bims-moremu 2025-11-16 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2025–11–16
thirty-six papers selected by
Anna Vainshtein, Craft Science Inc.

Alterations in peroxisome-mitochondria interplay in skeletal muscle accelerate muscle dysfunction.
Intrinsic dysfunction in muscle stem cells lacking dystrophin begins during secondary myogenesis.
Fast Myosin Binding Protein-C Is a Vital Regulator in Young and Aged Fast Skeletal Muscle Homeostasis.
Irisin Increases Sirtuin 1 to Improve Glucocorticoid-Induced Sarcopenia and Mitochondrial Dysfunction.
Ca2+, ROS, IL-6, and p38 MAPK signaling loops underlying alterations in myotube formation induced by a severe MH/CCD mutation in RyR1.
Gli1 regulates fibro/adipogenic progenitor function through modulation of Ido1 in muscle regeneration.
Rethinking Muscle Aging Through the Lens of Fibro-Adipogenic Progenitors.
STX4 Is Indispensable for Mitochondrial Homeostasis in Skeletal Muscle.
Enhancer Rewiring Orchestrates Inflammation and Loss of Cell Identity During Muscle Stem Cell Aging.
Pathophysiological mechanisms and emerging therapeutic strategies for muscle wasting: an integrative review.
Proteomics of Duchenne Muscular Dystrophy Patient iPSC-Derived Skeletal Muscle Cells Reveal Differential Expression of Cytoskeletal and Extracellular Matrix Proteins.
HSALR Mice Exhibit Co-Expression of Proteostasis Genes Prior to Development of Muscle Weakness.
Impaired cAMP-PKA-CREB1 signalling drives mitochondrial dysfunction in skeletal muscle during cancer cachexia.
miRNA changes with ageing and caloric restriction in male rat skeletal muscle: potential roles in muscle cell function.
Thyroid hormone imbalance, malnutrition, and sarcopenia: a triad of muscle health challenges.
Dysferlin and the Regulation of Ca2+ Release in Skeletal Muscle.
Hemizygous mutation of Jmjd3 in muscle stem cells increases H3K27 methylation on Pax7 leading to impaired myogenesis.
Microscopic and molecular aspects of skeletal muscle alterations in cerebral palsy.
An Isogenic Human Myoblast Cell Model for Cystinosis Myopathy Reveals Alteration of Key Myogenic Regulatory Proteins.
Pediatric CHOP Chemotherapy Acutely Disrupts Satellite‑Cell Dynamics and Blunts Muscle Mass in a Sex‑Specific Manner.
Irisin ameliorates age-associated skeletal muscle atrophy in mice: potential involvement of iron overload and SIRT1/p53 pathway.
Lactylation of mTOR enhances autophagy in skeletal muscle during exercise.
Redox Homeostasis in Metabolic Syndrome and Type II Diabetes: Role of Skeletal Muscle and Impact of Gold-Standard Treatments.
Mn quenching in activated zebrafish muscle fibers does not result from store-operated Ca entry.
Donepezil treatment, alone or combined with exercise, enhances skeletal muscle function in healthy and advanced aging disease mouse models.
Proteomic Profiling of Myofiber Repair Annexins and Their Role in Duchenne Muscular Dystrophy.
Distinct Intramuscular Extracellular Matrix Protein Responses to Exercise Training in COPD and Healthy Adults and Their Association with Muscle Remodeling.
Circulating protein biomarkers identified in two independent clinical trial cohorts of glucocorticoid-naive Duchenne muscular dystrophy patients.
Changes in motor unit conduction velocity after unilateral lower-limb suspension and active recovery are correlated with muscle ion channel gene expression.
Microscopic and molecular aspects of skeletal muscle alterations in cerebral palsy.
PathViT: Automated disease classification from skeletal muscle histopathology.
Reframing sarcopenia: the AWGS 2025 paradigm shift from disease to muscle health.
Akt-Axin1/TNKS-Tiam1-Rac1 mediates insulin-stimulated GLUT4 translocation in skeletal muscle cells.
Caffeine Decreases Mu scle and Tendon Protein Synthesis and Engineered Ligament Strength In Vitro and Attenuates Adaptation to Exercise in Mice.
Evaluating muscle aging during relaxed standing, squats and lunges through electrical bioimpedance.
Role of Peptides in Skeletal Muscle Wasting: A Scoping Review.

Nat Commun. 2025 Nov 10. 16(1): 9868

Alterations in peroxisome-mitochondria interplay in skeletal muscle accelerate muscle dysfunction.

Marco Scalabrin, Eloisa Turco, Ilaria Davigo, Riccardo Filadi, Leonardo Nogara, Gaia Gherardi, Lucia Barazzuol, Andrea Armani, Giulia Trani, Samuele Negro, Anais Franco-Romero, Yorrick Jaspers, Elisa Baschiera, Rossella De Cegli, Eugenio Del Prete, Tito Cali, Bert Blaauw, Leonardo Salviati, Michela Rigoni, Cristina Mammucari, Sylvie Caspar-Bauguil, Cedric Moro, Paola Pizzo, Marco Sandri, Stephan Kemp, Vanina Romanello.

