bims-moremu 2025-09-28 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2025–09–28
38 papers selected by
Anna Vainshtein, Craft Science Inc.

Time to Reset: The Interplay Between Circadian Rhythms and Redox Homeostasis in Skeletal Muscle Ageing and Systemic Health.
TGFBI Facilitates Myogenesis and Limits Fibrosis in Mouse Skeletal Muscle Regeneration.
Isolation of functional lysosomes from skeletal muscle.
The multimodal transcriptional response of denervated skeletal muscle involves regulation of Gramd1 genes impacting muscle size.
From aging to space: A comparative biology of skeletal muscle degeneration.
The growth factor FGF21 maintains neuromuscular junction through histone deacetylase HDAC4 in denervation-induced skeletal muscle atrophy.
MuRF1 Partners With TRIM72 to Impair Insulin Signaling in Skeletal Muscle Cells.
Phosphorylation-mimicking histone H3.3 rescues exercise-induced gene responses in an epigenetic aging model of mouse skeletal muscle.
Fiber-type vulnerability and proteostasis reprogramming in skeletal muscle during pancreatic cancer cachexia.
Muscle-specific increased expression of JAG1 improves the skeletal muscle phenotype in dystrophin-deficient mice.
Sphingolipids in Extracellular Vesicles Released From the Skeletal Muscle Plasma Membrane Control Muscle Stem Cell Fate During Muscle Regeneration.
Fibrillin-Related Proteins Control Calcium Homeostasis in Dystrophic Muscle Across Species.
UBR5: A New Player in Protein Quality Control for Skeletal Muscle Growth and Remodeling.
Muscle Regeneration Can Be Rescued in a Telomerase Deficient Zebrafish Model of Ageing by MMP Inhibition.
Functional and structural pathologies in skeletal muscle of a rat model of Duchenne muscular dystrophy.
Site-1 protease is a negative regulator of sarcolipin promoter activity.
FoxO1 in skeletal muscle atrophy: Multifaceted regulatory mechanisms and therapeutic opportunities.
Hibernating brown bear serum modulates the balance of TGF-β and BMP pathways in human muscle cells.
Role of Nuclear Envelope Proteins in the Structure and Function of the Neuromuscular Junction: Focus on Subsynaptic Nuclei.
Fragmented futures: ROCK1 drives mitochondrial fission and muscle loss in CKD.
Fractalkine is a key player in skeletal muscle metabolism and pathophysiology.
Lysosomal LRRC8 complex impacts lysosomal pH, morphology, and systemic glucose metabolism.
Early Markers of Cardiac and Skeletal Muscle Metabolic Derangement in the Apc(min/+) Male Mouse.
Skeletal Muscle Aging: Enhancing Skeletal Muscle Integrity and Function as a Potential Pharmacological Approach.
Optimizing Female Health: The Crucial Role of Exercise Initiation before and during the Menopausal Transition.
Mitochondrial cardiolipin remodeling facilitates efficient myoblast differentiation.
Estrogens and Antioxidants Prevent the Formation of Tubular Aggregates in Aging Male Mice.
Herbal terpenoids activate autophagy and mitophagy through modulation of bioenergetics and protect from metabolic stress, sarcopenia and epigenetic aging.
Elimination of myotonia improves myopathy in a muscleblind knockout model of myotonic dystrophy.
Semaglutide impacts skeletal muscle to a similar extent as caloric restriction in mice with diet-induced obesity.
γ-Tocotrienol attenuates oxidative stress and preserves mitochondrial function in inflammation-induced muscle atrophy.
VBIT-4 Rescues Mitochondrial Dysfunction and Reduces Skeletal Muscle Degeneration in a Severe Model of Duchenne Muscular Dystrophy.
Recovery of SIRT3-SOD2 Axis and Mitophagy by Short-Term Calorie Restriction in Old Rat Soleus Skeletal Muscle.
Myotonic dystrophy type 1: clinical diversity, molecular insights and therapeutic perspectives.
Directed evolution of liver-detargeted AAV vectors for systemic gene delivery to skeletal muscle and heart.
The mechanical loading environment associated with eccentric exercise is one of the key stimuli to trigger sarcomerogenesis: It's a stretch to say eccentric exercise does not promote serial sarcomerogenesis.
Genetic analysis of a family with skeletal muscle ion channelopathy and hereditary spastic paraplegia type 7 caused by SCN4A and SPG7 double mutations.
Blunted Exercise Response in Cancer Survivors: A Consequence of the Heart or Peripheral Muscle?

Antioxidants (Basel). 2025 Sep 18. pii: 1132. [Epub ahead of print]14(9):

Time to Reset: The Interplay Between Circadian Rhythms and Redox Homeostasis in Skeletal Muscle Ageing and Systemic Health.

Elizabeth Sutton, Vanja Pekovic-Vaughan.

  Skeletal muscle plays vital roles in locomotion, metabolic regulation and endocrine signalling. Critically, it undergoes structural and functional decline with age, leading to a progressive loss of muscle mass and strength (sarcopenia) and contributing to a systemic loss of tissue resilience to stressors of multiple tissue systems (frailty). Emerging evidence implicates misalignments in both the circadian molecular clock and redox homeostasis as major drivers of age-related skeletal muscle deterioration. The circadian molecular clock, through core clock components such as BMAL1 and CLOCK, orchestrates rhythmic gene, protein and myokine expression impacting diurnal regulation of skeletal muscle structure and metabolism, mitochondrial function, antioxidant defence, extracellular matrix organisation and systemic inter-tissue communication. In parallel, the master redox regulator, NRF2, maintains cellular antioxidant defence, tissue stress resistance and mitochondrial health. Disruption of either system impairs skeletal muscle contractility, metabolism, and regenerative capacity as well as systemic homeostasis. Notably, NRF2-mediated redox signalling is clock-regulated and, in turn, affects circadian clock regulation. Both systems are responsive to external cues such as exercise and hormones, yet studies do not consistently include circadian timing or biological sex as key methodological variables. Given that circadian regulation shifts with age and differs between sexes, aligning exercise interventions with one's own chronotype may enhance health benefits, reduce adverse side effects, and overcome anabolic resistance with ageing. This review highlights the essential interplay between circadian and redox systems in skeletal muscle homeostasis and systemic health and argues for incorporating personalised chrono-redox approaches and sex-specific considerations into future experimental research and clinical studies, aiming to improve functional outcomes in age-related sarcopenia and broader age-related metabolic and musculoskeletal conditions.

Keywords:  NRF2; ageing; chronotherapy; chronotype; circadian rhythms; exercise; frailty; myokines; oxidative stress; redox homeostasis; sarcopenia; skeletal muscle

DOI:  https://doi.org/10.3390/antiox14091132
Int J Mol Sci. 2025 Sep 17. pii: 9042. [Epub ahead of print]26(18):

TGFBI Facilitates Myogenesis and Limits Fibrosis in Mouse Skeletal Muscle Regeneration.

Na Rae Park, So-Yeon Jin, Soon-Young Kim, Seung-Hoon Lee, In-San Kim, Jung-Eun Kim.

  Skeletal muscles are essential for movement and support but are vulnerable to injury. Muscle regeneration relies on the extracellular matrix (ECM), which regulates key cellular processes. Transforming growth factor β-induced (TGFBI), an ECM component involved in cell adhesion, migration, and tissue development, has not been investigated in skeletal muscle regeneration. Here, we examined the role of TGFBI using Tgfbi knockout (KO) mice and C2C12 myoblasts. In vitro, C2C12 cells were treated with recombinant TGFBI following snake venom (SV)-induced injury, and myogenic differentiation and fusion were evaluated by quantitative real-time PCR (qRT-PCR) and Western blotting. In vivo, acute muscle injury was induced by SV injection into the tibialis anterior muscles of 12-week-old wild-type and Tgfbi KO mice, with regeneration assessed by histology and qRT-PCR. TGFBI was absent in uninjured muscle and C2C12 cells but was upregulated after injury. Recombinant TGFBI enhanced myogenic differentiation and restored SV-induced downregulation of myogenic and fusion markers. Although phenotypically normal under physiological conditions, Tgfbi KO mice exhibited impaired regeneration, characterized by persistent immature myofibers, elevated inflammatory cytokines, reduced myogenic marker expression, and increased fibrosis. These findings reveal TGFBI as a key regulator of skeletal muscle repair and a potential therapeutic target for muscle-related disorders.

Keywords:  differentiation; fibrosis; fusion; myoblasts; regeneration; skeletal muscle; snake venom; transforming growth factor β-induced

DOI:  https://doi.org/10.3390/ijms26189042
Am J Physiol Cell Physiol. 2025 Sep 22.

Isolation of functional lysosomes from skeletal muscle.

Thulasi Mahendran, Anastasiya Kuznyetsova, Neushaw Moradi, David A Hood.

