as hydrogel-based encapsulation), and adoption of combination therapies (e.g., co-administration with neurotrophic factors or targeted drugs), can effectively improve the delivery efficiency and therapeutic outcomes of MSCs.

Keywords:  clinical translation; immunity; mesenchymal stem cells; myasthenia gravis; skeletal muscle

DOI:  https://doi.org/10.3389/fcell.2025.1658062
J Pharmacol Exp Ther. 2025 Sep 15. pii: S0022-3565(25)40225-0. [Epub ahead of print]392(10): 103712

Exercise is required to maintain unacylated ghrelin response in adult male rat skeletal muscle, regardless of dietary fat consumption.

Nicole M Notaro, Joshua M Budd, Liam A Green, Brielle R Caruso, David J Dyck.

  Unacylated ghrelin (unAG) stimulates fatty acid oxidation (FAO) in isolated male rat skeletal muscle. However, 6 weeks of high-fat feeding results in "ghrelin resistance," or loss of this effect. Recent work has indicated that sedentary behavior may be a main contributor to the loss of skeletal muscle unAG response, potentially representing an early disruption in lipid metabolism in the development of metabolic disease. Therefore, the objective of this study was to investigate whether exercise is required to maintain the stimulatory effect of unAG on FAO in skeletal muscle and if the exercise intensity needed is dependent on dietary fat intake. Male rats were fed either a low- or high-fat diet for 6 weeks while remaining sedentary, or performing low- or high-intensity exercise. Soleus muscle strips were isolated and assessed for their ability to respond to unAG by increasing FAO. High-intensity exercise preserved unAG response under both low-fat and high-fat dietary conditions, an effect not observed in sedentary or low-exercise groups. Additional soleus muscle strips were collected from all groups to assess the activation of the AMP-activated protein kinase-acetyl-CoA carboxylase axis and Ca2+ signaling in response to unAG; however, these pathways were not found to be significantly activated. Exercise also increased corticotropin-releasing factor 2 receptor content, the putative receptor through which unAG signals in skeletal muscle, whereas high-fat feeding had an overall effect to reduce it. However, unAG treatment did not activate cAMP/protein kinase A signaling. These findings demonstrate a protective role of exercise in maintaining skeletal muscle unAG response, although mechanisms remain to be fully elucidated. SIGNIFICANCE STATEMENT: Unacylated ghrelin stimulates fatty acid oxidation and protects insulin response in skeletal muscle; this response is lost with physical inactivity. We demonstrate that high-intensity exercise preserves this response, potentially due to changes in corticotropin-releasing factor 2 receptor content.

Keywords:  Exercise; Ghrelin signaling; Hormonal regulation; Lipid metabolism; Skeletal muscle metabolism; Unacylated ghrelin

DOI:  https://doi.org/10.1016/j.jpet.2025.103712
Am J Physiol Cell Physiol. 2025 Oct 06.

Skeletal Muscle Alterations and Functional Repercussions in Patients with Colorectal Cancer-associated Cachexia.

Britt van de Haterd, Michèlle Hendriks, Bert Houben, Michelle E G Weijzen, Frank Vandenabeele, Kenneth Verboven, Anouk Agten.

  Cancer cachexia causes skeletal muscle wasting and metabolic dysfunction, worsening clinical outcomes in colorectal cancer (CRC). This study examines microscopic and macroscopic skeletal muscle fiber characteristics, and muscle volume in cachectic and non-cachectic CRC patients compared to healthy controls (HCs), and explores how these factors relate to physical performance. In total, 12 cachectic CRC patients, 25 non-cachectic CRC patients, and 25 HCs were included. Cachexia was determined by weight loss and Cachexia Staging Score. Biopsies from the vastus lateralis and erector spinae muscles were analyzed using immunohistochemistry for muscle fiber type cross-sectional area (CSA) and distribution, myonuclear content, and capillary density. Muscle volume was assessed using three-dimensional ultrasound, and CSA and density by computerized tomography scans. Physical function was evaluated with the Short Physical Performance Battery test, handgrip strength, and the Physical Activity Scale for Individuals with Physical Disabilities. Quality of life was assessed using the 36-item Short Form Survey. Cachectic CRC patients showed reduced type II muscle fiber cross-sectional area in the vastus lateralis compared to HCs and non-cachectic CRC patients. Non-cachectic CRC patients exhibited a slow-to-fast muscle fiber shift compared to HCs. Myonuclear content was lower in both cancer groups. Muscle volume and density were reduced in cachectic CRC patients. Positive correlations were found between microscopic and macroscopic skeletal muscle characteristics, muscle strength, physical performance, and quality of life, respectively. CRC patients, especially those with cachexia, showed type II muscle fiber atrophy, reduced myonuclear content, and impaired physical function, emphasizing the need for targeted prehabilitation interventions.