Skeletal muscles, which constitute 40-50% of body mass, regulate whole-body energy expenditure and glucose and lipid metabolism. Peroxisomes are dynamic organelles that play a crucial role in lipid metabolism and clearance of reactive oxygen species, however their role in skeletal muscle remains poorly understood. To clarify this issue, we generated a muscle-specific transgenic mouse line with peroxisome import deficiency through the deletion of peroxisomal biogenesis factor 5 (Pex5). Here, we show that Pex5 inhibition results in impaired lipid metabolism, reduced muscle force and exercise performance. Moreover, mitochondrial structure, content, and function are also altered, accelerating the onset of age-related structural defects, neuromuscular junction degeneration, and muscle atrophy. Consistent with these observations, we observe a decline in peroxisomal content in the muscles of control mice undergoing natural aging. Altogether, our findings show the importance of preserving peroxisomal function and their interplay with mitochondria to maintain muscle health during aging.

DOI: https://doi.org/10.1038/s41467-025-64833-w
Nat Commun. 2025 Nov 14. 16(1): 10031

Intrinsic dysfunction in muscle stem cells lacking dystrophin begins during secondary myogenesis.

Marie E Esper, Alexander Y T Lin, Dallas Bennett, Michael A Rudnicki.

Loss of dystrophin causes Duchenne Muscular Dystrophy (DMD), a neuromuscular disease characterized by muscle fragility and muscle stem cell (MuSC) impairment. Conventional understanding is that DMD manifests after birth from cumulative muscle damage. Here, examination of mdx mouse embryos lacking dystrophin reveals no impairment of the primary myogenic program. By contrast, histological and single cell RNA-sequencing analysis during secondary myogenesis uncovers an increase in the proportion of fetal (f) MuSCs and a marked reduction in myogenic progenitors and myocytes, leading to fewer smaller-caliber myofibers. Wild type fMuSCs express full-length dystrophin that interacts with MARK2, whereas mdx fMuSCs downregulate MARK2 and NUMB, exhibiting reduced PARD3 polarization. Strikingly, deletion of the Numb Associated Kinase, AAK1, rescues polarization of NUMB and myogenic progenitor generation in mdx fetal muscle. Together, our results elucidate an acute disease pathology during DMD fetal development and the potential for therapeutic intervention by targeting AAK1.

DOI: https://doi.org/10.1038/s41467-025-64999-3
J Cachexia Sarcopenia Muscle. 2025 Dec;16(6): e70106

Fast Myosin Binding Protein-C Is a Vital Regulator in Young and Aged Fast Skeletal Muscle Homeostasis.

Akhil Baby, Kalyani Ananthamohan, Brenna N McIntyre, Sankar Natesan, Taejeong Song.

   BACKGROUND: Skeletal muscle plays a vital role in voluntary movement and locomotion. Fast-twitch muscle fibres are characterized by their rapid contraction kinetics, high-force generation and a distinct gene expression profile compared to slow-twitch fibres. These fibres have a predominant expression of fast skeletal myosin binding protein-C (fMyBP-C). The role of fMyBP-C in skeletal muscle disease and aging remains poorly understood. To address this, our study employs mouse models with fMyBP-C ablation to investigate its significance in skeletal muscle physiology.
METHODS: Skeletal muscle samples from wild-type, db/db, MDX and ECC injury model (2-7 months) were analysed to determine the fMyBP-C levels. Next, male Mybpc2 knockout (C2-/-) mice, both young (3-5 months) and old (22 months), were utilized to investigate the role of fMyBP-C in aging. The effects of C2-/- and aging on the fibre type, size and number, as well as the overall muscle structure, were evaluated using immunohistochemistry and electron microscopy. In vivo and ex vivo muscle force generation was assessed to determine the functional impact of C2-/- and aging. RNA sequencing was conducted to identify the altered molecular pathways causing the muscle dysfunction in young and old C2-/- mice.
RESULTS: The expression of fMyBP-C was reduced (0.25-fold, p < 0.05) in the fast-twitch muscles of db/db mice, with a modest compensatory upregulation of slow skeletal MyBP-C (sMyBP-C) (~1.15-fold, p < 0.05). In MDX mice, fMyBP-C levels remain unchanged, whereas sMyBP-C levels were upregulated (~1.2-fold, p < 0.01). The fMyBP-C expression was 75% higher in the male skeletal muscles (p < 0.01) compared to females. Studies in young male C2-/- mice revealed a reduction in isometric tetanic force generation by 25% (p < 0.01) and relaxation rate by 42% (p < 0.001). The C2-/- mice also had 12.8% fewer type IIb fibres (p < 0.01), and a 20% reduction in type IIb fibre size (p < 0.01). Similarly, aged male C2-/- mice exhibited significant deficits in muscle strength, endurance and survival rate relative to their wild-type counterparts. The aged male C2-/- mice displayed a reduced size of type IIa, IIx and IIb muscle fibres compared to aged wild-type mice. RNA sequencing revealed that assembly and trimerization of collagen fibril pathway-related genes were altered in C2-/- mice.
CONCLUSION: fMyBP-C is a critical regulator of muscle function and homeostasis in young male fast-twitch muscle fibres. Its absence exacerbates the impact of aging on muscle structure and function. These findings suggest that fMyBP-C could serve as a promising therapeutic target for mitigating muscle wasting associated with aging and disease.