  Lysosomes are membrane-bound organelles responsible for the degradation of damaged or dysfunctional cellular components, including mitochondria. Their acidic internal environment and the presence of an array of hydrolytic enzymes facilitate the efficient breakdown of macromolecules such as proteins, lipids, and nucleic acids. Mitochondria play a critical role in maintaining skeletal muscle homeostasis to meet the energy demands under physiological and pathological conditions. Mitochondrial quality control within skeletal muscle during processes such as exercise, disuse, and injury is regulated by mitophagy, where dysfunctional mitochondria are targeted for lysosomal degradation. The limited understanding of quality control mechanisms in skeletal muscle necessitates the need for isolating intact lysosomes to assess organelle integrity and the degradative functions of hydrolytic enzymes. Although several methods exist for lysosome isolation, the complex structure of skeletal muscle makes it challenging to obtain relatively pure and functional lysosomes due to the high abundance of contractile proteins. Here we describe a method to isolate functional lysosomes from small amounts of mouse skeletal muscle tissue, preserving membrane integrity. We also describe functional assays that allow direct evaluation of lysosomal enzymatic activity and we provide data indicating reduced lysosomal degradative activity in lysosomes from aging muscle. We hope that this protocol provides a valuable tool to advance our understanding of lysosomal biology in skeletal muscle, supporting investigations into lysosome-related dysfunction in aging, disease, and exercise adaptations.

Keywords:  differential centrifugation; lysosomal enzymes; mitochondria; mitophagy; proteolysis

DOI:  https://doi.org/10.1152/ajpcell.00471.2025
Proc Natl Acad Sci U S A. 2025 Sep 30. 122(39): e2424246122

The multimodal transcriptional response of denervated skeletal muscle involves regulation of Gramd1 genes impacting muscle size.

Cristofer Calvo, Casey O Swoboda, Fabian Montecino-Morales, Siddhant Nagar, Michael J Petrany, Chengyi Sun, Hima Bindu Durumutla, Mattia Quattrocelli, Douglas P Millay.

  The development and maintenance of the neuromuscular junction (NMJ) requires reciprocal signals between the nerve terminals and multinucleated skeletal muscle fibers (myofibers). This interaction drives highly specialized transcription in the subsynaptic or NMJ myonuclei within mature myofibers leading to clustering of acetylcholine receptors (AChRs). Here, we utilized single-nucleus RNA sequencing (snRNA-seq) to delineate the transcriptional response of myonuclei to denervation. Through snRNA-seq on skeletal muscle from two independent mouse models of denervation, sciatic nerve transection and amyotrophic lateral sclerosis, we identify a multimodal transcriptional response of NMJ-enriched genes and an alteration in cholesterol homeostasis in myofibers. Gramd1, a family of genes involved in nonvesicular cholesterol transport, are enriched at the NMJ in innervated muscle and upregulated in both models of denervation by the NMJ and extrasynaptic myonuclei. In vivo gain and loss of function studies indicate that Gramd1 genes regulate myofiber sizes. Mechanistically, we did not detect obvious changes in AChR clustering due to Gramd1 knockdown but revealed a role in autophagy after denervation. We uncovered a dynamic transcriptional response of myonuclei to denervation and highlight a critical role for Gramd1 to maintain myofiber sizes.

Keywords:  Gramd1b/Aster; cholesterol; neuromuscular synapse; snRNA sequencing

DOI:  https://doi.org/10.1073/pnas.2424246122
Biochim Biophys Acta Mol Basis Dis. 2025 Sep 18. pii: S0925-4439(25)00406-5. [Epub ahead of print]1872(1): 168058

From aging to space: A comparative biology of skeletal muscle degeneration.

Rizwan Qaisar.

  Sarcopenia, the progressive loss of skeletal muscle mass and function with age, represents a major clinical concern, particularly in the context of disuse and unloading conditions such as simulated microgravity. This review explores the molecular, cellular, and physiological responses of skeletal muscle to simulated microgravity and compares them with those observed during aging-associated sarcopenia. A central focus is placed on impaired excitation-contraction coupling, altered calcium homeostasis, and dysregulation of signalling pathways critical for muscle maintenance. Simulated microgravity induces rapid suppression of the IGF-1/Akt/mTOR axis, activation of FOXO-mediated proteolysis, and mitochondrial dysfunction via AMPK-PGC-1α inhibition, paralleling but accelerating the trajectory observed with aging. Unique to the effects of simulated microgrvity is the early upregulation and partial reversibility of myostatin-Smad signalling and autophagy activation, which diverge in pattern and timing from aging. Additionally, mechanotransduction pathways such as YAP/TAZ and redox-sensitive systems like NRF2 respond differently in simulated microgravity and sarcopenia. We further highlight the emerging role of neuromuscular junction (NMJ) instability, fiber-type switching, and nuclear calcium signalling in both contexts, emphasizing their contribution to excitation-transcription coupling and long-term muscle adaptation. The insights from simulated microgravity models not only deepen our mechanistic understanding of sarcopenia but also offer a controlled platform to explore interventions. By delineating the overlapping and distinct molecular signatures of disuse-induced and age-related muscle loss, this review provides a foundation for developing targeted countermeasures for muscle atrophy in both clinical and spaceflight settings.

Keywords:  Aging; Excitation–contraction coupling; Mitochondrial dysfunction; Muscle signalling pathways; Simulated microgravity; Skeletal muscle atrophy

DOI:  https://doi.org/10.1016/j.bbadis.2025.168058
J Biol Chem. 2025 Sep 23. pii: S0021-9258(25)02608-0. [Epub ahead of print] 110756

The growth factor FGF21 maintains neuromuscular junction through histone deacetylase HDAC4 in denervation-induced skeletal muscle atrophy.

Lirong Zheng, Takashi Sasaki, Liyang Ni, Tsutomu Hashidume, Mitsuki Kawabe, Yu Takahashi, Yoshio Yamauchi, Makoto Shimizu, Ryuichiro Sato.

  Skeletal muscles undergo atrophy in response to denervation and neuromuscular disease. Understanding the mechanisms by which denervation drives muscle atrophy is crucial for developing therapies against neurogenic muscle atrophy. Here, we identified muscle-secreted fibroblast growth factor 21 (FGF21) as a key inducer of atrophy following muscle denervation. In denervated skeletal muscles, Fgf21 is the most robustly upregulated member of the Fgf family and acts in an autocrine/paracrine manner to promote muscle atrophy. Silencing Fgf21 in muscle prevents denervation-induced muscle wasting by preserving neuromuscular junction (NMJ) innervation. Conversely, forced expression of FGF21 in muscle reduces NMJ innervation, leading to muscle atrophy. Mechanistically, TGFB1 released by denervated fibro-adipogenic progenitors (FAPs) upregulates Fgf21 expression through the JNK/c-Jun axis. The resulting increase in FGF21 protein reduces the cytoplasmic level of histone deacetylase 4 (HDAC4), culminating in muscle atrophy. HDAC4 knockdown abolishes the atrophy-resistant effects observed in Fgf21-deficient denervated muscles, resulting in muscle atrophy. Our findings reveal a novel role and heretofore unrecognized mechanism of FGF21 in skeletal muscle atrophy, suggesting that inhibiting muscular FGF21 could be a promising strategy for mitigating skeletal muscle atrophy.

Keywords:  Denervation; FGF21; Fibro-adipogenic progenitors; Neuromuscular junction; Skeletal muscle atrophy; TGFB

DOI:  https://doi.org/10.1016/j.jbc.2025.110756
FASEB J. 2025 Oct 15. 39(19): e71084

MuRF1 Partners With TRIM72 to Impair Insulin Signaling in Skeletal Muscle Cells.

Ibrahim Musa, Alex Peter Seabright, Jonathan Barlow, Yusuke Nishimura.

  Muscle RING-finger protein 1 (MuRF1, gene name: TRIM63) is well known as a critical molecular regulator in skeletal muscle atrophy. Despite the identification of several substrates and interaction partners for MuRF1, the precise molecular mechanisms by which MuRF1 causes skeletal muscle atrophy remain unclear. To gain further insight into the underlying mechanism of skeletal muscle atrophy, we applied targeted biochemical approaches and identified tripartite motif-containing protein 72 (TRIM72) as a novel MuRF1-interacting protein. Subsequent analysis using MuRF1 knockout and rescue experiments showed that TRIM72 protein abundance is dependent on the presence of MuRF1 protein. Furthermore, TRIM72 protein level was increased by dexamethasone treatment in C2C12 myotubes, alongside increased MuRF1 protein level. Dexamethasone decreases IRS1/Akt signaling and glucose uptake specifically in wild type myotubes, but not in MuRF1 KO myotubes. Further analysis showed that overexpression of TRIM72 impairs IRS1/Akt signaling without the presence of MuRF1, indicating that MuRF1 induces a negative impact on insulin signaling through a plausible cooperation with TRIM72. Our findings provide novel non-degradative molecular roles of MuRF1 that link together skeletal muscle atrophy and impaired insulin sensitivity.

Keywords:  CRISPR‐Cas9; E3 ligase; glucose uptake; protein–protein interaction

DOI:  https://doi.org/10.1096/fj.202502066RR
Lab Anim Res. 2025 Sep 24. 41(1): 25

Phosphorylation-mimicking histone H3.3 rescues exercise-induced gene responses in an epigenetic aging model of mouse skeletal muscle.