Keywords:  Cachexia; Colorectal cancer; Cross-sectional area; Muscle Atrophy; Muscle fiber typing

DOI:  https://doi.org/10.1152/ajpcell.00533.2025
Aging Cell. 2025 Oct;24(10): e70191

Experimental Evidence Against Taurine Deficiency as a Driver of Aging in Humans.

Vincent Marcangeli, Marina Cefis, Rami Hammad, Jordan Granet, Jean-Philippe Leduc-Gaudet, Pierrette Gaudreau, Mylène Aubertin-Leheudre, Marc Bélanger, Richard Robitaille, José A Morais, Gilles Gouspillou.

  Taurine deficiency was recently proposed as a driver of aging in various species, including humans. To test this hypothesis, we assessed whether circulating taurine was associated with aging and physical performance in 137 physically inactive and physically active men aged 20-93. No association between circulating taurine levels and age, muscle mass, strength, physical performance, or mitochondrial function was observed, thereby challenging the implication of taurine deficiency as a primary driver of aging in humans.

Keywords:  aging biomarker; functional capacities; geroscience; mitochondria; mitochondrial function; physical activity; sarcopenia; skeletal muscle; taurine

DOI:  https://doi.org/10.1111/acel.70191
Sci Rep. 2025 Oct 06. 15(1): 34810

Integrated transcriptomics unveils mitochondrial oxidative phosphorylation dysfunction as a shared mechanism in sarcopenia and obesity.

Ruixuan Yu, Lei Miao, Jinchao Wang, Dingding Wang, Yajun Liu, Ling Wang, Renxian Wang.

  Sarcopenia and obesity, two prevalent metabolic disorders in aging populations, often coexist and share overlapping pathophysiological mechanisms, yet the molecular mechanisms underlying their comorbidity remain elusive. This study aimed to identify key gene expression signatures and pathways underlying their comorbidity through integrative transcriptomic and bioinformatics analyses. Gene expression datasets from sarcopenia (GSE111016, skeletal muscle) and obesity (GSE152991, adipose tissue) were downloaded from the GEO database. Differentially expressed genes (DEGs) were identified using the limma package, and 208 common differentially expressed genes (CDEGs) were selected via Venn diagram intersection. Functional enrichment analyses (GO and KEGG) were performed to explore shared biological processes and pathways. A protein-protein interaction (PPI) network was constructed using STRING and Cytoscape, and key CDEGs were identified via ten topological algorithms (e.g., MCC, Degree) in the CycloHubba plugin. Pearson correlation analysis and qPCR were used to validate gene co-expression patterns and expression levels in tissue samples. GO and KEGG analyses revealed that CDEGs were significantly enriched in mitochondrial oxidative phosphorylation, electron transport chain, and thermogenesis pathways, with overlap in neurodegenerative disease pathways. The PPI network and multi-algorithm integration identified four key CDEGs: SDHB, SDHD, ATP5F1A, and ATP5F1B, all of which are components of mitochondrial respiratory chain complexes. These genes exhibited strong positive correlations (r > 0.86, p < 10⁻¹²) in both datasets and were significantly downregulated in sarcopenia and obesity tissues, as validated by qPCR. This study confirms mitochondrial dysfunction, particularly impaired oxidative phosphorylation, as a common pathological mechanism linking sarcopenia and obesity. The key genes SDHB, SDHD, ATP5F1A, and ATP5F1B represent potential therapeutic targets for managing these comorbid metabolic disorders. Future research should explore their functional roles in energy metabolism and cross-tissue crosstalk to develop targeted interventions.

Keywords:  Bioinformatics; Mitochondrial dysfunction; Obesity; Oxidative phosphorylation; Sarcopenia

DOI:  https://doi.org/10.1038/s41598-025-18824-y
Radiographics. 2025 Nov;45(11): e240190

Myopathies: Radiologist's Essential Tips for Clinical, Pathologic, and Imaging Findings.

Yumi Tai, Nobuyuki Eura, Toshiteru Miyasaka, Ryota Nakano, Tomoko Ochi, Nagaaki Marugami, Toshihiro Tanaka, Kazuma Sugie.

Myopathies are a heterogeneous group of disorders affecting the structure and metabolism of skeletal muscles. The causes of myopathies include hereditary factors (muscular dystrophy, distal myopathies, metabolic myopathies) and acquired factors (infections, endocrine abnormalities, drug-induced causes, idiopathic inflammatory myopathies). Recent advances have enabled clinicians to diagnose myopathies through genetic testing, highlighting the importance of differential diagnoses in clinical practice. Typical symptoms of myopathy include muscle weakness and atrophy. Recognizing symptom onset, progression, affected muscles, and associated symptoms (cataracts, skin rashes, lung issues, joint problems) facilitates accurate diagnosis. Myositis-specific autoantibodies and electromyography are valuable for diagnosing conditions such as dermatomyositis and myotonic dystrophy. Imaging, particularly muscle MRI, is crucial for diagnosis, optimal biopsy site selection, and assessment of disease activity. Muscle MRI allows identification of fat replacement, edema, and inflammatory changes. US and PET/CT offer additional diagnostic and evaluation benefits. Muscle pathologic analysis is essential for diagnosing muscular disorders and assessing structural changes, fiber size variation, necrosis, regeneration, fibrosis, and abnormal structures. Congenital myopathies such as RYR1- and NEB-related myopathies exhibit distinct MRI patterns. Muscular dystrophies, including dystrophinopathies and myotonic dystrophy type 1, display characteristic MRI findings. Limb-girdle muscular dystrophy subtypes reveal specific involvement patterns, leading to diagnosis. Metabolic and mitochondrial myopathies require biochemical testing, muscle biopsy, and genetic analysis. Idiopathic inflammatory and treatment-related myopathies also exhibit distinct imaging features. Continued research and enhanced diagnostic techniques will improve myopathy management. Radiologists must be knowledgeable about the clinical, pathologic, and imaging findings to ensure accurate diagnoses and optimal patient care. ©RSNA, 2025 Supplemental material is available for this article.