Keywords:  aging; fMyBP‐C; fast‐twitch muscle fibre; homeostasis; muscle function

DOI:  https://doi.org/10.1002/jcsm.70106
Cells. 2025 Oct 27. pii: 1675. [Epub ahead of print]14(21):

Irisin Increases Sirtuin 1 to Improve Glucocorticoid-Induced Sarcopenia and Mitochondrial Dysfunction.

Hongwei Shi, Wen Sun, Xiaoyuan Cao, Xuepeng Fan, Wenjuan Xie, Xiaojing Hao, Simiao Wang, Jiayin Lu, Yi Yan, Xiaomao Luo, Yanjun Dong, Haidong Wang, Juan Wang.

  Sarcopenia, characterized by progressive skeletal muscle mass, strength, and functional loss, imposes a substantial global health burden. Irisin, a myokine derived from fibronectin type III domain-containing protein 5 (FNDC5), is critical for muscle health. Here, we investigate its role in mitigating glucocorticoid-induced sarcopenia using a mouse and C2C12 myotubes model. We quantified FNDC5/irisin levels in skeletal muscle and plasma and assessed muscle function (body weight, grip strength, wire-hanging, and locomotor activity), histology, and mitochondrial features following irisin administration to dexamethasone-treated mice. Western blot analyzed synthesis/hydrolysis regulators, apoptosis markers, and mitochondrial regulators in mouse muscle tissues and C2C12 myotubes. The results show that FNDC5/irisin was significantly downregulated in sarcopenic mice and atrophic C2C12 myotubes; exogenous irisin rescued muscle mass loss and functional impairment, improving body weight, muscle mass, grip strength, and mobility. Mechanistically, irisin bound SIRT1 with -12.7 kcal/mol affinity, activating a deacetylation cascade that suppressed FoxO3a transcriptional activity (attenuating proteasomal degradation) and enhanced mTORC1-mediated protein synthesis in C2C12 myotubes. Additionally, irisin potentiated PGC-1α signaling in mouse myocytes, promoting mitochondrial biogenesis and restoring contractile function in dystrophic fibers. Collectively, these findings demonstrate irisin alleviates glucocorticoid-induced muscle atrophy via SIRT1-dependent pathways, rebalancing muscle physiology and systemic energy homeostasis. This highlights irisin-based therapeutics as a promising exercise surrogate for sarcopenia management, offering novel clinical avenues.

Keywords:  glucocorticoids; irisin; mitochondrial dysfunction; muscle atrophy; sirtuin 1

DOI:  https://doi.org/10.3390/cells14211675
Am J Physiol Cell Physiol. 2025 Nov 10.

Ca2+, ROS, IL-6, and p38 MAPK signaling loops underlying alterations in myotube formation induced by a severe MH/CCD mutation in RyR1.

Maikel Valle-Clara, Guillermo Avila.

  Mutations in the gene encoding the skeletal muscle ryanodine receptor (RyR1) can result in muscle diseases, termed RyR1-related myopathies (RyR1-RM). Examples include malignant hyperthermia (MH), central core disease (CCD), and centronuclear myopathy (CNM). The muscles involved often have more (and mispositioned) nuclei than normal. A subset of the corresponding mutant proteins shows an overactive or leaky sarcoplasmic reticulum (SR) channel behavior that depletes the SR Ca2+ content and increases the level of cytosolic Ca2+. In addition, two remarkable effects of these RyR1 variants have been reported in cultured myogenic cells: enhanced expression of interleukin-6 (IL-6) and stimulation of myoblast fusion (myonuclei accretion). Here, we have investigated whether the latter effect is due to a possible IL-6-dependent autocrine loop. Toward this goal, we analyzed the impact of the overactive Y523S mutant compared to the wild-type RyR1 after expression in C2C12 cells. The results show that this mutation indeed drastically promotes myoblast fusion up to ~300%. Moreover, this action depends on the sequential activation of SR Ca2+ release, store-operated Ca2+ channels, reactive oxygen species (ROS, cytosolic and mitochondrial), calpain, and calcineurin. Additionally, a neutralizing antibody directed against IL-6 and a p38 inhibitor completely suppressed the stimulation of myoblast fusion. Furthermore, in RyR1-expressing cells, myotube formation was promoted by either exogenous IL-6 or conditioned medium obtained from the Y523S-expressing cells. These findings suggest an autocrine mechanism involving the interplay between Ca2+, ROS, IL-6, and p38 signaling pathways in controlling myonuclei density, which could be essential to explain the pathogenesis of RyR1-RM.

Keywords:  calcium channel; intracellular calcium; myogenesis; oxidative stress; skeletal muscle disease

DOI:  https://doi.org/10.1152/ajpcell.00509.2025
Int J Biol Sci. 2025 ;21(14): 6197-6214

Gli1 regulates fibro/adipogenic progenitor function through modulation of Ido1 in muscle regeneration.

Lili Han, Fengmin Zhang, Jujin Zhang, Xiaonan Li, Kunpeng Wang, Biao Liu, Jiawen Song, Xinyan Liu, Yun Qian, Kai Li, Yingnan Lei, Claudia Spits, Yi Chang, Chengle Zhuang, Zhen Yu, Yun Zhao, Jiayin Peng.

  Gli1 is a critical marker of diverse stem cell populations across multiple tissues and is essential for tissue regeneration. However, its functional relevance in skeletal muscle has remained largely unexplored. Here, we demonstrate that Gli1 primarily expressed in muscle stem cells (MuSCs) and fibro/adipogenic progenitors (FAPs) in skeletal muscle. Utilizing conditional knockout mouse models, we found that systemic loss of Gli1 impairs muscle regeneration; however, this effect is not attributable to MuSC-dependent mechanisms. Rather, conditional deletion of Gli1 in FAPs lead to significant regenerative impairment, characterized by aberrant FAP expansion and their enhanced adipogenic potential. In vivo, Gli1-deficient FAPs contributed to increased intramuscular adipocyte accumulation, while in vitro assays confirmed enhanced lipid droplet formation under adipogenic conditions. Mechanistically, Gli1 directly activates the transcription of the key metabolic enzyme indoleamine 2,3-dioxygenase 1 (Ido1), and inhibition or knockdown of Ido1 phenocopied the effects of Gli1 loss. Together, these findings uncover a previously unrecognized role for Gli1 in orchestrating muscle regeneration by modulating FAP fate and function, providing new insights into the cellular and molecular framework governing muscle repair.

Keywords:  adipogenesis; fibro/adipogenic progenitors; muscle regeneration; muscle stem cells; proliferation

DOI:  https://doi.org/10.7150/ijbs.116134
Aging Dis. 2025 Nov 06.

Rethinking Muscle Aging Through the Lens of Fibro-Adipogenic Progenitors.

Feng-Min Zhang, Xian-Zhong Zhang, Zhen Yu, Cheng-Le Zhuang, Li-Li Han.

Aging of skeletal muscles is accompanied by a progressive deposition of adipose and fibrotic tissue within the interstitial compartment. This process profoundly disrupts the structural integrity and contractile function of the muscle. Such maladaptive remodeling not only compromises muscle performance but also impairs its regenerative capacity, predisposing old individuals to frailty and sarcopenia. Fibro-adipogenic progenitors (FAPs) have been identified as the principal cellular source of the pathological adipogenic and fibrogenic remodeling. These stromal cells integrate mechanical, biochemical, and immune signals within the muscle niche, ultimately determining whether muscle repair leads to effective regeneration or maladaptive remodeling. In young muscle, transient FAP activation supports satellite cell-mediated myogenesis through extracellular matrix remodeling and pro-regenerative signaling. However, in aging muscle, this precise regulation is disrupted. The aged niche is characterized by chronic inflammatory stress, altered matrix composition, and impaired immune-stromal communication. These changes drive FAPs toward maladaptive phenotypes that promote fibrosis, intramuscular fat accumulation, and regenerative failure. FAP dysfunction is increasingly recognized as a central mechanism contributing to age-related sarcopenia, increased susceptibility to injury, and delayed recovery. Given their dual ability to promote both regeneration and degeneration, understanding how aging reprograms FAP fate and function offers a promising avenue to rejuvenating the aged muscle niche. Here, we summarize current insights into the roles and dynamics of FAPs in aged muscle and discusses their potential as therapeutic targets to restore regenerative capacity and mitigating muscle aging.

DOI: https://doi.org/10.14336/AD.2025.1162
J Cachexia Sarcopenia Muscle. 2025 Dec;16(6): e70113

STX4 Is Indispensable for Mitochondrial Homeostasis in Skeletal Muscle.

Joseph M Hoolachan, Rekha Balakrishnan, Erika M McCown, Karla E Merz, Chunxue Zhou, Elizabeth Bloom-Saldana, Patrick T Fueger, Angelica Hamilton, Tali Kiperman, Ke Ma, Eunjin Oh, Lei Jiang, Patrick Pirrotte, Orian Shirihai, Debbie C Thurmond.

   BACKGROUND: Mitochondrial homeostasis is vital for optimal skeletal muscle integrity. Mitochondrial quality control (MQC) mechanisms that are essential for maintaining proper functions of mitochondria include mitochondrial biogenesis, dynamics and mitophagy. Previously, Syntaxin 4 (STX4), traditionally considered a cell surface protein known for glucose uptake in skeletal muscle, was also identified at the outer mitochondrial membrane. STX4 enrichment was sufficient to reverse Type 2 diabetes-associated mitochondrial damage in skeletal muscle by inactivation of mitochondrial fission. However, whether STX4 could modulate skeletal muscle mitochondrial homeostasis through MQC mechanisms involving mitochondrial biogenesis or mitophagy remains to be determined.
METHODS: To determine the requirements of STX4 in mitochondrial structure, function and MQC processes of biogenesis and mitophagy, we implemented our in-house generated inducible skeletal muscle-specific STX4-knockout (skmSTX4-iKO) mice (Stx4fl/fl; Tg (HSA-rtTA/TRE-Cre)/B6) and STX4-depleted immortalized L6.GLUT4myc myotubes via siRNA knockdown (siSTX4).
RESULTS: We found that non-obese skmSTX4-iKO male mice (> 50% reduced STX4 abundance, soleus and gastrocnemius ***p < 0.001, tibialis anterior (TA) ****p < 0.0001) developed insulin resistance (**p < 0.01), together with reduced energy expenditure (AUC *p < 0.05), respiratory exchange ratio (AUC **p < 0.01) and grip strength (*p < 0.05). STX4 ablation in muscle also impaired mitochondrial oxygen consumption rate (****p < 0.0001). Mitochondrial morphological damage was heterogenous in STX4-depleted muscle, presenting with small fragmented mitochondria (****p < 0.0001) and decreased electron transport chain (ETC) abundance (CI ***p < 0.001, CII *p < 0.05, CIV **p < 0.01) in oxidative soleus muscle, whereas glycolytic-rich TA fibres displayed enlarged swollen mitochondria (****p < 0.0001) with no change in ETC abundance. Notably, > 60% reduction of STX4 in siSTX4 L6.GLUT4myc myotubes (****p < 0.0001) also decreased ETC abundance (CI **p < 0.01, CII ***p < 0.001, CIV **p < 0.01) without changes in mitochondrial glucose metabolism, as shown by [U-13C]glucose isotope tracing. For MQC, both skmSTX4-iKO male mice (*p < 0.05) and siSTX4 L6.GLUT4myc myotubes (*p < 0.05) showed decreased mitochondrial DNA levels alongside reduced mRNA expression of mitochondrial biogenesis genes Ppargc1a (PGC1-α, *p < 0.05) and Tfam (*p < 0.05) in skmSTX4-iKO soleus muscle and PGC1-α (mRNA **p < 0.01, protein *p < 0.05), NRF1 (mRNA **p < 0.01 and protein *p < 0.05) and Tfam (mRNA *p < 0.05) in siSTX4 L6.GLUT4myc myotubes. Furthermore, live cell imaging using the mt-Keima mitophagy biosensor in siSTX4 L6.GLUT4myc cells revealed significantly impaired mitochondrial turnover by mitophagy (*p < 0.05) and mitochondria-lysosome colocalization (*p < 0.05). STX4 depletion also reduced canonical mitophagy markers, PINK1 and PARKIN in both skmSTX4-iKO muscle (PARKIN *p < 0.05, PINK1 **p < 0.01) and siSTX4 L6.GLUT4myc myotubes (PARKIN **p < 0.01, PINK1 *p < 0.05).
CONCLUSIONS: Our study demonstrated STX4 as a key mitochondrial regulator required for mitochondrial homeostasis in skeletal muscle.

Keywords:  STX4; mitochondria; muscle; quality control

DOI:  https://doi.org/10.1002/jcsm.70113
Aging Cell. 2025 Nov 14. e70289

Enhancer Rewiring Orchestrates Inflammation and Loss of Cell Identity During Muscle Stem Cell Aging.

Changyou Shi, Na Yang, Evelyn Pizano, Lin Wang, James R Occean, Chang-Yi Cui, Ling Liu, Christopher Dunn, Frimpong Boadu, Qiong Meng, Nirad Banskota, Jen-Hao Yang, Jinshui Fan, Supriyo De, Jianlin Cheng, Thomas A Rando, Vittorio Sartorelli, Payel Sen.

  Loss of regeneration is a key feature of aging organs, often linked to stem cell exhaustion. Skeletal muscle stem cells (MuSCs) undergo age-related numerical and functional decline, contributing to reduced regenerative potential. Using low-input multi-omics, we systematically profiled the epigenome, transcriptome, and 3D genome of MuSCs from individual mice across 3 age groups (young, old, and geriatric) and both sexes. At baseline, young male MuSCs showed reduced expression of cell cycle-related mRNAs. In aged mice, particularly males, MuSCs exhibited early alterations (emerging during the transition from young to old age) including enhanced proinflammatory signaling, and loss of cell identity. Late alterations (emerging during the transition from old to geriatric age) included heightened inflammation, widespread enhancer activation, and extensive 3D genome rewiring. Proinflammatory pathways were enriched for interferon signaling and correlated with endogenous retroviral expression and NFκB activity. Late-stage epigenome and 3D genome rewiring reflected downstream degenerative changes in muscle organization, response to cytokines, and loss of myogenic identity. Thus, progressive molecular shifts may explain the aggravated proliferative deficit and functional impairment observed in MuSCs during aging.

Keywords:  adult stem cells; aging; chromatin; epigenome; multi‐omics; muscle

DOI:  https://doi.org/10.1111/acel.70289
Front Physiol. 2025 ;16 1674892

Pathophysiological mechanisms and emerging therapeutic strategies for muscle wasting: an integrative review.

Jiahao Huang, Tianshan Wen, Huijun Wei, Jiliang Kang, Junyue Lu, Taian Zhou, Youliang Wen, Haoyuan Huang.

  Muscle wasting is a continuum of diseases that entail incremental skeletal muscle mass, as well as functionality, loss and is an important cause of morbidity, mortality, as well as quality of life reduction. This pathophysiology, diagnosis, as well as emerging treatment of significant muscle wasting illnesses, that is, sarcopenia, cachexia, disuse muscle atrophy, as well as neuromuscular illnesses, entail intricate interactions of defective protein synthetic processes, upregulated proteolysis, inflammatory cytokine activation, defective mitochondria, as well as hormone disturbances. Diagnostic methodologies have progressed from crude body dimension measures to sophisticated imaging modalities, as well as molecular biomarkers, but standardization remains contentious. Treatments entail targeted nutrition, as well as exercise regimes, as well as emerging drugs, as well as regenerative medicine therapies. Preclinical-to-clinical translation gaps, even striking, still exist despite promising advances. Some of these include diagnosis-based inequalities, patients' heterogeneity, limited therapeutic advantages, as well as implementation difficulties within healthcare. Future directions have emphasis on personalized medicine strategies that entail multi-omics signatures, combinatorial therapy of several targets, electronic health platforms for dynamic surveillance, as well as prevention modalities. Integrated healthcare platforms, multinational collaborative platforms, as well as regulatory reforms favoring muscle health across the life continuum, are needed for accomplishing the emerging challenge of controlling emerging muscle wasting burdens of the old, as well as those beset by chronic illnesses.

Keywords:  cachexia; muscle atrophy; myostatin; proteolysis; regenerative medicine; sarcopenia

DOI:  https://doi.org/10.3389/fphys.2025.1674892
Cells. 2025 Oct 28. pii: 1688. [Epub ahead of print]14(21):

Proteomics of Duchenne Muscular Dystrophy Patient iPSC-Derived Skeletal Muscle Cells Reveal Differential Expression of Cytoskeletal and Extracellular Matrix Proteins.

Sarah-Marie Gallert, Mitja Fölsch, Lampros Mavrommatis, Urs Kindler, Karin Schork, Martin Eisenacher, Matthias Vorgerd, Beate Brand-Saberi, Britta Eggers, Katrin Marcus, Holm Zaehres.

  Proteomics of dystrophic muscle samples is limited by the amount of protein that can be extracted from patient biopsies. Cells and tissues derived from patient-derived induced pluripotent stem cells (iPSCs) can be an expandable alternative source. We have patterned iPSCs from three Duchenne muscular dystrophy (DMD) patient lines into skeletal muscle cells using a two-dimensional as well as our three-dimensional organoid differentiation system. Probes with sufficient protein amounts could be extracted and prepared for mass spectrometry. In total, 3007 proteins in 2D and 2709 proteins in 3D were detected in DMD patient probes. A total of 83 proteins in 2D and 338 proteins in 3D can be described as differentially expressed between DMD and control patient probes in a post hoc test. We have identified and we propose Myosin-9, Collagen 18A, Tropomyosin 1, BASP1, RUVBL1, and NCAM1 as proteins specifically altered in their expression in DMD for further investigation. Proteomics of skeletal muscle organoids resulted in greater consistency of results between cell lines in comparison to the two-dimensional myogenic differentiation protocol.

Keywords:  Duchenne Muscular Dystrophy; biomarker; disease modelling; mass spectrometry; organoids; patient-induced pluripotent stem cells; proteomics; skeletal muscle

DOI:  https://doi.org/10.3390/cells14211688
Int J Mol Sci. 2025 Nov 06. pii: 10793. [Epub ahead of print]26(21):

HSALR Mice Exhibit Co-Expression of Proteostasis Genes Prior to Development of Muscle Weakness.

Dusan M Lazic, Vladimir M Jovanovic, Jelena Karanovic, Dusanka Savic-Pavicevic, Bogdan Jovanovic.

  Myotonic dystrophy type 1 (DM1) is a progressive multisystemic disease caused by a CTG repeat expansion in the DMPK gene. The toxic mutant mRNA sequesters MBNL proteins, disrupting global RNA metabolism. Although alternative splicing in DM1 skeletal muscle pathology has been extensively studied, early-stage transcriptomic changes remained uncharacterized. To gain deeper and contextual insight into DM1 transcriptome, we performed the first Weighted Gene Co-expression Network Analysis (WGCNA) on skeletal muscle RNA sequencing data from the widely used DM1 mouse model HSALR (~250 CTG repeats). We identified 532 core genes using data from 16-week-old mice, an age before the onset of muscle weakness. Additional differential expression analysis across multiple HSALR datasets revealed 42 common up-regulated coding and non-coding genes. Within identified core genes, the pathway gene-pair signature analysis enabled contextual selection of functionally related genes involved in maintaining proteostasis, including endoplasmic reticulum (ER) protein processing, the ubiquitin-proteasome system (UPS), macroautophagy and mitophagy, and muscle contraction. The enrichment of ER protein processing with prevailing core genes related to ER-associated degradation suggests adaptive chaperone and UPS activation, while core genes such as Ambra1, Mfn2, and Usp30 indicate adaptations in mitochondrial quality control. Coordinated early alterations in processes maintaining protein homeostasis, critical for muscle mass and function, possibly reflect a response to cellular stress due to repeat expansion and appears before muscle weakness development. Although the study relies exclusively on transcriptomic analyses, it offers a comprehensive, hypothesis-generating perspective that pinpoints candidate pathways, preceding muscle weakness, for future mechanistic validation.

Keywords:  ER-associated degradation; HSALR; WGCNA; autophagy; mitophagy; myotonic dystrophy type 1; protein homeostasis; proteostasis; repeat expansions; ubiquitin-proteasome system

DOI:  https://doi.org/10.3390/ijms262110793
Nat Metab. 2025 Nov 12.

Impaired cAMP-PKA-CREB1 signalling drives mitochondrial dysfunction in skeletal muscle during cancer cachexia.

Elia Angelino, Lorenza Bodo, Roberta Sartori, Valeria Malacarne, Beatrice D'Anna, Nicolò Formaggio, Suvham Barua, Tommaso Raiteri, Andrea Lauria, Simone Reano, Alessandra Murabito, Monica Nicolau, Fabiana Ferrero, Camilla Pezzini, Giulia Rossino, Francesco Favero, Michele Valmasoni, Nicoletta Filigheddu, Alessio Menga, Davide Corà, Emilio Hirsch, Salvatore Oliviero, Vittorio Sartorelli, Valentina Proserpio, Alessandra Ghigo, Marco Sandri, Paolo E Porporato, Daniela Talarico, Giuseppina Caretti, Andrea Graziani.

Skeletal muscle wasting is a defining feature of cancer cachexia, a multifactorial syndrome that drastically compromises patient quality of life and treatment outcomes. Mitochondrial dysfunction is a major contributor to skeletal muscle wasting in cancer cachexia, yet the upstream molecular drivers remain elusive. Here we show that cancer impairs the activity of cAMP-dependent protein kinase A (PKA) and of its transcriptional effector CREB1 in skeletal muscle, ultimately contributing to the downregulation of a core transcriptional network that supports mitochondrial integrity and function. The restoration of cAMP-PKA-CREB1 signalling through pharmacological inhibition of the cAMP-hydrolysing phosphodiesterase 4 (PDE4) rescues the expression of mitochondrial-related genes, improves mitochondrial function and mitigates skeletal muscle wasting in male mice. Altogether, our data identify tumour-induced suppression of the cAMP-PKA-CREB1 axis as a central mechanism contributing to mitochondrial dysfunction in skeletal muscle during cancer cachexia. Furthermore, these findings highlight PDE4, particularly the PDE4D isoform, as a potential therapeutic target to preserve muscle mitochondrial function and counteract muscle wasting in cancer cachexia.

DOI: https://doi.org/10.1038/s42255-025-01397-5
Biogerontology. 2025 Nov 11. 26(6): 202

miRNA changes with ageing and caloric restriction in male rat skeletal muscle: potential roles in muscle cell function.

Gulam Altab, Brian J Merry, Charles W Beckett, Priyanka Raina, Ana Soriano-Arroquia, Bruce Zhang, Aphrodite Vasilaki, Katarzyna Goljanek-Whysall, João Pedro de Magalhães.

  The mechanisms underlying skeletal muscle ageing, whilst poorly understood, are thought to involve dysregulated micro (mi)RNA expression. Using young and aged rat skeletal muscle tissue, we applied high-throughput RNA sequencing to comprehensively study alterations in miRNA expression occurring with age, as well as the impact of caloric restriction (CR) on these changes. Furthermore, the function of the proteins targeted by these age- and CR-associated miRNAs was ascertained. Numerous known and novel age-associated miRNAs were identified of which CR normalised > 35% to youthful levels. Our results suggest miRNAs upregulated with age to downregulate proteins involved in muscle tissue development and metabolism, as well as longevity pathways, such as AMPK and autophagy. Furthermore, our results suggest miRNAs downregulated with age to upregulate pro-inflammatory proteins, particularly those involved in innate immunity as well as the complement and coagulation cascades. Interestingly, CR was particularly effective at normalising miRNAs upregulated with age, rescuing their associated protein-coding genes but was less effective at rescuing anti-inflammatory miRNAs downregulated with age. Lastly, the effects of a specific miRNA, miR-96-5p, identified by our analysis to be upregulated with age, were studied in cultured C2C12 myoblasts. We demonstrated miR-96-5p to decrease cell viability and markers of mitochondrial biogenesis, myogenic differentiation and autophagy. Overall, our results provide novel information regarding how miRNA expression changes in skeletal muscle, as well as the potential functional consequences of these changes and how they are ameliorated by CR.

Keywords:  Ageing; Caloric restriction; Non-coding RNA; Sarcopenia; Transcriptomics; miRNA

DOI:  https://doi.org/10.1007/s10522-025-10336-6
J Basic Clin Physiol Pharmacol. 2025 Nov 17.

Thyroid hormone imbalance, malnutrition, and sarcopenia: a triad of muscle health challenges.

Annarita Nappi, Serena Sagliocchi, Annunziata Gaetana Cicatiello, Caterina Miro.

  Sarcopenia and malnutrition are increasingly recognized as major determinants of morbidity and functional decline in aging and chronically ill populations. Thyroid hormones (THs), particularly triiodothyronine (T3), play a critical role in regulating skeletal muscle homeostasis, influencing myogenesis, mitochondrial function, metabolic rate, and fibre-type specification. Alterations in thyroid function, both hypo- and hyperthyroidism, negatively impact muscle protein turnover, leading to impaired strength and muscle wasting. Notably, nutritional status modulates TH metabolism at multiple levels: malnutrition impairs deiodinase activity, alters TH transport, and reduces peripheral T3 availability, thereby contributing to the low T3 syndrome frequently observed in frail or undernourished individuals. Conversely, excessive T3 levels, as seen in hyperthyroid states or during inappropriate replacement therapy, exacerbate catabolism and accelerate muscle loss. This review synthesizes current evidence on the bidirectional interactions among thyroid dysfunction, nutritional deficiencies, and sarcopenia, proposing an integrative pathophysiological model. We discuss the clinical implications of TH replacement in sarcopenic and malnourished patients, highlighting the need for personalised, multimodal interventions that include hormonal, nutritional, and physical strategies to prevent or mitigate muscle deterioration in endocrine and geriatric contexts.

Keywords:  Thyroid hormones; malnutrition; muscle health; sarcopenia

DOI:  https://doi.org/10.1515/jbcpp-2025-0160
Cells. 2025 Nov 03. pii: 1724. [Epub ahead of print]14(21):

Dysferlin and the Regulation of Ca2+ Release in Skeletal Muscle.

Robert J Bloch, Joaquin Muriel, Valeriy Lukyanenko.

  Dysferlin is a large transmembrane protein that is mutated or absent in Limb Girdle Muscular Dystrophy Type R2 (LGMD R2). Although it may have several functions in healthy skeletal muscle, most research on dysferlin has addressed its roles in repair of the sarcolemma and in maintaining proper control of Ca2+ homeostasis at the triad junction, where it concentrates. Here, we review the literature on the role of dysferlin in both membrane repair and in Ca2+ homeostasis, with a focus on the latter. We propose that pathophysiology in LGMD R2 is in part the result of increased leak of Ca2+ at the triad junction, which in turn reduces the amplitude of Ca2+ transients and, by activating Ca2+-induced Ca2+ release, or CICR, at the triad junction, induces Ca2+ waves. We discuss the mechanisms that regulate Ca2+ leak and Ca2+ levels at the triad junction under physiological and pathophysiological conditions. Our results suggest that suppression of abnormal leak and CICR may be therapeutic for LGMD R2 and other diseases of muscle linked to dysregulation of Ca2+ homeostasis.

Keywords:  RyR; couplon; excitation-contraction coupling; membrane repair; sarcolemma

DOI:  https://doi.org/10.3390/cells14211724
Am J Physiol Cell Physiol. 2025 11 10.

Hemizygous mutation of Jmjd3 in muscle stem cells increases H3K27 methylation on Pax7 leading to impaired myogenesis.

James G Tidball, Lina Petrossian, Cynthia M McKee, Michelle Wehling-Henricks.

  Development of myogenic cells, called satellite cells, is determined by transcription factors that regulate their quiescence (e.g. Pax7), activation (e.g. MyoD) and terminal differentiation (e.g., myogenin). Demethylation of lysine 3 on histone 27 (H3K27) activates expression of Myod and Myog. In this investigation, we investigated the effects of a satellite-cell-targeted, hemizygous mutation of the H3K27 demethylase Jmjd3 in healthy muscle. Using sequencing of chromatin fragments precipitated from Jmjd3 mutant and control satellite cells using anti-H3K27me3, we found that the Pax7 promoter was the only chromatin that experienced significantly increased H3K27 methylation in mutant cells. However, RNA sequencing showed that 143 genes were down-regulated in mutant cells, including Myod, a direct target of Pax7, and at least 72 other genes that contained E-boxes targeted by MyoD. Gene ontology analysis showed enrichment of genes involved in myogenesis in the down-regulated genes. Reduced expression of Pax7, Myod, and Myog was confirmed by QPCR, western blots and immunohistochemistry. Mutant muscles also had smaller diameter fibers, fewer myonuclei and diminished myogenic cell fusion, indicating impaired growth and differentiation. These findings show that Jmjd3 affects demethylation of H3K27 at the Pax7 promoter and increased H3K27 methylation reduces expression of Pax7 and its target genes, disrupting muscle growth.

Keywords:  Skeletal muscle; muscle development; myogenesis

DOI:  https://doi.org/10.1152/ajpcell.00681.2025
Dev Med Child Neurol. 2025 Nov 12.

Microscopic and molecular aspects of skeletal muscle alterations in cerebral palsy.

DOI: https://doi.org/10.1111/dmcn.70086
J Cachexia Sarcopenia Muscle. 2025 Dec;16(6): e70116

An Isogenic Human Myoblast Cell Model for Cystinosis Myopathy Reveals Alteration of Key Myogenic Regulatory Proteins.

Louise Medaer, Roger Mora, Zhuoheng Zhou, Nefele Giarratana, Laura Yedigaryan, Rita La Rovere, Elena Levtchenko, Vincent Mouly, Els Verhoeyen, Sebastiaan Eeltink, Achim Treumann, Tim Vervliet, Maurilio Sampaolesi, