bims-moremu 2025-05-25 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2025–05–25
24 papers selected by
Anna Vainshtein, Craft Science Inc.

Human skeletal muscle-specific hypertrophy with exercise training and aging: a comprehensive review.
Heat therapy preserves myofibre size and SERCA-mediated Ca2+ uptake in the mouse soleus after tenotomy surgery.
Global mitophagy inhibition via BNIP3 ablation is not sufficient to alleviate skeletal muscle impairments in male and female tumor-bearing mice.
Skeletal Muscle as a Mediator of Interorgan Crosstalk During Exercise: Implications for Aging and Obesity.
FOXK2 in skeletal muscle development: a new pathogenic gene for congenital myopathy with ptosis.
Histone Lactylation Antagonizes Senescence and Skeletal Muscle Aging by Modulating Aging-Related Pathways.
Comparison of Phasic Store-Operated Calcium Entry in Rat Slow- and Fast-Twitch Muscle Fibers.
Reduced myogenic differentiation capacity of satellite cell-derived myoblasts in male ICR mice compared with male C57BL/6 and BALB/c mice.
Improvement of mitochondrial function in Duchenne muscular dystrophy skeletal muscle cells by coenzyme Q10 delivery to mitochondria.
Integrated single-cell multiome analysis reveals muscle fiber-type gene regulatory circuitry modulated by endurance exercise.
Serial sarcomerogenesis does not contribute to the initial repeated bout effect in skeletal muscle.
Inhibitory effects of high extracellular L-glutamate concentrations on skeletal myogenesis.
Beneficial but diverse influence of custom-designed hydrogels modified with IL-4 and SDF-1 peptides on selected populations of cells essential for skeletal muscle regeneration.
mTORC1 signalling and protein synthesis are elevated in response to amino acids in human myotubes obtained from young, old, and old trained men.
Circadian rhythms in muscle health and diseases.
Skeletal muscle TFEB overexpression does not increase neurogenesis markers in the young female hippocampus.
Mitochondrial Electron Transfer Chain Activation in Atrophic Muscle: Implications for Calcium Signaling and Chondrocyte Apoptosis in Osteoarthritis.
The Influence of Sex on Fiber-Specific Indices of Oxidative Capacity in Human Skeletal Muscle.
Skeletal muscle mitochondrial health in type 1 diabetes: the role of exercise capacity and lifestyle factors.
Combining dynamin 2 myopathy and neuropathy mutations rescues both phenotypes.
Repurposed Nrf2 activator dimethyl fumarate rescues muscle inflammation and fibrosis in an aggravated mdx mouse model of Duchenne muscular dystrophy.
Cardiovascular System is Influenced by Skeletal Muscle-derived Extracellular Vesicles, Myokines and MicroRNAs Based on Interorgan Communication: A Systematic Review.
Systemic Inflammation and Disruption of the Local Microenvironment Compromise Muscle Regeneration: Critical Pathogenesis of Autoimmune-Associated Sarcopenia.
Exercise-induced CLCF1 attenuates age-related muscle and bone decline in mice.

J Appl Physiol (1985). 2025 May 22.

Human skeletal muscle-specific hypertrophy with exercise training and aging: a comprehensive review.

Caroline S Vincenty, Gilhyeon Yoon, Kaitlyn Rogers, Masatoshi Naruse, Scott Trappe, Todd A Trappe.

  Age-related skeletal muscle atrophy is a muscle group-specific process. Therefore, we were interested in understanding exercise-induced hypertrophy across different muscles in older individuals. This review provides a comprehensive summary of the available information on muscle-specific hypertrophy responses to exercise training with aging (≥60y). In total, 6018 peer-reviewed publications were reviewed for inclusion (e.g., supervised resistance (RE) or aerobic (AE) exercise training; MRI, CT, or ultrasound determined muscle size), resulting in 1417 individuals from 68 studies (RE: n=1254; AE: n=163). Data were divided across age (60-69y, 70-79y, 80-89y, ≥90y) and duration (≤9, 10-14, 15-19, 20-24, ≥25wks), with the majority coming from the sexa- and septuagenarians (n=1335, 94%) and 10-14wks of training (n=806, 57%). The number of muscle groups (RE: 7, AE: 8) and subcomponent muscles (RE: 10, AE: 16) were a low representation of the whole-body musculature, with 79% of the data (n=1113) coming from the quadriceps. The 10-14wk responses showed a range of unique muscle-specific hypertrophy and atrophy (RE: 60-69y: 2-14% across six muscles; 70-79y: 1-12% across nine muscles; AE: 70-79y: -6% to +9% across 22 muscles). The large quadriceps-only resistance exercise training dataset (60-79 yrs) showed that no additional hypertrophy was observed with increased training repetitions (i.e., dose), and that men and women elicited an equivalent hypertrophic training response. The optimal exercise training mode(s) and dose(s) for all of the skeletal muscles of sexa-, septa-, octo-, and nonagenarian women and men is far from being elucidated based on the current scientific literature.

Keywords:  aging; exercise; sarcopenia; skeletal muscle

DOI:  https://doi.org/10.1152/japplphysiol.00892.2024
Physiol Rep. 2025 May;13(10): e70385

Heat therapy preserves myofibre size and SERCA-mediated Ca2+ uptake in the mouse soleus after tenotomy surgery.

Michael K Barfoot, Jessica L Braun, Phillip J Wallace, Bianca M Marcella, Ryan W Baranowski, Rebecca E K MacPherson, Stephen S Cheung, Val A Fajardo.

  Heat therapy (HT) has been shown to induce physiological adaptations in muscle, including a reduction in the severity of muscle atrophy resulting from unloading. The muscle atrophy caused by unloading can be partially attributed to the dysregulation of Ca2+ in the muscle cell, which can activate calpain-mediated proteolysis. The sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) is a primary regulator of Ca2+ in muscle, and SERCA dysfunction has been repeatedly demonstrated in various models of muscle unloading. Heat shock protein 70 (HSP70) is a heat-inducible chaperone protein that binds to SERCA and protects against its dysfunction. While previous research has shown HT to upregulate HSP70 in rodent muscle, even in the unloaded state, the effects of HT on SERCA function in rodent skeletal muscle under these conditions remain unknown. Here, we characterized the effects of 4 weeks of HT on soleus muscle size, HSP70 expression, SERCA function, and maximal calpain activity in male C57BL/6J mice subjected to muscle unloading through tenotomy. Four weeks of HT preserved the cross-sectional area of soleus myofibres following tenotomy, while also upregulating HSP70, maintaining SERCA-mediated Ca2+ uptake, and reducing maximal calpain activity. Therefore, our research offers new insights into the advantages of HT for muscle health and physiology.

Keywords:  HSP70; SERCA; calpain; muscle unloading

DOI:  https://doi.org/10.14814/phy2.70385
J Appl Physiol (1985). 2025 May 16.

Global mitophagy inhibition via BNIP3 ablation is not sufficient to alleviate skeletal muscle impairments in male and female tumor-bearing mice.

Francielly Morena, Ana Regina Cabrera, Toby L Chambers, Pieter J Koopmans, Seongkyun Lim, Stavroula Tsitkanou, Sabin Khadgi, Calvin Peterson, Eleanor R Schrems, Ruqaiza Muhyudin, Sepideh Shakeri, Kevin Zhao, Devan Mishra, Tyrone Washington, Kevin A Murach, Nicholas P Greene.

  Cancer cachexia (CC) is marked by severe skeletal muscle loss and dysfunction, associated with mitochondrial degeneration. Our previous studies showed induction of the mitophagy marker BNIP3 3-weeks post-Lewis Lung Carcinoma (LLC) induction. We hypothesize excessive mitophagy contributes to muscle wasting in CC. To test this, we used a Bnip3 knockout (KO) mouse model with LLC-induced CC to assess its impact on muscle outcomes. 8-weeks-old male and female mice were injected with 1x106 LLC cells or PBS (sham controls). After 4 weeks, we assessed muscle function through dorsiflexor electrophysiology, muscle protein synthesis via deuterium oxide labeling, and mitochondrial respiration. Plantaris and white-gastrocnemius muscles were analyzed for mitochondrial respiratory function, tibialis anterior (TA) for muscle cross-sectional area, and mixed-gastrocnemius for protein and mRNA analysis. Bnip3 KO showed some benefits in males, including attenuated fat loss and splenomegaly and near-significant attenuation of EDL mass loss. In females, Bnip3 KO did not prevent relative muscle atrophy or functional impairments. In males, KO lowered protein synthesis independent of cancer. Despite KO reducing mitophagy markers, it did not improve muscle mitochondrial respiration or functional outcomes. In both sexes, KO mice exhibited unbalanced mitochondrial dynamics with increased fission and reduced fusion, processes also impaired by LLC. Overall, global Bnip3 ablation may not offer significant benefits for CC by itself. These findings suggest targeting aberrant mitophagy via complete Bnip3 deletion is insufficient to alleviate cancer-induced muscle detriments in both biological sexes, while BNIP3-mediated mitophagy may be needed to maintain protein anabolism.

Keywords:  Cachexia; Lung cancer; fractional synthesis rates; mitochondrial respiration; muscle contractility

DOI:  https://doi.org/10.1152/japplphysiol.00009.2025
Circ Res. 2025 May 23. 136(11): 1407-1432

Skeletal Muscle as a Mediator of Interorgan Crosstalk During Exercise: Implications for Aging and Obesity.

Julia A Shero, Maléne E Lindholm, Marco Sandri, Kristin I Stanford.

  Physical exercise is critical for preventing and managing chronic conditions, such as cardiovascular disease, type 2 diabetes, hypertension, and sarcopenia. Regular physical activity significantly reduces cardiovascular and all-cause mortality. Exercise also enhances metabolic health by promoting muscle growth, mitochondrial biogenesis, and improved nutrient storage while preventing age-related muscle dysfunction. Key metabolic benefits include increased glucose uptake, enhanced fat oxidation, and the release of exercise-induced molecules called myokines, which mediate interorgan communication and improve overall metabolic function. These myokines and other exercise-induced signaling molecules hold promise as therapeutic targets for aging and obesity-related conditions.

Keywords:  cardiovascular diseases; epinephrine; hypertension; muscle, skeletal; sarcopenia

DOI:  https://doi.org/10.1161/CIRCRESAHA.124.325614
EMBO Mol Med. 2025 May 23.

FOXK2 in skeletal muscle development: a new pathogenic gene for congenital myopathy with ptosis.

Peixuan Wu, Nan Song, Yang Xiang, Zhe Tao, Bing Mao, Ruochen Guo, Xin Wang, Dan Wu, Zhenzhen Zhang, Xin Chen, Duan Ma, Tianyu Zhang, Bingtao Hao, Jing Ma.

  Congenital ptosis, a genetic disorder involving levator palpebrae muscle dysfunction, is often associated with congenital myopathy. The genetic causes of this condition remain poorly understood. In this study, we identified FOXK2 mutations in five pedigrees with congenital myopathy and ptosis through whole exome sequencing and Sanger sequencing. Zebrafish with foxk2 deficiency exhibited underdeveloped skeletal muscles and reduced mobility, while mice with Foxk2 deletion in skeletal muscle stem cells (MuSCs) showed generalized skeletal muscle abnormalities. Further analysis revealed that FOXK2 deficiency impaired myogenic differentiation in C2C12 cells and disrupted mitochondrial homeostasis in both mouse MuSCs and C2C12 cells. Rescue experiments confirmed the loss-of-function effects of FOXK2 mutation. Coenzyme Q10 treatment improved mitochondrial function and alleviated skeletal muscle development defects in Foxk2-deficient mice. Preliminary omics analysis suggested FOXK2 directly regulates the expression of mitochondrial function-related genes by modulating chromatin accessibility at its binding sites. Our study identifies FOXK2 as a novel pathogenic gene for congenital myopathy with ptosis and highlights its essential role in skeletal muscle development and mitochondrial homeostasis, offering insights for potential diagnostics and therapies.

Keywords:  Coenzyme Q10; FOXK2; Mitochondrial Homeostasis; Ptosis; Skeletal Muscle Development

DOI:  https://doi.org/10.1038/s44321-025-00247-x
Adv Sci (Weinh). 2025 May 19. e2412747

Histone Lactylation Antagonizes Senescence and Skeletal Muscle Aging by Modulating Aging-Related Pathways.

Fanju Meng, Jianuo He, Xuebin Zhang, Wencong Lyu, Ran Wei, Shiyi Wang, Zhehao Du, Haochen Wang, Jinlong Bi, Xueyang Hua, Chao Zhang, Yiting Guan, Guoliang Lyu, Xiao-Li Tian, Lijun Zhang, Wenbing Xie, Wei Tao.

  Epigenetic alterations are among the prominent drivers of cellular senescence and/or aging, intricately orchestrating gene expression programs during these processes. This study shows that histone lactylation, plays a pivotal role in counteracting senescence and mitigating dysfunctions of skeletal muscle in aged mice. Mechanistically, histone lactylation and lactyl-CoA levels markedly decrease during cellular senescence but are restored under hypoxic conditions primarily due to elevated glycolytic activity. The enrichment of histone lactylation at promoters is essential for sustaining the expression of genes involved in the cell cycle and DNA repair pathways. Furthermore, the modulation of enzymes crucial for histone lactylation, leads to reduced histone lactylation and accelerated cellular senescence. Consistently, the suppression of glycolysis and the depletion of histone lactylation are also observed during skeletal muscle aging. Modulating the enzymes can also lead to the loss of histone lactylation in skeletal muscle, downregulating DNA repair and proteostasis pathways and accelerating muscle aging. Running exercise increases histone lactylation, which in turn upregulate key genes in the DNA repair and proteostasis pathways. This study highlights the significant roles of histone lactylation in modulating cellular senescence as well as muscle aging, providing a promising avenue for antiaging intervention via metabolic manipulation.

Keywords:  epigenetics; histone lactylation; senescence; skeletal muscle aging

DOI:  https://doi.org/10.1002/advs.202412747
Acta Physiol (Oxf). 2025 Jun;241(6): e70059

Comparison of Phasic Store-Operated Calcium Entry in Rat Slow- and Fast-Twitch Muscle Fibers.

Elena Lilliu, Rocky Choi, Karlheinz Hilber, Bradley Launikonis, Xaver Koenig.

   AIM: This study investigates the activation and regulation of phasic store-operated calcium entry (pSOCE) in fast- and slow-twitch skeletal muscle fibers. Specifically, we aimed to enhance the sensitivity of pSOCE detection in slow-twitch fibers by optimizing ionic conditions and to compare the physiological relevance of pSOCE between fiber types.
METHODS: We employed mechanically skinned fast-twitch extensor digitorum longus (EDL) muscle fibers loaded with spectrally distinct Ca2+-sensitive dyes to simultaneously measure action potential-induced sarcoplasmic reticulum Ca2+ release and t-tubular system Ca2+ dynamics with millisecond resolution. Experimental conditions were optimized by reducing cytosolic Mg2+ and EGTA buffering to enhance Ca2+ release in slow-twitch soleus fibers. Confocal microscopy was used to track t-tubular system Ca2+ depletion and reuptake during electric field stimulation.
RESULTS: Skinned soleus fibers exhibited ~8-fold lower Ca2+ release per action potential compared to EDL fibers, yet pSOCE amplitudes were comparable. Reducing Mg2+ and EGTA levels increased Ca2+ release and left pSOCE kinetics in EDL fibers unaltered, but enabled pSOCE measurements in soleus fibers. While pSOCE in EDL fibers followed a linear dependence on the ambient Ca2+ concentration in the t-tubular system, such a relationship was violated in soleus fibers.
CONCLUSION: These findings reveal a novel, fiber-type-specific difference in pSOCE regulation. When compared to EDL fibers, soleus fibers exhibited a higher sensitivity to SOCE activation despite releasing less Ca2+ from the sarcoplasmic reticulum upon an action potential. These differences may allow soleus fibers to sustain Ca2+ homeostasis more effectively, be more resilient against disruptions in Ca2+ handling, and entail protection against disease states.

Keywords:  EC‐coupling; calcium; skeletal muscle; slow‐twitch muscle; store‐operated calcium entry

DOI:  https://doi.org/10.1111/apha.70059
In Vitro Cell Dev Biol Anim. 2025 May 19.

Reduced myogenic differentiation capacity of satellite cell-derived myoblasts in male ICR mice compared with male C57BL/6 and BALB/c mice.

Takahiro Suzuki, Yuriko Nishi, Taku Koyama, Minori Nakada, Rio Arimatsu, Yusuke Komiya, Aoi Ogawa, Rika Osaki, Takahiro Maeno, Ai Saiga Egusa, Mako Nakamura, Ryuichi Tatsumi, Koichi Ojima, Takanori Nishimura.

  Many strains of wild-type laboratory mice have been developed for studies in the life sciences, including skeletal muscle cell biology. Muscle regeneration capacity differs among wild-type mouse strains. However, few studies have focused on whether myogenic stem cells (satellite cells) are directly related to mouse strain-dependent myoregeneration gaps using in vitro culture models. In this study, we selected three major wild-type mouse strains, CD1 (outbred; Jcl:ICR [ICR]), C57BL/6NJcl (inbred; B6), and BALB/cAJcl (inbred; C), which are widely used in laboratory experiments. Initially, we compared myotube fusion capabilities using satellite cell-derived myoblasts. The results showed that cell cultures isolated from male ICR mice could not efficiently form myotubes owing to low expression levels of myogenic regulatory factors (e.g., MyoD, myogenin, myocyte enhancer factor [MEF] 2A, and MEF2C) compared with B6 and C mouse strains. Next, we compared the myofiber-type compositions of muscle tissues and cultured myotubes among male mice from each of the three strains. Although each muscle tissue used for satellite cell isolation similarly expressed fast-twitch myofiber markers in all mouse strains, male ICR-derived myoblasts formed abundant amounts of slow-type myotubes. By contrast, myotubes from male B6 and C mice expressed substantial levels of fast-twitch myofiber markers. We also performed a comparative experiment in female ICR, B6, and C mouse strains, similar to the male mouse experiments. The myogenic differentiation potencies of myoblasts and myofiber-type compositions of myotubes in female mouse strains were similar. Thus, male ICR-derived satellite cells (myoblasts) had low myogenic differentiation potential, which may be associated with the tendency slow-twitch myotube formation.

Keywords:  Mouse strain; Myoblasts; Myofiber type; Myogenic differentiation; Myotubes; Satellite cells

DOI:  https://doi.org/10.1007/s11626-025-01035-0
Biochem Biophys Res Commun. 2025 May 17. pii: S0006-291X(25)00717-X. [Epub ahead of print]771 152003

Improvement of mitochondrial function in Duchenne muscular dystrophy skeletal muscle cells by coenzyme Q10 delivery to mitochondria.

Itsumi Sato, Daisuke Sasaki, Jiro Abe, Keitaro Yamanouchi, Atsuhito Takeda, Yuma Yamada.

  Duchenne muscular dystrophy (DMD) is a genetic disease, with no curative therapy, and is associated with mitochondrial dysfunction in skeletal muscle. Thus, mitochondrial treatment is a potential therapy for DMD. However, few studies have reported on such treatments because of the difficulty of drug delivery to mitochondria. Here, we used MITO-Porter to deliver coenzyme Q10 to the mitochondria of primary skeletal muscle cells isolated from DMD model rats. Our results show the therapeutic potential of mitochondrial activation for DMD.

Keywords:  Coenzyme Q(10); Decreased mitochondrial respiratory capacity; Drug delivery system; Duchenne muscular dystrophy; Nanoparticle; Skeletal muscle cell

DOI:  https://doi.org/10.1016/j.bbrc.2025.152003
Genome Res. 2025 May 20. pii: gr.280051.124. [Epub ahead of print]

Integrated single-cell multiome analysis reveals muscle fiber-type gene regulatory circuitry modulated by endurance exercise.

Aliza Batya Rubenstein, Gregory R Smith, Zidong Zhang, Xi Chen, Toby Leigh Chambers, Frederique Ruf-Zamojski, Natalia Mendelev, Wan Sze Cheng, Michel Zamojski, Mary Anne S Amper, Venugopalan D Nair, Andrew Reid Marderstein, Stephen B Montgomery, Olga G Troyanskaya, Elena Zaslavsky, Todd Trappe, Scott Trappe, Stuart C Sealfon.

Endurance exercise induces multi-system adaptations that improve performance and benefit health. Gene regulatory circuit responses within individual skeletal muscle cell types, which are key mediators of exercise effects, have not been studied. We mapped transcriptome, chromatin, and regulatory circuit responses to acute endurance exercise in muscle using same-cell RNA-seq/ATAC-seq multiome assay. High-quality data was obtained from 37,154 nuclei comprising 14 cell types in vastus lateralis samples collected before and 3.5 hours after either 40 min cycling exercise at 70% VO2max or 40 min supine rest. Both shared and cell type specific regulatory programs were identified. Differential gene expression and accessibility sites were largely distinct within nuclei for each cell type and muscle fiber, with the largest numbers of regulatory events observed in the three muscle fiber types (slow, fast, and intermediate) and lumican (LUM) expressing fibro-adipogenic progenitor cells. Single-cell regulatory circuit triad reconstruction (transcription factor, chromatin interaction site, regulated gene) also identified largely distinct gene regulatory circuits modulated by exercise in the three muscle fiber types and LUM-expressing fibro-adipogenic progenitor cells, involving a total of 328 transcription factors acting at chromatin sites regulating 2,025 genes. This web-accessible single-cell dataset and regulatory circuitry map serve as a resource for understanding the molecular underpinnings of the metabolic and physiological effects of exercise and to guide interpretation of the exercise response literature in bulk tissue.

DOI: https://doi.org/10.1101/gr.280051.124
J Biomech. 2025 May 17. pii: S0021-9290(25)00279-9. [Epub ahead of print]187 112767

Serial sarcomerogenesis does not contribute to the initial repeated bout effect in skeletal muscle.

Ethan Vlemmix, Avery Hinks, Geoffrey A Power.

Neuromuscular function is impaired following an unaccustomed bout of eccentric exercise. However, through the repeated bout effect (RBE), the muscle is protected from impaired neuromuscular function following a subsequent bout of eccentric exercise. It has been speculated that the addition of sarcomeres in series (sarcomerogenesis) contributes to the RBE by reducing mechanical strain on muscle fibers during active lengthening. However, whether sarcomerogenesis actually contributes to the RBE is unknown. We investigated whether a single bout of damaging eccentric exercise induces serial sarcomerogenesis, and if this offers a protective effect on the muscle. Using an in-vivo set up, twenty-four Sprague-Dawley rats performed maximal eccentric contractions of the plantar flexors to impair mechanical function. Thirteen days following the initial eccentric exercise bout, twelve rats were sacrificed, to assess serial sarcomere number (SSN) of the soleus and medial gastrocnemius (MG) via laser diffraction. The remaining twelve rats completed an identical second bout of eccentric exercise to assess the RBE. A single bout caused long lasting impairments in torque production (-3% for 100 Hz; -16 % for 10 Hz; P < 0.05 compared to baseline). Following the repeated bout, there was a protective effect with all torque measures recovering by 2 days post-exercise (P > 0.05 compared to baseline). SSN did not differ between the control and exercised legs for either muscle (P > 0.05). There was a robust RBE following the second bout of eccentric exercise, with no increase in SSN indicating serial sarcomerogenesis is not one of the primary initial mechanisms contributing to the RBE.

DOI: https://doi.org/10.1016/j.jbiomech.2025.112767
Sci Rep. 2025 May 19. 15(1): 17364

Inhibitory effects of high extracellular L-glutamate concentrations on skeletal myogenesis.

Himiko Ban, Koji Nobe, Soushi Kobayashi.

  L-glutamate (Glu) is accumulated abundantly in skeletal muscle cells and plays a central role in energy production, amino acid metabolism, and protein synthesis. If intracellular Glu leaks due to plasma membrane fragility or injury, it may adversely affect the surrounding myocytes. In the present study, we examined the effects of high extracellular Glu concentration on skeletal myogenesis. Five mM Glu stimulation decreased the expression of fast-twitch myosin heavy chain isoforms and myogenin, an indicator of C2C12 cell differentiation into myocytes, and inhibited the cell fusion. This stimulation reduced the expression of metabotropic glutamate receptor 5 (mGluR5) and N-methyl-D-aspartate receptor 1 (NMDAR), which are glutamate receptors on the C2C12 plasma membrane. Furthermore, phosphorylation of p38 mitogen-activated protein kinase, myocyte enhancer factor 2A, and cAMP response element binding protein, which are downstream of these Glu receptors, was reduced, and the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) decreased. Moreover, reduced mGluR5 and NMDAR expression and muscle weight were observed in the tibialis anterior muscle of mice with increased aging markers. These findings provide insights into the molecular mechanisms contributing to age-related muscle fragility and highlight the potential detrimental effects of elevated Glu on muscle health.

Keywords:   l-glutamate; C2C12; Glutamate receptor; Myogenesis; Skeletal muscle

DOI:  https://doi.org/10.1038/s41598-025-01840-3
Int J Biol Macromol. 2025 May 15. pii: S0141-8130(25)04834-2. [Epub ahead of print] 144282

Beneficial but diverse influence of custom-designed hydrogels modified with IL-4 and SDF-1 peptides on selected populations of cells essential for skeletal muscle regeneration.

Anna Ostaszewska, Zuzanna Michalska, Maria Dzierzynska, Martyna Fularczyk, Kacper Bielak, Agnieszka Morawska, Magdalena Kosmala, Izabela Kulig, Justyna Morytz, Hanna Trusiak, Małgorzata Zimowska, Sylwia Rodziewicz-Motowidlo, Maria A Ciemerych, Karolina Archacka, Edyta Brzoska.

  Under specific circumstances, such as extensive injuries, the development of degenerative diseases, or aging, the naïve potential of skeletal muscle to regenerate may be limited. For this reason, different tools and approaches are being tested which could result in the improvement of skeletal muscle reconstruction. Among them are hydrogels, investigated also by us, additionally functionalized with fragments of proteins known to support skeletal muscle regeneration, i.e., stromal-derived factor 1 or interleukin 4. In the current study, we evaluated the impact of such custom-designed hydrogels on different human cells important for efficient muscle regeneration, i.e., myoblasts, crucial for myofiber reconstruction, fibroblasts, ensuring ECM formation, and endothelial cells, securing new vessel development in regenerated muscles. Our results indicate that hydrogels functionalized with SDF-1 and IL-4 peptides induce beneficial but diverse effects in analyzed cell types, influencing either their proliferation, migration, or differentiation. Most importantly, hydrogels tested by us do not harm analyzed cell types, indicating that in vivo skeletal muscle regeneration might be improved by them.

Keywords:  Cell differentiation; Interleukin-4; Peptide hydrogel; Skeletal muscle regeneration; Stromal derived factor-1

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.144282
In Vitro Cell Dev Biol Anim. 2025 May 20.

mTORC1 signalling and protein synthesis are elevated in response to amino acids in human myotubes obtained from young, old, and old trained men.

Stephanie D Gagnon, Jiani Qian, Vladimir Belhac, Neil R W Martin.

  Ageing and reduced levels of physical activity are associated with desensitisation of skeletal muscle to the anabolic effects of amino acids. In vitro studies have indicated that many properties of skeletal muscle tissue are retained in human myotubes, including metabolic alterations associated with exercise and disease. However, the interaction between ageing and physical activity on amino acid sensing and growth has not been explored in human myotubes in vitro. Muscle-derived cells were isolated from biopsies taken from eight young (Y: 23.4 ± 1.9 yr), six older (O: 72.5 ± 5.0 yr), and nine older exercise trained (OT: 71.0 ± 4.1 yr, n = 9) men, and myotube cultures were generated and investigated for growth parameters and amino acid induced changes in mTORC1 signalling and protein synthesis. Our results indicated that muscle cell fusion was similar between groups, but myotube diameter was lower in cultures derived from O individuals. Despite this, mTORC1 signalling, as indicated by immunoblots for phosphorylation of mTORSer2448, rpS6Ser235/236, and 4E-BP1Thr37/46 increased to a similar extent in response to amino acid availability in Y, O, and OT myotubes. Furthermore, measures of protein synthesis using the SUnSET assay were increased similarly between groups after the addition of amino acids. These data suggest that skeletal muscle desensitisation to amino acids with ageing is not observed in myotubes cultured in vitro, which could be reflective of the healthy individuals tested in our study or point towards the importance of the muscle niche in the impairments in muscle metabolism in ageing.

Keywords:  Ageing; Anabolic resistance; Exercise; MTOR; Myotubes

DOI:  https://doi.org/10.1007/s11626-025-01041-2
Int Rev Cell Mol Biol. 2025 ;pii: S1937-6448(24)00153-9. [Epub ahead of print]393 45-72

Circadian rhythms in muscle health and diseases.

Jeffrey J Kelu.

  All major life forms from bacteria to humans have internal clocks that regulate essential biological processes in a roughly 24-h cycle. In mammals, the central clock in the suprachiasmatic nucleus (SCN) is historically considered the top of a hierarchical organisation that dominates subordinate clocks in peripheral tissues and dictates the circadian behaviours of an organism. Recent studies, however, underscore the importance of the local circadian oscillators, such as the skeletal muscle clock, in regulating local metabolism and physiology. Studies in animal models show that the muscle peripheral clock per se is required for the expression of genes involved in glucose, lipid, and amino acid metabolism. Disruption of the muscle clock leads to glucose intolerance, insulin resistance, and alterations in muscle size and force. This highlights the vital role of the muscle clock in controlling muscle physiology and metabolism. In humans, a perturbation in the muscle circadian rhythms is seen in metabolic disorders such as type 2 diabetes, and muscle diseases such as dystrophies. Disruption of muscle metabolism is also seen when the internal rhythms are misaligned with the external rhythms (circadian misalignments) as in shift work. Understanding the mechanisms by which the muscle clock regulates circadian functions may help the development of new strategies, such as chronotherapy, to potentially prevent or treat muscle pathologies and maintain muscle health.

Keywords:  Circadian clock; Metabolism; Muscle peripheral clock; Physiology

DOI:  https://doi.org/10.1016/bs.ircmb.2024.10.002
MicroPubl Biol. 2025 ;2025

Skeletal muscle TFEB overexpression does not increase neurogenesis markers in the young female hippocampus.

Mia Hakian, Ian Matthews, Constanza J Cortes.

Adult hippocampal neurogenesis (AHN), the process in which new neurons are formed in the dentate gyrus of the hippocampus, declines with age and is highly responsive to voluntary wheel running in mice. This exercise-activated increase in AHN is believed to contribute to the cognitive and neurotrophic benefits of exercise on the aging and neurodegenerative disease-afflicted brain. However, our current understanding of the decline in AHN remains male-centric, with very few studies examining the effects of age and/or running on AHN in the female brain. Our lab has recently shown that skeletal muscle-specific overexpression of Transcription Factor E-B (TFEB), a master regulator of lysosomal and mitochondrial function, mimics many of the neuroprotective benefits of exercise during aging and in the context of Alzheimer's disease (AD) pathologies, but the effect of muscle-TFEB overexpression on AHN was unknown. Here we report that female AHN declines in a similar timeline as to what has been reported for the male hippocampus, following a precipitous decline at around 3 months of age that culminates at around 8 months of age. Furthermore, we report that muscle-TFEB overexpression does not prevent this age-associated decrease in AHN, suggesting that the neuroprotective benefits observed in our muscle-TFEB model are independent of AHN.

DOI: https://doi.org/10.17912/micropub.biology.001612
Free Radic Biol Med. 2025 May 20. pii: S0891-5849(25)00681-1. [Epub ahead of print]

Mitochondrial Electron Transfer Chain Activation in Atrophic Muscle: Implications for Calcium Signaling and Chondrocyte Apoptosis in Osteoarthritis.

Ailin Li, Tingting Pang, Jie Yang, Yunli Wang, Li Dong, Zhenwei Zhou, Yunfei Li, Xiangyang Leng, Haisi Dong, Yufeng Wang.

  Skeletal muscle wasting directly impacts the stability of the knee joint, leading to the development of osteoarthritis (OA). However, the underlying mechanism of the interaction between skeletal muscle and cartilage remains unclear. Therefore, the cross-talk between skeletal muscle and cartilage was investigated in rat models of muscle atrophy and the combination of OA and muscle atrophy through gait analysis, grip strength testing, micro-CT, and histological staining. The underlying mechanism was identified through metabolomics, RNA-sequencing, and verification experiments. It is first confirmed that skeletal muscle wasting induces reduction of joint function and the acceleration of cartilage injury. Furthermore, OA chondrocytes exhibited worsened injury when co-cultured with atrophied muscle. Mechanistically, metabolomics revealed the differential metabolites in muscle mainly enriched mitochondrial electron transport chain signaling pathway, which is the primary source of reactive oxygen species (ROS). RNA-sequencing of cartilage combined with verification experiments further indicated that the calcium signaling pathway in injured cartilage was activated, leading to the increase in chondrocyte apoptosis and inflammation, which attributed to the elevated levels of ROS in muscle atrophy, which stimulates synovium to further produce ROS and then release it into knee joint fluid. These observations suggest that elevated ROS levels in atrophied muscle may activate the calcium signaling pathway, leading to the increase of chondrocyte apoptosis, and ultimately exacerbate OA, which have potential to be a novel therapeutic target for OA treatment.

Keywords:  ROS; atrophied muscle; calcium signaling pathway; osteoarthritis

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.05.398
Am J Physiol Regul Integr Comp Physiol. 2025 May 23.

The Influence of Sex on Fiber-Specific Indices of Oxidative Capacity in Human Skeletal Muscle.

Celine Bailleul, Nathan Hodson, Sidney Abou Sawan, Dinesh Kumbhare, Daniel R Moore, Jenna B Gillen.

  There are reports that females compared to males display increased skeletal muscle oxidative capacity in resting mixed-muscle fiber samples from the vastus lateralis, including markers of mitochondrial content and capillarization. Given that sex comparisons at the mixed-fiber level may be explained by differences in muscle fiber type between males and females, it remains unclear if the oxidative capacity of type I and/or II fibers differ between sexes. The purpose of this study was to evaluate the influence of sex on fiber-specific indices of mitochondrial content and capillarization in healthy untrained males and females. Resting skeletal muscle samples from eumenorrheic females (n=14; 23±5yr; 23.3±3.2kg/m2) and males (n=13; 23±4yr; 23.1±2.4kg/m2) were analyzed via immunofluorescence staining. There were no sex differences in indices of capillarization (all p>0.06) or mitochondrial content (all p>0.42) in type I or type II muscle fibers. However, we observed lower capillary density in type II vs. type I muscle fibers in males (280±66 vs. 364±88 capillaries/mm2; p<0.001) but not females (335±77 vs. 329±48 capillaries/mm2; p=0.76), owing to greater cross-sectional area (CSA) of type II vs. type I fibers in males only (males p=0.03; females p=0.44). Females compared to males also displayed greater proportionate area of type I fibers (44±12 vs. 31±4%; p=0.03) and smaller CSA of type IIx fibers (3033±902 vs. 5573±1352 um2; p=0.002). Our results suggest that while muscle fiber-type composition and size differ between males and females, there are no sex differences in mitochondrial content and capillarization of type I or II muscle fibers in untrained adults.

Keywords:  capillarization; fiber composition; mitochondria; sex differences; skeletal muscle

DOI:  https://doi.org/10.1152/ajpregu.00298.2024
Diabetologia. 2025 May 21.

Skeletal muscle mitochondrial health in type 1 diabetes: the role of exercise capacity and lifestyle factors.

Richie P Goulding, Braeden T Charlton, Ellen A Breedveld, Jelle Y Huijts, Matthijs van der Laan, Anne R Strating, Wendy Noort, Aryna Kolodyazhna, Anita E Grootemaat, Frank W Bloemers, Nicole N van der Wel, Rob C I Wüst.

   AIMS/HYPOTHESIS: Previous studies reporting lower skeletal muscle mitochondrial function in type 1 diabetes did not account for cardiorespiratory fitness, a key confounder when assessing mitochondrial function. We hypothesised that, compared with healthy individuals, muscle mitochondrial phenotypic differences would be abolished in individuals with type 1 diabetes when matched for age, sex, BMI and maximal oxygen uptake ( V˙O2max ).
METHODS: Seventeen individuals with type 1 diabetes and seventeen healthy control individuals matched for age, sex, BMI and V˙O2max participated and underwent a muscle biopsy from the vastus lateralis. Mitochondrial respiration was assessed by high-resolution respirometry, and mitochondrial density and morphology were assessed by transmission electron microscopy.
RESULTS: V˙O2max (individuals with type 1 diabetes 40±10 kg-1 min-1; control individuals 41±8 ml kg-1 min-1; p=0.51) and mitochondrial oxidative phosphorylation capacity (individuals with type 1 diabetes 101±35 [pmol O2] s-1 mg-1; control individuals 99±23 [pmol O2] s-1 mg-1, p=0.82) did not differ between groups. Both intermyofibrillar (individuals with type 1 diabetes 6.07±2.16%; control individuals 6.01±1.11%; p=0.92) and subsarcolemmal (individuals with type 1 diabetes 18.70±8.16%; control individuals 19.29±7.36%; p=0.83) mitochondrial densities were not different between groups. Mitochondrial respiration normalised by density did not differ between groups. However, individuals with type 1 diabetes and higher HbA1c displayed lower rates of mitochondrial respiration than those with lower HbA1c, whereas those with higher BMI displayed lower mitochondrial densities than those with lower BMI.
CONCLUSIONS/INTERPRETATION: Collectively, our study demonstrates that when matched for age, sex, BMI and V˙O2max , maximal muscle mitochondrial respiration and morphology in people with type 1 diabetes are not impaired. These findings highlight the importance of habitual exercise, optimal glucose management and a healthy BMI in maintaining mitochondrial health in individuals with type 1 diabetes.

Keywords:  Maximal oxygen uptake; Mitochondrial density; Mitochondrial respiration; Muscle bioenergetics; Muscle mitochondria; Skeletal muscle; Type 1 diabetes

DOI:  https://doi.org/10.1007/s00125-025-06451-1
Nat Commun. 2025 May 20. 16(1): 4667

Combining dynamin 2 myopathy and neuropathy mutations rescues both phenotypes.

Marie Goret, Evelina Edelweiss, Jérémy Jehl, David Reiss, Patricio Aguirre-Pineda, Sylvie Friant, Jocelyn Laporte.

Mutations within a single gene can lead to diverse human genetic diseases affecting highly specialized tissues. Notably, dominant mutations in the DNM2 gene, encoding the mechanoenzyme dynamin, lead to distinct neuromuscular disorders: centronuclear myopathy (CNM) and Charcot-Marie-Tooth neuropathy (CMT). CNM is characterized by myofiber structural anomalies while CMT presents peripheral nerve defects, both culminating in muscle weakness and atrophy. Despite their shared genetic origin, the mechanisms driving these diseases remain elusive, and no cure is available. Here, we present in vitro assays underlining opposing effects of DNM2 mutations, gain-of-function in CNM and loss-of-function in CMT. In vivo, we explored the potential compensatory effects of CNM and CMT mutations by breeding Dnm2S619L/+ CNM with Dnm2K562E/+ CMT mouse models. Dnm2S619L/K562E offspring exhibit strongly improved motor coordination and muscle strength and mass, compared to single-mutant littermates. Dnm2S619L/K562E mice present normalized muscle structure and nerve fiber organization. This study reveals that two distinct disease-causing mutations within the DNM2 gene compensate each other in vivo, leading to corrections of most individual phenotypes. The inverse modulation of DNM2 activity emerges as a promising therapeutic strategy to address CNM and CMT diseases.

DOI: https://doi.org/10.1038/s41467-025-59925-6
Redox Biol. 2025 May 14. pii: S2213-2317(25)00189-2. [Epub ahead of print]84 103676

Repurposed Nrf2 activator dimethyl fumarate rescues muscle inflammation and fibrosis in an aggravated mdx mouse model of Duchenne muscular dystrophy.

Stephanie Kourakis, Cara A Timpani, Ryan M Bagaric, Bo Qi, Benazir A Ali, Rebecca Boyer, Guinevere Spiesberger, Nitika Kandhari, Xu Yan, Jujiao Kuang, Ankita Tulangekar, Judy B de Haan, Deanna Deveson-Lucas, Nicole Stupka, Dirk Fischer, Emma Rybalka.

  In inherited neuromuscular disease, Duchenne muscular dystrophy (DMD), glucocorticoids significantly slow disease progression yet impart side effects severe enough to preclude use in a significant proportion of patients. Extending our findings that acute treatment with FDA approved multiple sclerosis drug, dimethyl fumarate (DMF), rescues muscle pathology in juvenile mdx mice, we aimed to conduct tiered pre-clinical testing toward translation. To aggravate disease phenotype in adult mdx muscles that usually lack human equivalent muscle pathology, we used bi-weekly treadmill running for 4 weeks which increased plasma DMD biomarker, creatine kinase, by 2-fold and quadriceps fibrosis by ∼30 %. Using this model, we screened DMF for 5 weeks in a head-to-head comparison, and in combination, with standard-of-care prednisone (PRED), to model the most likely clinical trial scenario. We show comparable efficacy between DMF and PRED at reducing inflammation via NF-κB suppression and CD68+ macrophage infiltration. Moderate term DMF monotherapy had additional anti-fibrotic and anti-lipogenic effects on skeletal and cardiac muscle beyond those seen with PRED treatment, although combination therapy exacerbated fibrosis in quadriceps. Our study supports DMF as a repurposing candidate for DMD, especially for patients who cannot tolerate chronic glucocorticoid treatment. We also highlight the importance of evaluating combination therapy to identify potential off-target effects between emerging therapeutics and glucocorticoids towards better designed clinical trials.

Keywords:  Dimethyl fumarate; Duchenne muscular dystrophy; Muscle pathology; Therapeutics

DOI:  https://doi.org/10.1016/j.redox.2025.103676
Int J Med Sci. 2025 ;22(10): 2382-2397

Cardiovascular System is Influenced by Skeletal Muscle-derived Extracellular Vesicles, Myokines and MicroRNAs Based on Interorgan Communication: A Systematic Review.

Jiaxin Chen, Jingxin Zong, Sha Su, Xiang Ji, Lei Wang, Xiaowan Han, Mingjing Zhao.

  Background/Aims: To illustrate the types and roles of skeletal muscle-derived bioactive molecules in mediating the communication from skeletal muscle to the heart and blood vessels. Methods: A systematic literature search was performed in four different databases. Eligible articles were screened using the inclusion and exclusion criteria. Two researchers independently performed literature screening and selection, data extraction and literature quality analysis. Results: This study included 29 articles (2 clinical studies and 27 basic studies). Data analysis of the included studies revealed that skeletal muscle synthesizes and releases abundant extracellular vesicles (EVs), myokines (FSTL1, FNDC5/irisin and others) and microRNAs (miRNA-126 and others) to mediate the communication from skeletal muscle to the heart and blood vessels. Certain skeletal muscle-derived EVs, myokines and miRNAs were found to enhance cardiac function, reduce cardiac fibrosis and inhibit cardiac injury, and improve apoptosis and inflammation. In the blood vessels, these bioactive molecules stimulated angiogenesis, improved endothelial cell function, protected against vascular stiffness, and attenuated atherosclerosis and neointimal hyperplasia. Notably, IL-10, FSTL1, b-FGF, VEGF, irisin, musclin, myonectin, exo-miRNA26a, and miRNA-126 definitely played protective roles in the heart and blood vessels through interorgan communication. Conclusion: Skeletal muscle synthesizes and releases EVs, myokines and miRNAs, which mediate the communication from skeletal muscle to the heart and blood vessels. The majority of these bioactive molecules are associated with cardiovascular protective effects. And they may provide new targets for more in-depth mechanism and clinical researches of communication from skeletal muscle to the heart and blood vessels.

Keywords:  bioactive molecules; blood vessels; heart; interorgan communication; myokines; skeletal muscle

DOI:  https://doi.org/10.7150/ijms.111775
Interact J Med Res. 2025 May 23. 14 e64456

Systemic Inflammation and Disruption of the Local Microenvironment Compromise Muscle Regeneration: Critical Pathogenesis of Autoimmune-Associated Sarcopenia.

Yingjuan Zhang, Qingqian Wu, Yi Wang, Qingyan Chen, Shuang Han, Bei Li, Qingwen Zhao, Qianzhuo Wang, Yule Wang, Yue Gao.

   Unlabelled: Sarcopenia is defined by age-related reductions in muscle mass, strength, and physiological function, and it is especially prevalent among individuals with autoimmune diseases. Autoimmune disorders, characterized by immune dysregulation, cause systemic inflammation and damage to multiple tissues through unregulated immune activity. Research indicates that autoimmune diseases negatively impact skeletal muscle functions and may worsen the progression of sarcopenia. This viewpoint comprehensively discusses the pathogenesis and potential mechanism of sarcopenia in 3 autoimmune diseases: inflammatory bowel disease, rheumatoid arthritis, and type 1 diabetes mellitus. Mechanistically, chronic immune microenvironment alterations induce compartment-specific redistribution of leukocyte subsets and cytokine networks. These perturbations disrupt critical signaling pathways governing muscle protein synthesis, satellite cell activation, and mitochondrial bioenergetics, leading to impaired regeneration and accelerated sarcopenia progression. By delineating shared and distinct pathomechanisms across these models, this analysis reframes our understanding of immune-mediated muscle wasting. Beyond mechanistic insights, it establishes a translational framework for targeted therapies and highlights emerging research directions bridging immunology and age-related musculoskeletal decline.

Keywords:  immune diseases; inflammatory bowel disease; rheumatoid arthritis; sarcopenia; type 1 diabetes mellitus

DOI:  https://doi.org/10.2196/64456
Nat Commun. 2025 May 22. 16(1): 4743

Exercise-induced CLCF1 attenuates age-related muscle and bone decline in mice.

Jae Sook Kang, Jung Ha Kim, Min Ju Kim, Byungkuk Min, Seung-Min Lee, Ga-Yeon Go, Ji-Won Kim, Seongwan Kim, Ju Yeon Kwak, Sung-Wook Chun, Wook Song, Hyo Youl Moon, Sun Gun Chung, Dong-Ho Park, Ji Hoon Park, Chuna Kim, Kwang-Pyo Lee, Eun-Soo Kwon, Nacksung Kim, Ki-Sun Kwon, Yong Ryoul Yang.

Skeletal muscle undergoes many alterations with aging. However, the impact of aging on muscle's ability to secrete myokines and its subsequent effects on the body remain largely unexplored. Here, we identify myokines that have the potential to ameliorate age-related muscle and bone decline. Notably, circulating levels of cardiotrophin-like cytokine factor 1 (CLCF1) decrease with age, while exercise significantly upregulates CLCF1 levels in both humans and rodents. Restoring CLCF1 levels in aged male mice improves their physical performance, glucose tolerance, and mitochondrial activity. Furthermore, CLCF1 protects against age-induced bone loss by inhibiting osteoclastogenesis and promoting osteoblast differentiation in aged male mice. These improvements mirror some of the effects of exercise training. Conversely, blocking CLCF1 activity significantly abolishes these beneficial effects, confirming the crucial role of CLCF1 in mediating the positive effects of exercise on muscle and bone health in male mice. These findings collectively suggest that CLCF1 may contribute to the regulation of age-associated musculoskeletal deterioration, and warrant further investigation into its potential role as a modulator of musculoskeletal health during aging.

DOI: https://doi.org/10.1038/s41467-025-59959-w