DOI: https://doi.org/10.1148/rg.240190
IUBMB Life. 2025 Oct;77(10): e70068

MyomiRs Expression in Limb Girdle Muscular Dystrophy.

G Breveglieri, M T Altieri, M T Rodia, R Costa, F Frabetti, G Cenacchi, G Sabbioni, M Borgatti.

This manuscript is a comprehensive review focused on the role of microRNAs (miRs)-short RNA molecules-in Limb Girdle Muscular Dystrophy (LGMD). LGMD encompasses various and heterogeneous rare genetic neuromuscular diseases, characterized by the progressive wasting and deterioration of muscle fibers, predominantly affecting the pelvic and shoulder girdles. Similar to other muscular dystrophies, LGMD exhibits a dysregulated expression of miRs that are crucial for gene expression regulation and cellular processes. Notably, myomiRNAs, which are preferentially expressed in muscle tissue and linked to muscle cell proliferation and differentiation, appear to be particularly affected. Numerous studies have aimed to identify differentially expressed miRNAs in both physiological and pathological conditions with different purposes: (a) the identification of molecular markers for diagnostic and prognostic purposes, and for evaluation of the effects of possible therapeutic strategies; (b) the detection of a molecular signature to differentiate both LGMD from other muscular dystrophies and LGMD subtypes from each other. The main conclusions so far emerged from published studies are: (a) a high number of differentially expressed miRs have been found in both the serum and muscle fibers of LGMD patients (canonical myomiRNAs, including miR-1, miR-133a/b, and miR-206, are frequently found to be dysregulated across various LGMD subtypes); (b) circulating levels of miR-206 were found to be significantly elevated in LGMD patients compared to healthy subjects and have been suggested as a potential biomarker of general muscle damage in various muscular dystrophies; (c) possible identification of subtype-specific molecular signatures (for instance, the combination of six specific miRs has been proposed to discriminate LGMD patients from controls and to identify particular LGMD subtypes, such as LGMDR1, LGMDR2, LGMDR3, and LGMDR4); (d) currently not validated miRNA biomarkers have been described for clinical use yet in LGMD due to heterogeneity of published studies (regarding the type of biological material and techniques used) and limited number of involved patients. Therefore, while miRs show great promise for improving the molecular understanding, stratification, and management of LGMD patients, further rigorous research and validation in larger, standardized patient cohorts are necessary to confirm the clinical reliability of these identified miRNAs.

DOI: https://doi.org/10.1002/iub.70068
Cell Mol Life Sci. 2025 Oct 11. 82(1): 356

Cell therapy for Duchenne muscular dystrophy: promises, challenges, and controversies.

Agnieszka Łoboda, Józef Dulak.

  Despite extensive studies, Duchenne muscular dystrophy, a neuromuscular disorder caused by the lack of dystrophin, a key muscle structural protein, remains an incurable disease. One of the potential treatment options currently being investigated is cell therapy, although it has not yet been clinically established. Several strategies, including muscle satellite cells, mesoangioblasts (vessel-associated multipotent stem cells), and induced pluripotent stem cell (iPSC)-derived muscle cells, have emerged as tools for restoring dystrophin expression and regenerating damaged muscle tissue. Nevertheless, each of these approaches faces significant limitations, including poor cell engraftment, low delivery efficiency, and the risk of immune rejection. Furthermore, long-term safety, the possibility of tumorigenicity, and off-target effects must be rigorously evaluated. Importantly, the latter technology, utilizing cardiomyocytes differentiated from iPSC, holds the potential for addressing cardiomyopathy, the major cause of death of DMD patients. At the same time, several interventions using cells with claimed stem cell potential have emerged, raising both scientific and ethical concerns. This review summarizes recent advancements in the development of cell therapies for DMD, highlighting promising progress while critically analysing questionable approaches.

Keywords:  Cardiomyopathy; DMD; Induced pluripotent stem cells; Myoblasts; Satellite cells

DOI:  https://doi.org/10.1007/s00018-025-05904-5