Sho Maruyama, Fuminori Kawano.

   BACKGROUND: With aging, the canonical histone H3.1/3.2 in skeletal muscle is progressively replaced by the non-canonical variant H3.3. Although H3.3 is thought to be involved in age-related epigenetic regulation due to its role as a histone variant, its functional characteristics remain largely unknown. Serine 31 (S31) is a unique amino acid residue of H3.3 that undergoes phosphorylation. Therefore, the present study aimed to investigate the relationship between skeletal muscle aging and H3.3 phosphorylation at S31 (H3.3S31ph).
RESULTS: We first demonstrated that H3.3S31ph levels were significantly reduced in the tibialis anterior muscle of 75-wk-old mice compared to 8-wk-old mice. We then examined the effects of viral vector-mediated expression of wild-type H3.3 or a phosphorylation-mimicking H3.3 mutant (H3.3S31E) on gene responsiveness to acute exercise in aging skeletal muscle. In muscles expressing wild-type H3.3, which simulates epigenetic alterations observed during skeletal muscle aging, the transcriptional response to acute exercise was lost by 30 weeks post-treatment (60 weeks of age). In contrast, expression of H3.3S31E successfully rescued the gene responses to acute exercise. This rescue was accompanied by increased enrichment of H3K4me3 and H3K27me3 following acute exercise in the H3.3S31E group, whereas no such histone modification changes were observed in the wild-type H3.3 group. Additionally, robust involvement of exogenous H3.3 in exercise-related histone turnover was observed in the wild-type H3.3 group, but not in the H3.3S31E group, suggesting that phosphorylation at S31 limits the dynamic behavior of H3.3.
CONCLUSIONS: Impaired transcriptional responsiveness to exercise in a simulated epigenetic aging model induced by exogenous H3.3 expression was rescued by the phosphorylation-mimicking H3.3S31E variant in middle-aged skeletal muscle. The findings of the present study demonstrate that H3.3S31ph plays a critical role in regulating the stability of H3.3 within chromatin.

Keywords:  Aging; Epigenetics; Histone modifications; Histone variant; Mutant histone

DOI:  https://doi.org/10.1186/s42826-025-00254-6
bioRxiv. 2025 Sep 17. pii: 2025.09.15.676415. [Epub ahead of print]

Fiber-type vulnerability and proteostasis reprogramming in skeletal muscle during pancreatic cancer cachexia.

Bowen Xu, Aniket S Joshi, Meiricris Tomaz da Silva, Silin Liu, Ashok Kumar.

Cachexia is a debilitating syndrome marked by progressive skeletal muscle wasting, commonly affecting cancer patients, particularly those with pancreatic cancer. Despite its clinical significance, the molecular mechanisms underlying cancer cachexia remain poorly understood. In this study, we utilized single-nucleus RNA sequencing (snRNA-seq) and bulk RNA-seq, complemented by biochemical and histological analyses, to investigate molecular alterations in the skeletal muscle of the KPC mouse model of pancreatic cancer cachexia. Our findings demonstrate that KPC tumor growth induces myofiber-specific changes in the expression of genes involved in proteolytic pathways, mitochondrial biogenesis, and angiogenesis. Notably, tumor progression enhances the activity of specific transcription factors that regulate the mTORC1 signaling pathway, along with genes involved in translational initiation and ribosome biogenesis. Skeletal muscle-specific, inducible inhibition of mTORC1 activity further exacerbates muscle loss in tumor-bearing mice, highlighting its protective role in maintaining muscle mass. Additionally, we uncovered novel intercellular signaling networks within the skeletal muscle microenvironment during pancreatic cancer-induced cachexia. Together, these results reveal previously unrecognized molecular mechanisms that regulate skeletal muscle homeostasis and identify potential therapeutic targets for the treatment of pancreatic cancer-associated cachexia.

DOI: https://doi.org/10.1101/2025.09.15.676415
Proc Natl Acad Sci U S A. 2025 Sep 30. 122(39): e2506437122

Muscle-specific increased expression of JAG1 improves the skeletal muscle phenotype in dystrophin-deficient mice.

Felipe de Souza Leite, Matthias R Lambert, Tracy Yuanfan Zhang, James R Conner, Joao A Paulo, Sheldon Furtado Oliveira, Sanjukta Guha Thakurta, Jennifer Bowles, Emanuela Gussoni, Steven P Gygi, Jeffrey J Widrick, Louis M Kunkel.

  Therapeutic strategies for Duchenne muscular dystrophy (DMD) will likely require complementary approaches. One possibility is to explore genetic modifiers that improve muscle regeneration and function. The beneficial effects of the overexpression of Jagged-1 were described in escaper golden retriever muscular dystrophy (GRMD) dogs that had a near-normal life and validated in dystrophin-deficient zebrafish. To clarify the underlying biology of JAG1 overexpression in dystrophic muscles, we generated a transgenic mouse (mdx5cv-JAG1) model that lacks dystrophin and overexpresses human JAG1 in striated muscles. Skeletal muscles from mdx5cv-JAG1 and mdx5cv mice were studied at 1-, 4-, and 12-mo time points. JAG1 expression in mdx5cv-JAG1 increased by 3 to 5 times compared to mdx5cv. Consequently, mdx5cv-JAG1 muscles were significantly bigger and stronger than dystrophic controls, along with an increased number of myofibers. Proteomics data show increased dysferlin in mdx5cv-JAG1 muscles and an association of the histone methyltransferase Nsd1 with the phenotype. Our data support the positive effect of JAG1 overexpression in dystrophic muscles.

Keywords:  Duchenne muscular dystrophy; Jagged-1; genetic modifier; mouse model; physiology

DOI:  https://doi.org/10.1073/pnas.2506437122
J Extracell Vesicles. 2025 Sep;14(9): e70164

Sphingolipids in Extracellular Vesicles Released From the Skeletal Muscle Plasma Membrane Control Muscle Stem Cell Fate During Muscle Regeneration.

Rhyma Hakkar, Caroline E Brun, Pascal Leblanc, Emmanuelle Meugnier, Emmanuelle Berger-Danty, Olivier Blanc-Brude, Stefano Tacconi, Audrey Jalabert, Laura Reininger, Sandra Pesenti, Catherine Calzada, Vincent Gache, Sanjay B Vasan, Julien Pichon, Thibaut Larcher, Elizabeth Errazuriz-Cerda, Christelle Cassin, Bong Hwan Sung, Alissa Weaver, Antonella Bongiovanni, Karl Rouger, Jean-Paul Pais de Barros, Karim Bouzakri, Sophie Rome.

  Extracellular vesicles (EVs) represent a cytokine-independent pathway though which skeletal muscle (SkM) cells influence the fate of neighbouring cells, thereby regulating SkM metabolic homeostasis and regeneration. Although SkM-EVs are increasingly being explored as a therapeutic strategy to enhance muscle regeneration or to induce the myogenic differentiation of induced pluripotent stem cells (iPSCs), the mechanisms governing their release from muscle cells remain poorly described. Moreover, because muscle regeneration involves a tightly regulated inflammatory response it also important to determine how inflammation alters SkM-EV cargo and function in order to design more effective EV-based therapies. To address this knowledge gap, we isolated and characterized the large and small EVs (lEVs, sEVs) released from SkM cells under basal conditions and in response to TNF-α, a well-established inflammatory mediator elevated in both acute muscle injury and chronic inflammatory conditions such as type 2 diabetes. We then evaluated the regenerative roles of these EV subtypes in vivo using a mouse model of cardiotoxin-induced muscle injury, with a specific focus on their bioactive sphingolipid content. Using transmission, scanning or cryo-electron microscopy, lipidomic profiling and an adenoviral construct to express labelled CD63 in myotubes, we demonstrated that SkM cells release both sEVs and lEVs primarily from the plasma membrane. Notably, sEVs were generated from specialized membrane folds enriched in the EV markers ALIX (ALG-2 interacting protein X) and TSG101, as well as lipid raft-associated lipids. During regeneration, sEVs promoted M1 macrophage polarization and migration and muscle stem cell (MuSC) differentiation, thereby accelerating muscle repair. In contrast, lEVs inhibited and promoted MuSC proliferation and impaired the transition from the pro-inflammatory to the anti-inflammatory response, an essential step for promoting MuSC differentiation. Treatment of isolated muscle fibres with SkM-EVs revealed that the distinct effects of sEVs and lEVs on MuSC behaviour and macrophage phenotype could be largely explained by differences in their lipid composition, particularly the ratio of sphingosine-1-phosphate (S1P) subspecies. However, TNF-α exposure altered these ratios in sEVs and impaired their regenerative functions on MuSC and their effect on macrophage migration and polarization. These results demonstrate for the first time the importance of the sphingolipid content of EVs released by skeletal muscle in their regenerative function within muscle tissue, largely explained by their role as carriers of different subspecies of sphingosine-1-phosphate. This suggests that modulating the sphingolipid composition of EVs could be a viable strategy to enhance the regenerative potential of muscle tissue in addition to therapeutic interventions.

Keywords:  extracellular vesicles; lipidomic; muscle stem cells; regeneration; skeletal muscle; sphingosine‐1‐phosphate

DOI:  https://doi.org/10.1002/jev2.70164
MicroPubl Biol. 2025 ;2025

Fibrillin-Related Proteins Control Calcium Homeostasis in Dystrophic Muscle Across Species.

Damiano Marchiafava, Andres Vidal Gadea.

Duchenne muscular dystrophy (DMD) involves progressive muscle degeneration associated with impaired calcium homeostasis, particularly defective calcium clearance during muscle relaxation. However, the mechanisms linking extracellular matrix (ECM) integrity to calcium regulation remain unclear. We investigated whether MUA-3 , a Caenorhabditis elegans fibrillin-related ECM protein, contributes to calcium dysregulation in dystrophic muscle. Using fluorescent calcium imaging in transgenic worms expressing muscle-specific GCaMP2, we found that mua-3 downregulation selectively elevated resting calcium levels in healthy muscle, phenocopying the dystrophic calcium signature. Critically, partial mua-3 downregulation had no additional effect in dystrophic ( dys-1 ) muscle, where mua-3 expression was already reduced by 57%, suggesting loss of mua-3 function contributes to dystrophic pathology. In human dystrophic myoblasts, we observed parallel findings: elevated sarcoplasmic calcium concurrent with significant downregulation of fibrillin genes FBN1/FBN2 . These findings identify fibrillin-related proteins as potential regulators of muscle calcium homeostasis across species and suggest that ECM-calcium coupling represents a conserved pathological mechanism in muscular dystrophy.

DOI: https://doi.org/10.17912/micropub.biology.001697
Exerc Sport Sci Rev. 2025 Oct 01. 53(4): 205-213

UBR5: A New Player in Protein Quality Control for Skeletal Muscle Growth and Remodeling.

David C Hughes, Sue C Bodine.

  A balance between protein synthesis and degradation regulates skeletal muscle size. Proteolytic mechanisms, like the ubiquitin-proteasome system, are critical processes in protein quality control. Counterintuitively, the E3 ubiquitin ligase, UBR5, appears to be involved in skeletal muscle hypertrophy and regrowth and interacts with protein synthesis. We present the novel hypothesis for protein quality control being critical for skeletal muscle growth and remodeling.

Keywords:  N-degron pathway; exercise; proteasome system; protein turnover; skeletal muscle

DOI:  https://doi.org/10.1249/JES.0000000000000372
Aging Cell. 2025 Sep 25. e70238

Muscle Regeneration Can Be Rescued in a Telomerase Deficient Zebrafish Model of Ageing by MMP Inhibition.

Yue Yuan, Carlene Dyer, Robert D Knight.

  Ageing progressively impairs skeletal muscle regeneration, contributing to reduced mobility and quality of life. While the molecular changes underlying muscle ageing have been well characterised, their impact on muscle stem cell (muSC) behaviour during regeneration remains poorly understood. Here, we leverage telomerase-deficient tert mutant zebrafish larvae as an in vivo model of accelerated ageing to perform real-time analysis of muSC dynamics following muscle injury. We demonstrate that the ageing-like inflammatory environment in tert mutant disrupts muSC migration, impairs activation and proliferation, and compromises regenerative capacity. We further show that sustained inflammation, mediated by persistent macrophage presence and elevated matrix metalloproteinase (MMP) activity, limits muSC recruitment and migration efficiency. Pharmacological inhibition of MMP9/13 activity and genetic depletion of macrophages partially restore muSC migratory behaviour and regenerative outcomes. Notably, we demonstrate that muSC migration dynamics correlate with regenerative success, providing a functional readout for therapeutic screening. Our findings reveal zebrafish tert mutants offer a tractable system for dissecting age-associated changes to cell behaviour and for identifying rejuvenation interventions.

Keywords:  ageing; cell behaviour; macrophage; muscle stem cell; regeneration; rejuvenation; satellite cell; zebrafish

DOI:  https://doi.org/10.1111/acel.70238
bioRxiv. 2025 Sep 16. pii: 2025.09.11.675592. [Epub ahead of print]

Functional and structural pathologies in skeletal muscle of a rat model of Duchenne muscular dystrophy.

Young Il Lee, Cora C Hart, C Spencer Henley-Beasley, Jeffrey S Herr, Eli Zerpa, Elisabeth R Barton, David W Hammers, H Lee Sweeney.

Background: Duchenne muscular dystrophy (DMD) is a lethal pediatric degenerative muscle disease for which there is no cure. Robust preclinical models that recapitulate major clinical features of DMD are required to investigate efficacy of potential DMD therapeutics. Rat models of DMD have emerged as promising small animal models to accomplish this; however, there have been no comprehensive studies investigating the functional skeletal muscle decrements associated with the modeling of DMD in rats.
Methods: CRISPR/Cas9 gene editing was used to generate a dystrophin-deficient Sprague-Dawley muscular dystrophy rat (MDR). Biochemical and immunofluorescent analyses were performed to confirm loss of dystrophin in striated muscles of this rat model. In situ and ex vivo muscle function was assessed in wild-type (WT) and MDR muscles at 3, 6, and 12 months of age, followed by histopathological analyses.
Results: MDR muscle tissues exhibited loss of full-length dystrophin and reduced content of other dystrophin glycoprotein complex members. MDR extensor digitorum longus (EDL) muscles and diaphragms displayed pronounced and progressive muscle weakness beginning at 3 months of age, compared to WT littermates. EDLs also exhibit susceptibility to eccentric contraction-induced damage. Functional deficits in soleus muscles were less severe and were associated with a right shift in force-frequency relationship and a muscle fiber-type shift. MDR muscles display progressive histopathology including degenerative lesions, fibrosis, regenerative foci, and modest adipose deposition.
Conclusions: MDR is a preclinical model of DMD that exhibits many translational features of the human disease, including a large dynamic range of muscle decrements, that has high utility for the evaluation of potential therapeutics for DMD.

DOI: https://doi.org/10.1101/2025.09.11.675592
Commun Biol. 2025 Sep 24. 8(1): 1351

Site-1 protease is a negative regulator of sarcolipin promoter activity.

Isha Sharma, Meredith O Kelly, Katelyn Hanners, Ella S Shin, Muhammad G Mousa, Shelby Ek, Gretchen A Meyer, Rita T Brookheart.

The timed contraction and relaxation of myofibers in tissues such as the heart and skeletal muscle occur via the tightly regulated movement of calcium ions into and out of the sarcoplasmic reticulum (SR). In skeletal muscle, this phenomenon enables humans to exercise, perform day-to-day tasks, and to breathe. Sarcolipin, a small regulatory protein, prevents calcium ions from entering the SR by binding to and inhibiting SERCA, contributing to myofiber contraction. Disruptions in sarcolipin (SLN) expression are implicated in the pathophysiology of obesity and musculoskeletal disease. However, the mechanisms regulating sarcolipin expression are not clearly understood. We recently showed that site-1 protease (S1P) is a regulator of skeletal muscle function and mass. Here, we report that deleting S1P in mouse skeletal muscle increases sarcolipin expression, without impacting calcium SR flux. In cultured cells, S1P negatively regulates sarcolipin by activating the transcription factor ATF6, which inhibits basal- and calcineurin-stimulated sarcolipin promoter activity. We identify a cAMP response element binding protein (CREB) binding site on the sarcolipin promoter that is necessary for promoter activation, and show that in muscle, CREB binds to the sarcolipin promoter. These discoveries expand our knowledge of S1P biology and the mechanisms controlling calcium regulatory genes.

DOI: https://doi.org/10.1038/s42003-025-08647-y
Acta Histochem. 2025 Sep 23. pii: S0065-1281(25)00065-0. [Epub ahead of print]127(4): 152293

FoxO1 in skeletal muscle atrophy: Multifaceted regulatory mechanisms and therapeutic opportunities.

Cheng-Ya Song, Tian-Yi Zhou, Han-Bo Shi, Xin-Yi Li, Kan Hong.

  Skeletal muscle, which accounts for nearly 40 % of total body mass, serves as the primary effector organ for locomotion, metabolism, and thermoregulation. Skeletal muscle atrophy, a common condition associated with aging, disease, and disability, significantly compromises patients' quality of life. This review focuses on the occurrence and progression of skeletal muscle atrophy. Forkhead box protein O1 (FoxO1) is a key regulatory factor that mediates pathological mechanisms through multidimensional molecular networks. It influences skeletal muscle metabolism via post-translational modifications (PTMs), dysregulated autophagy, an imbalanced inflammatory microenvironment, and the regulation of satellite cell function. Therapeutic strategies targeting FoxO1, such as resveratrol-induced SIRT1 activation and miR-486 mimics, have shown promising results in preclinical models. This review highlights the central role of FoxO1 in molecular pathways, proposes a potential framework for addressing muscle atrophy, and offers new insights into the treatment of sarcopenia and related diseases.

Keywords:  FoxO1; Mechanism; Muscle atrophy; Therapy

DOI:  https://doi.org/10.1016/j.acthis.2025.152293
Int J Biochem Cell Biol. 2025 Sep 19. pii: S1357-2725(25)00132-3. [Epub ahead of print] 106864

Hibernating brown bear serum modulates the balance of TGF-β and BMP pathways in human muscle cells.

Chloé Richard, Charlène Pourpe, Guillaume Fourneaux, Gwendal Cueff, Laurent Parry, Cécile Coudy-Gandilhon, Jonas Kindberg, Alina L Evans, Andrea Miller, Guillemette Gauquelin-Koch, Christophe Tatout, Cécile Polge, Daniel Taillandier, Fabrice Bertile, Etienne Lefai, Lydie Combaret.

  Muscle atrophy is observed in several pathophysiological situations, including physical inactivity, leading to negative health consequences, without any effective treatment currently available. Conversely, brown bears resist muscle atrophy during hibernation, despite prolonged physical inactivity and fasting. We previously reported that hibernating brown bear serum increases protein content in human myotubes and inhibits proteolysis. To go further, we deciphered here the transcriptional effects of brown bear serum in human myotubes using large-scale transcriptomics. After 48hours, the winter-hibernating bear serum (WBS) induced a specific transcriptomic program, affecting mostly biological pathways related to muscle growth and BMP signalling, compared to the summer-active bear (SBS) serum. WBS predominantly reduced, at mRNA and protein levels, activators and inhibitors of BMP signalling, which is associated with muscle mass maintenance. Moreover, BMP activity was more responsive to a stimulation by BMP7 at supra-physiological concentrations in human myotubes cultured in WBS versus SBS conditions. Meanwhile, WBS also up-regulated expression of genes encoding repressors of the pro-atrophic TGF-β pathway, decreased phosphorylated SMAD3 nuclear protein levels, and down-regulated TGF-β target genes. Furthermore, WBS treatment resulted in reduced TGF-β signalling responsiveness in human myotubes stimulated with TGF-β3 at physiological concentrations. Overall, even though WBS induced larger transcriptomic changes in the BMP compared to TGF-β pathway, the functional consequences were more pronounced for the TGF-β pathway with a marked inhibition. This study suggests that bioactive compounds in WBS may protect human muscle cells during catabolic situations, by regulating the TGF-β/BMP balance. These findings open new perspectives for therapies targeting muscle atrophy.

Keywords:  Hibernation; Human myotubes; Muscle atrophy; RNA sequencing; Skeletal muscle; TGFβ superfamily; Ursus arctos

DOI:  https://doi.org/10.1016/j.biocel.2025.106864
Subcell Biochem. 2025 ;115 23-35

Role of Nuclear Envelope Proteins in the Structure and Function of the Neuromuscular Junction: Focus on Subsynaptic Nuclei.

Céline Douarre, Bruno Cadot, Antoine Muchir, Stéphanie Bauché.

  The role of the nuclear envelope (NE) in skeletal muscle function was first recognized 30 years ago when mutations in NE-associated genes, such as SUN-1, Syne1, Syne2, and LMNA, were linked to muscular dystrophies, also known as nuclear envelopathies. These findings underscored the critical role of NE components in maintaining muscle fiber integrity and function. NE proteins, including lamin A/C, SUN-1/2, nesprins, and LAP1, play a key role in anchoring and positioning nuclei within muscle fibers. In particular, the correct positioning of subsynaptic nuclei (SSNs) beneath the neuromuscular junction (NMJ) is essential for their differentiation and functional specialization, ensuring efficient neuromuscular transmission. The crucial role of the NE in SSNs and NMJ function has been further emphasized by its association with an atypical form of congenital myasthenic syndrome (CMS). Despite significant advances in understanding NMJ formation and motor neuron-myofiber communication, the mechanisms governing gene regulation in SSNs remain largely unexplored.

Keywords:  Congenital myasthenic syndrome; Emery-dreifuss muscular dystrophy; Neuromuscular junction; Nuclear envelope; Subsynaptic nuclei

DOI:  https://doi.org/10.1007/978-3-032-00537-3_2
Kidney Int. 2025 Oct;pii: S0085-2538(25)00578-2. [Epub ahead of print]108(4): 529-532

Fragmented futures: ROCK1 drives mitochondrial fission and muscle loss in CKD.

Mia Y Kawaida, Terence E Ryan.

Patients with chronic kidney disease (CKD) experience skeletal muscle wasting that leads to weakness and negatively impacts quality of life. Decreases in mitochondrial health and function have long been associated with skeletal muscle wasting in CKD, yet mechanisms linking mitochondrial alterations to muscle atrophy are lacking. In this issue, Si et al. present experimental work in mice with CKD linking Rho-associated protein kinase-1 activation to increased mitochondrial fission, oxidative stress, and atrophy. They also investigate therapeutic strategies to alter this mitochondria-muscle atrophy axis to promote better outcomes in CKD.

DOI: https://doi.org/10.1016/j.kint.2025.07.012
FEBS J. 2025 Sep 25.

Fractalkine is a key player in skeletal muscle metabolism and pathophysiology.

Gourabamani Swalsingh, Punyadhara Pani, Sakthivel Sadayappan, Naresh Chandra Bal.

  Fractalkine (CX3CL1) is increasingly recognised for its role in regulating the metabolism of various tissues, including skeletal muscle. The circulating level of CX3CL1 is influenced by multiple organs including the brain, adipose tissue and immune cells, with skeletal muscles emerging as a significant source. Growing evidence shows that CX3CL1 modulates muscle metabolism through autocrine and paracrine mechanisms as well as influencing properties (i.e. migration, secretion, cellular communication) of local immune cells. Within skeletal muscle, CX3CL1-signaling is involved in the regulation of fibre-type composition, mitochondrial remodeling, local inflammation, and regenerative capacity. These actions affect muscle plasticity and adaptability in both resting and active states. CX3CL1 also facilitates substrate uptake, particularly glucose and lipids, by interacting synergistically with insulin-signaling pathways, especially during metabolic stress or exercise. Furthermore, CX3CL1 contributes to the coordination of skeletal muscle function with other key metabolic organs such as adipose tissue, liver and brain. Notably, CX3CL1 appears to play a role in the pathogenesis of several chronic diseases, including type 2 diabetes (T2D), obesity, cardiovascular disease (CVD), insulin resistance (IR) and arthritis. These findings underscore the relevance of CX3CL1 in both health and disease. Here, we critically assess recent advances in CX3CL1 research, including its mechanism of action, and explore its potential implications in physiological and pathological scenarios.

Keywords:  CX3CL1; exercise insulin; mitochondria metabolism; skeletal muscle; substrate utilisation

DOI:  https://doi.org/10.1111/febs.70267
Sci Adv. 2025 Sep 26. 11(39): eadt6366

Lysosomal LRRC8 complex impacts lysosomal pH, morphology, and systemic glucose metabolism.

Ashutosh Kumar, Yonghui Zhao, Litao Xie, Rahul Chadda, John D Tranter, Ryan T Mikami, Nihil Abraham, Juan Hong, Ethan Feng, David R Rawnsley, Haiyan Liu, Kayla M Henry, Gretchen Meyer, Meiqin Hu, Haoxing Xu, Antentor Hinton, Chad E Grueter, E Dale Abel, Andrew W Norris, Abhinav Diwan, Rajan Sah.

The lysosome integrates anabolic signaling and nutrient sensing to regulate intracellular growth pathways. The leucine-rich repeat-containing 8 (LRRC8) channel complex forms a lysosomal anion channel and regulates PI3K-AKT-mTOR signaling, skeletal muscle differentiation, growth, and systemic glucose metabolism. Here, we define the endogenous LRRC8 subunits localized to a subset of lysosomes in differentiated myotubes. We show that LRRC8A affects leucine-stimulated mTOR; lysosome size; number; pH; expression of lysosomal proteins LAMP2, P62, and LC3B; and lysosomal function. Mutating an LRRC8A lysosomal targeting dileucine motif sequence (LRRC8A-L706A;L707A) in myotubes recapitulates the abnormal AKT signaling and altered lysosomal morphology and pH observed in LRRC8A knockout cells. In vivo, LRRC8A-L706A;L707A knock-in mice exhibit increased adiposity, impaired glucose tolerance and insulin resistance associated with reduced skeletal muscle PI3K-AKT-mTOR signaling, glucose uptake, and impaired incorporation of glucose into glycogen. These data reveal a lysosomal LRRC8-mediated metabolic signaling function regulating lysosomal function, systemic glucose homeostasis, and insulin sensitivity.

DOI: https://doi.org/10.1126/sciadv.adt6366
Cancer Rep (Hoboken). 2025 Sep;8(9): e70290

Early Markers of Cardiac and Skeletal Muscle Metabolic Derangement in the Apc(min/+) Male Mouse.

Traci L Parry, Nicole Wood, Jacob Garritson, Michael J Muehlbauer, Louisa Tichy, Jason T Brantley, James R Bain, Reid Hayward.

   BACKGROUND AND AIMS: Cancer cachexia is a metabolic and wasting disease that occurs in up to 80% of cancer patients. Currently, there are no clear diagnostic criteria, its effects are irreversible, and it cannot be treated. Most patients progress undetected to late stages of cancer cachexia, stop responding to traditional treatment, and die without an effective intervention. While the literature has begun to characterize late (refractory) cachexia muscle metabolic changes, less is known about early changes that may precede obvious muscle dysfunction and wasting. Therefore, this investigation aimed to characterize early phase heart and skeletal muscle metabolic changes in a preclinical model of colorectal cancer.
METHODS: The Apc(min/+) mouse spontaneously forms tumors along the intestinal tract and is a well-accepted preclinical colorectal cancer model. To identify early changes in muscle metabolism during colorectal cancer development, heart and gastrocnemius tissues from 15-week-old male Apc(min/+) and litter-matched non-carrier mice (wildtype) were analyzed by untargeted GC/MS metabolomics.
RESULTS: In the heart, metabolic pathways related to taurine/hypotaurine metabolism; biosynthesis of unsaturated fatty acids; alanine, glutamate, and aspartate; arginine and proline; and arginine biosynthesis were affected by colorectal cancer. In skeletal muscle, metabolic pathways involving arginine biosynthesis; alanine, glutamate, aspartate, and proline metabolism were affected by cancer cachexia. Taken together, these data demonstrate altered arginine metabolism and proline metabolism in hearts and skeletal muscle of cachectic mice. Interestingly, cardiac muscle showed a non-preferential fuel switch towards less energetically favorable glycolysis (vs. fatty acid metabolism) that coincided with cardiac dysfunction, while skeletal muscle exhibited glucose dysregulation and possible insulin resistance.
CONCLUSION: These data characterize early cardiac and skeletal muscle metabolic derangements that lead to muscle dysfunction and atrophy during colorectal cancer. Such data could help identify patients in early phases of cachexia or identification of cardiac and skeletal muscle specific therapeutic targets aimed at early intervention.

Keywords:  atrophy; cachexia; cancer; cardiac; heart; muscle; tumor

DOI:  https://doi.org/10.1002/cnr2.70290
Pharmaceuticals (Basel). 2025 Sep 18. pii: 1407. [Epub ahead of print]18(9):

Skeletal Muscle Aging: Enhancing Skeletal Muscle Integrity and Function as a Potential Pharmacological Approach.

Sibhghatulla Shaikh, Khurshid Ahmad, Jeong Ho Lim, Syed Sayeed Ahmad, Eun Ju Lee, Inho Choi.

  With the increase in global life expectancy, preserving skeletal muscle (SM) health is essential for the overall well-being of older adults. Gradual decline in muscle mass, strength, and physical performance significantly contributes to frailty, reduced mobility, and heightened vulnerability to chronic diseases. These challenges underscore the need to formulate innovative strategies for safeguarding muscle health in aging demographics. This review analyzes the major biological and lifestyle factors influencing age-related changes, establishing a framework for understanding SM deterioration. The review focuses on structural and functional alterations of SM extracellular matrix components to identify potential intervention points for muscle waste mitigation. Additionally, we discuss novel interventions designed to preserve muscle mass and functionality. In older individuals, emerging pharmacological strategies, including innovative peptides and natural compounds, may mitigate catabolic processes, enhance muscle regeneration, and increase resilience. Concurrent lifestyle interventions, including specialized exercise regimens, nutritional enhancement, and stress reduction, augment these pharmacological approaches. This review provides a thorough resource for researchers, clinicians, and healthcare professionals focused on functional capacity enhancement in older adults.

Keywords:  aging; aging factors; natural compounds; pharmacological activity; skeletal muscle

DOI:  https://doi.org/10.3390/ph18091407
Exerc Sport Sci Rev. 2025 Oct 01. 53(4): 195-204

Optimizing Female Health: The Crucial Role of Exercise Initiation before and during the Menopausal Transition.

Mette Hansen, Lasse Gliemann, Ylva Hellsten.

  In this review, we hypothesize that delaying physical training initiation until several years after menopause reduces the benefits of exercise on muscle function and cardiovascular health. Early engagement in exercise may counteract the negative effects of estradiol loss by activating pathways with similar molecular targets as estrogen, thereby helping to preserve muscle function and cardiovascular health during the postmenopausal period.

Keywords:  cardiovascular health; estrogen; estrogen receptors; estrogen-related receptor alpha; exercise training; menopause; muscle function

DOI:  https://doi.org/10.1249/JES.0000000000000371
J Lipid Res. 2025 Sep 23. pii: S0022-2275(25)00171-3. [Epub ahead of print] 100909

Mitochondrial cardiolipin remodeling facilitates efficient myoblast differentiation.

Yohsuke Ohba, Chinami Fujiwara, Makoto Arita.

  During myoblast differentiation, mitochondria undergo dynamic changes in their morphology and function. Although the mitochondrial membrane lipid environment is closely related to mitochondrial integrity, how mitochondrial lipid composition changes during myoblast differentiation and whether it is involved in efficient differentiation remains unclear. In this study, we applied LC-MS/MS-based untargeted lipidomics to the mitochondria isolated from C2C12 murine myoblasts and found that the proportion of linoleic acid (C18:2)-containing cardiolipin (CL) increased during the early stages of differentiation. In parallel, the expression of tafazzin, a mitochondrial CL remodeling enzyme, increased in line with myoblast differentiation. Notably, the increase in C18:2-containing CL was not suppressed by the knockdown of MyoD, a master transcription factor for myoblast differentiation. In contrast, the inhibition of CL biosynthesis and remodeling significantly suppressed differentiation progression, which was partially rescued by exogenous supplementation with C18:2. Similar trends in CL remodeling were observed when primary stem cells isolated from mouse skeletal muscle differentiated into myotubes. These results demonstrate that mitochondrial CL remodeling at an early stage is required to promote efficient myoblast differentiation.

Keywords:  cell signaling; lipidomics; mitochondria; muscle; phospholipid

DOI:  https://doi.org/10.1016/j.jlr.2025.100909
Int J Mol Sci. 2025 Sep 18. pii: 9122. [Epub ahead of print]26(18):

Estrogens and Antioxidants Prevent the Formation of Tubular Aggregates in Aging Male Mice.

Giorgia Rastelli, Matteo Serano, Barbara Girolami, Alice Brasile, Vincenzo Sorrentino, Laura Pietrangelo, Feliciano Protasi.

  Tubular aggregates (TAs), ordered arrays of sarcoplasmic reticulum (SR) tubes, are the main morphological alteration found in muscle biopsies from patients affected by TA myopathy (TAM). TAM has been linked to mutations in the genes encoding for STIM1 and ORAI1, which are two proteins that mediate Store-Operated Ca2+ entry (SOCE). SOCE is a mechanism that allows recovery of extracellular Ca2+ during fatigue, when the SR becomes depleted. As TAs also form in fast-twitch muscle fibers of aging male mice (not in females), we studied the effect of sex hormones on the aggregation of TAs during aging. We administered estrogen (ad libitum in drinking water) to male mice from 10 to 18 months of age and then evaluated the following: (a) the presence of TAs using histology and electron microscopy (EM); (b) oxidative stress, a mechanism that could underlie damage to proteins and membranes (and possibly their accumulation in TAs); and (c) SOCE function during ex vivo stimulation in the presence or absence of external Ca2+ or SOCE blocker (BTP-2). The results collected indicate that treatment with estrogen (a) significantly reduced the formation of TAs; (b) reduced oxidative stress, which was elevated in aging male mice; and (c) restored SOCE, i.e., the capability of aged EDL muscles to use external Ca2+ by promoting maintenance of Ca2+ Entry Units (CEUs, the intracellular junctions that mediate SOCE). Finally, we also show that formation of TAs is reduced by treatment of mice with N-acetilcysteine (NAC), a potent antioxidant also administered ad libitum in drinking water.

Keywords:  electron microscopy; sarcoplasmic reticulum; skeletal muscle; store-operated calcium entry

DOI:  https://doi.org/10.3390/ijms26189122
Nat Aging. 2025 Sep 24.

Herbal terpenoids activate autophagy and mitophagy through modulation of bioenergetics and protect from metabolic stress, sarcopenia and epigenetic aging.

Gabriele Civiletto, Dario Brunetti, Giulia Lizzo, Kamila Muller, Guillaume E Jacot, Ioanna Daskalaki, Federico Sizzano, Minji Huh, Ivano Di Meo, Maria Nicol Colombo, José L Sanchez-Garcia, Bertrand J Bétrisey, Alix Zollinger, Patricia Lino, Christopher Neal, Anne-Laure Egesipe, Joy Richard, Myriam Chimen, Aurélie Hermant, Benjamin Brinon, Lorane Texari, Sylviane Metairon, Mohammed Adnan Qureshi, Dhaval S Patel, Siva A Vanapalli, Marco Malavolta, Arwen W Gao, Amelia Lalou, Mauro Provinciali, Fiorenza Orlando, Valeria Tiranti, Robert T Brooke, Steve Horvath, Johan Auwerx, Jerome N Feige, Philipp Gut.

Small molecular food components contribute to the health benefits of diets rich in fruits, vegetables, herbs and spices. The cellular mechanisms by which noncaloric bioactives promote healthspan are not well understood, limiting their use in disease prevention. Here, we deploy a whole-organism, high-content screen in zebrafish to profile food-derived compounds for activation of autophagy, a cellular quality control mechanism that promotes healthy aging. We identify thymol and carvacrol as activators of autophagy and mitophagy through a transient dampening of the mitochondrial membrane potential. Chemical stabilization of thymol-induced mitochondrial depolarization blocks mitophagy activation, suggesting a mechanism originating from the mitochondrial membrane. Supplementation with thymol prevents excess liver fat accumulation in a mouse model of diet-induced obesity, improves pink-1-dependent heat stress resilience in Caenorhabditis elegans, and slows the decline of skeletal muscle performance while delaying epigenetic aging in SAMP8 mice. Thus, terpenoids from common herbs promote autophagy during aging and metabolic overload, making them attractive molecules for nutrition-based healthspan promotion.

DOI: https://doi.org/10.1038/s43587-025-00957-4
bioRxiv. 2025 Sep 21. pii: 2025.09.19.677400. [Epub ahead of print]

Elimination of myotonia improves myopathy in a muscleblind knockout model of myotonic dystrophy.

Matthew T Sipple, Sakura Hamazaki, Vanessa Todorow, Lily A Cisco, Katherine M Lupia, Christina S Heil, Peter Meinke, Charles A Thornton, John D Lueck.

A cardinal sign of myotonic dystrophy type 1 (DM1) is slow of muscle relaxation after voluntary contraction known as myotonia. Myotonia results from mis-regulated splicing of chloride channel 1 (ClC-1), leading to loss of channel function and runs of involuntary action potentials in muscle fibers. Heralding the onset of weakness, myotonia is often the first symptom of DM1, and raising the possibility that muscle hyperexcitability promotes the subsequent development of myopathy. We used genome editing to test this possibility by deleting the alternatively spliced and frameshift inducing ClC-1 exon 7a (E7a) in the Mbnl1 knockout model of DM1. Although several ClC-1 exons exhibit mis-regulated splicing in DM1, deletion of this single cryptic exon was sufficient to restore ClC-1 function and eliminate myotonia systemically and permanently. As determined by long-read sequencing, deletion of E7a reduced the frequency of other splicing defects in ClC-1 transcripts, likely as a passive consequence of restoring reading frame and nonsense surveillance. Furthermore, we observed significantly improved muscle force generation, fiber-type distribution, and histology, and partial restoration of the muscle transcriptome, including differential gene expression and alternative splicing, in non-myotonic Mbnl1 knockout mice. These results suggest that E7a inclusion is a lynchpin splice event that contributes to skeletal myopathy, highlighting myotonia as a therapeutic target and an outcome of interest in DM1.

DOI: https://doi.org/10.1101/2025.09.19.677400
J Physiol. 2025 Sep 22.

Semaglutide impacts skeletal muscle to a similar extent as caloric restriction in mice with diet-induced obesity.

S Jeromson, B Baranowski, M Akcan, B D Waters, K Eisner, A Bellucci, S Trang, A Abolhassani, M A Tello-Palencia, A Schweitzer, B Stefanska, C J Mitchell, David C Wright.

  Semaglutide is a GLP-1 receptor agonist that is highly efficacious in reducing food intake and body weight. While semaglutide reduces adipose tissue, there is also a loss of lean mass including skeletal muscle, though it is unclear whether this translates to a loss of muscle function. The effect of discontinuation of semaglutide on rebound weight gain and shifts in body composition is also not well understood. We investigated the impact of semaglutide and matched caloric restriction on body composition in mice with diet-induced obesity. Mice were treated with semaglutide or fed a calorie-matched diet for 4 weeks. Semaglutide and pair-feeding induced significant weight loss with a concomitant reduction in energy expenditure. Weight loss was greater with semaglutide than caloric restriction, despite matched energy intake. Muscle transcriptomic analyses revealed distinct molecular responses between semaglutide and pair-feeding. In a follow-up experiment, semaglutide and pair-feeding was discontinued after 4 weeks, and body weight and food intake were tracked for 6 weeks. At the end of the withdrawal period there was a loss of treatment effects. Lean and fat mass rebounded to baseline levels at the end of the withdrawal period. Muscle size and strength were also comparable between groups. These findings demonstrate that semaglutide reduces muscle size and strength to the same extent as caloric restriction but may be more effective at promoting fat loss. Interestingly, the loss of lean mass and skeletal muscle recovered following treatment discontinuation. KEY POINTS: Semaglutide results in greater weight loss than caloric restriction. Semaglutide treatment increases fat loss compared with caloric restriction. Muscle mass and strength is reduced to a similar extent by semaglutide and restricted feeding.

Keywords:  obesity; semaglutide; skeletal muscle; weight loss

DOI:  https://doi.org/10.1113/JP289449
Redox Biol. 2025 Sep 19. pii: S2213-2317(25)00387-8. [Epub ahead of print]87 103874

γ-Tocotrienol attenuates oxidative stress and preserves mitochondrial function in inflammation-induced muscle atrophy.

Jun Yi Chong, Tsui-Chin Huang, Sheng-Ming Chueh, Cheng-Yi Ma, Tzu-Ting Kuo, Jia-Jun He, Yii-Jwu Lo, Kuan-Chieh Peng, Mohamed Ali, Hsin-Yi Chang, Shih-Min Hsia.

  Muscle atrophy, marked by the loss of skeletal muscle mass and strength, presents a major health concern with diverse etiologies, including chronic inflammation. Effective interventions are urgently needed for its prevention and treatment. Although α-tocopherol, the most abundant form of vitamin E, is known for its antioxidant benefits in muscle health, γ-tocotrienol exhibits superior antioxidant and anti-inflammatory properties. This study investigates the protective effects of γ-tocotrienol against muscle atrophy and compares its efficacy with α-tocopherol. Muscle atrophy was induced in differentiated C2C12 myotubes using lipopolysaccharide (LPS), with vitamin E pre-treatment applied prior to LPS challenge. Myotube morphology, expression of atrophy-related markers, and underlying molecular pathways were examined through immunofluorescence, western blotting, and quantitative proteomics. LPS treatment induced significant myotube atrophy without affecting cell viability. Notably, γ-tocotrienol pre-treatment preserved myotube size and suppressed key atrophy markers, including the E3 ubiquitin ligases MuRF-1 and Fbxo32/Atrogin-1. Proteomic analysis quantified 5,371 proteins and revealed that γ-tocotrienol alleviated atrophy by enhancing extracellular matrix organization and attenuating oxidative stress and mitochondrial dysfunction. These protective effects were further confirmed in vivo, where γ-tocotrienol administration preserved muscle strength, suppressed pro-inflammatory signaling, and restored mitochondrial biogenesis in LPS-treated mice. Collectively, these findings demonstrate that γ-tocotrienol offers superior protection against muscle atrophy compared to α-tocopherol, highlighting its therapeutic potential for individuals at risk of muscle wasting.

Keywords:  Mitochondrial oxidative stress; Muscle atrophy; Proteomics; Vitamin E; γ-Tocotrienol

DOI:  https://doi.org/10.1016/j.redox.2025.103874
Int J Mol Sci. 2025 Sep 11. pii: 8845. [Epub ahead of print]26(18):

VBIT-4 Rescues Mitochondrial Dysfunction and Reduces Skeletal Muscle Degeneration in a Severe Model of Duchenne Muscular Dystrophy.

Mikhail V Dubinin, Anastasia E Stepanova, Irina B Mikheeva, Anastasia D Igoshkina, Ekaterina N Kraeva, Alena A Cherepanova, Eugeny Yu Talanov, Anna V Polikarpova, Maxim E Astashev, Vyacheslav A Loginov, Tatiana V Egorova.

  Duchenne muscular dystrophy (DMD) is a severe X-linked recessive disorder caused by mutations in the DMD gene, leading to progressive muscle degeneration and fibrosis. A key pathological feature of DMD is mitochondrial dysfunction driven by calcium overload, which disrupts oxidative phosphorylation and triggers cell death pathways. This study shows the therapeutic potential of VBIT-4, a novel inhibitor of the mitochondrial voltage-dependent anion channel (VDAC), in two dystrophin-deficient mouse models: the mild mdx and the severe D2.DMDel8-34 strains. VBIT-4 administration (20 mg/kg) reduced mitochondrial calcium overload, enhanced resistance to permeability transition pore induction, and improved mitochondrial ultrastructure in D2.DMDel8-34 mice, while showing negligible effects in mdx mice. VBIT-4 suppressed mitochondrial and total calpain activity and reduced endoplasmic reticulum stress markers, suggesting a role in mitigating proteotoxic stress. However, it did not restore oxidative phosphorylation or reduce oxidative stress. Functional assays revealed limited improvements in muscle strength and fibrosis reduction, exclusively in the severe model. These findings underscore VDAC as a promising target for severe DMD and highlight the critical role of mitochondrial calcium homeostasis in DMD progression.

Keywords:  Duchenne muscular dystrophy; VBIT-4; VDAC; calcium overload; proteotoxic stress; skeletal muscle mitochondria

DOI:  https://doi.org/10.3390/ijms26188845
Antioxidants (Basel). 2025 Sep 17. pii: 1125. [Epub ahead of print]14(9):

Recovery of SIRT3-SOD2 Axis and Mitophagy by Short-Term Calorie Restriction in Old Rat Soleus Skeletal Muscle.

Rosa Di Lorenzo, Anna Picca, Guglielmina Chimienti, Christiaan Leeuwenburgh, Vito Pesce, Angela Maria Serena Lezza.

  Age-related mitochondrial dysfunction is involved in the progressive loss of mass and strength of skeletal muscle with aging. The effects of a short-term calorie restriction (ST-CR) were assessed in the oxidative skeletal soleus muscle (Sol) from 27-month-old rats and compared with those of a CR in combination with resveratrol (RSV) (ST-CR + RSV). PGC-1α and PRXIII proteins showed a marked decrease in both ST-CR and ST-CR + RSV rats. The SIRT3 protein presented a very relevant increase in both ST groups. ST-CR and ST-CR + RSV elicited a marked increase in SOD2 protein amount and activity. ST-CR and ST-CR + RSV led to recovery of the SIRT3-SOD2 axis as a fast/early response. ST-CR and ST-CR + RSV did not affect the MFN2 protein, whereas both treatments induced a relevant increase in DRP1 protein. ST-CR and ST-CR + RSV induced a decrease in Parkin protein, suggestive of rescued mitophagy, leading to the elimination of dysfunctional mitochondria. Such a response likely enhanced the fission-mediated elimination of mitochondria, supported by the marked increase in DRP1. MtDNA copy number and TFAM protein were not changed by any ST treatment. The mtDNA oxidative damage level was strongly increased by both ST treatments. All the effects elicited by ST-CR and ST-CR + RSV were specific to the oxidative type fibers.

Keywords:  aging; caloric restriction; mitochondrial biogenesis; mitophagy; rat soleus skeletal muscle; resveratrol

DOI:  https://doi.org/10.3390/antiox14091125
Nat Rev Neurol. 2025 Sep 22.

Myotonic dystrophy type 1: clinical diversity, molecular insights and therapeutic perspectives.

Lisa Rahm, Melissa A Hale, Renée H L Raaijmakers, Alexandra Marrero Quiñones, Tejal Patki, Nicholas E Johnson, Hans van Bokhoven, Karlien Mul.

Myotonic dystrophy type 1 (DM1) is the most prevalent muscular dystrophy in adulthood and is one of the most clinically diverse monogenic diseases. Although it is classified as a neuromuscular disease, DM1 is a multisystem disorder that affects nearly all organ systems, particularly skeletal and smooth muscles, the central nervous system and the heart. Its phenotypic variability extends beyond a continuum of severity, encompassing differences in age of onset and organ involvement. DM1 is caused by a trinucleotide (CTG) repeat expansion within the 3' untranslated region of the DMPK gene, leading to a toxic RNA gain-of-function mechanism that disrupts RNA splicing, causing widespread cellular dysfunction. Despite progress in understanding DM1 pathogenesis, gaps remain in elucidating genotype-phenotype correlations, genetic modifiers and mechanisms that influence disease progression. Breakthroughs in the past five to ten years have uncovered important insights into the molecular underpinnings of DM1 and accelerated therapeutic innovation. Targeted interventions such as small molecules, antisense oligonucleotides and gene-editing technologies are progressing into clinical trials. Additionally, emerging research on somatic instability, epigenetic modifications and novel biomarkers suggests approaches for precision medicine. This Review synthesizes recent clinical and molecular discoveries, highlighting implications for therapy development. By integrating clinical heterogeneity with mechanistic insights, we provide a framework for future translational research and therapeutic innovation in this life-limiting disease.

DOI: https://doi.org/10.1038/s41582-025-01139-x
Mol Ther Methods Clin Dev. 2025 Dec 11. 33(4): 101571

Directed evolution of liver-detargeted AAV vectors for systemic gene delivery to skeletal muscle and heart.

Elad Firnberg, Sigmund K S Tejada, Samantha A Yost, April R Giles, Heonhwa Choi, Steven J Foltz, Randolph Qian, Jared B Smith, Benjamin Heithoff, Kirk Elliott, Chun-Feng David Hou, Ashley D Bernstein, Subha Karumuthil-Melethil, Victor Shugui Chen, Ayda Mayer, Andrew C Mercer, Jason T Kaelber, Ye Liu, Olivier Danos.

  Adeno-associated virus (AAV) gene therapies that require systemic administration of high vector doses are associated with hepatotoxicity risk, given the liver tropism of most AAV vectors. We combined screening of natural serotypes, targeted mutagenesis, and directed evolution to identify liver-detargeted muscle-tropic capsids. We found that AAVhu.32 is liver-detargeted compared to AAV9, and AAV5 exhibits high skeletal muscle biodistribution albeit with low transgene expression. Following two rounds of peptide insertion library-based directed evolution of AAV9.AAA (a previously described variant) and AAV5, we identified peptides NVG7 and NVG13, respectively, that confer increased muscle transduction compared to the base capsid with liver-detargeting compared to AAV9 in mouse. In non-human primate (NHP), the liver-detargeted profile of these capsids was confirmed in a pooled capsid study and via comparison to AAV9 NHP literature data. Incorporating AAA.NVG7 into AAVhu.32 led to further improved transduction in mouse heart and brain. The structure and phenotype of the loop insertion in AAV9.AAA.NVG7 is dependent on the sequence of an adjacent loop in a case of sign epistasis between the two sites. These capsids may provide an improved safety profile and increased activity in muscle compared to current AAV capsids.

Keywords:  adeno-associated virus; directed evolution; gene therapy; liver-detargeting; muscular dystrophy

DOI:  https://doi.org/10.1016/j.omtm.2025.101571
J Sport Health Sci. 2025 Sep 20. pii: S2095-2546(25)00071-7. [Epub ahead of print] 101089

The mechanical loading environment associated with eccentric exercise is one of the key stimuli to trigger sarcomerogenesis: It's a stretch to say eccentric exercise does not promote serial sarcomerogenesis.

Geoffrey A Power, Martino V Franchi, Avery Hinks.

DOI: https://doi.org/10.1016/j.jshs.2025.101089
Gene. 2025 Sep 23. pii: S0378-1119(25)00571-2. [Epub ahead of print] 149782

Genetic analysis of a family with skeletal muscle ion channelopathy and hereditary spastic paraplegia type 7 caused by SCN4A and SPG7 double mutations.

Hong-Ping Yu, Zi-Yan Xu, Meng-Qian Wu, Qian Chen, Zhi-Hai Zheng, Wei Wen, Pan Lin, Jing Zou, Jian-Hui Zhang, Dan-Dan Ruan, Ruo-Li Wang, Li Chen, Mei-Zhu Gao, Li Zhang, Li-Sheng Liao, Fan Lin, Hong Li, Zhu-Ting Fang, Wei Wang, Xing-Lin Ruan, Jie-Wei Luo, Yun-Fei Li.

  Hereditary spastic paraplegia (HSP) is a rare and genetically heterogeneous neurodegenerative disorder, primarily defined by progressive lower-limb spasticity and weakness. Among the numerous genes implicated, pathogenic variants in the spastic paraplegia 7 (SPG7) gene represent one of the most common causes of HSP, whereas mutations in SCN4A, a skeletal muscle ion channel gene, are typically associated with a diverse spectrum of phenotypes, including hyperkalemic and hypokalemic periodic paralysis, potassium-aggravated myotonia, and congenital paramyotonia. To date, however, the coexistence of pathogenic variants in SPG7 and SCN4A within the same pedigree, and their potential pathogenic interplay, has not been documented. In this study, we performed comprehensive genetic profiling, including whole-exome sequencing, mitochondrial genome analysis, dynamic mutation screening, copy number variation assessment, and Sanger sequencing. We identified a novel heterozygous SPG7 variant (c.578A>G; p.E193G) alongside a known pathogenic SCN4A missense mutation (c.2111C>T; p.T704M). Remarkably, individuals harboring both variants presented with highly complex phenotypes that combined classical HSP manifestations with ion channel dysfunctions, such as congenital paramyotonia and hypokalemic periodic paralysis. These findings provide the first evidence of a possible genetic interaction between SPG7 and SCN4A, expanding the recognized clinical and molecular spectrum of HSP. Our results underscore the diagnostic value of multi-gene testing in patients with atypical or overlapping neuromuscular symptoms and highlight the importance of considering potential polygenic contributions when interpreting the clinical heterogeneity of HSP.

Keywords:  HSP; HypoPP; Non-nutritional myotonia; Paramyotonia congenita; SCN4A; Skeletal muscle ion channel disease

DOI:  https://doi.org/10.1016/j.gene.2025.149782
JACC CardioOncol. 2025 Sep 25. pii: S2666-0873(25)00301-1. [Epub ahead of print]

Blunted Exercise Response in Cancer Survivors: A Consequence of the Heart or Peripheral Muscle?

Lei Xu, Wenzhe Zhao.

DOI: https://doi.org/10.1016/j.jaccao.2025.06.012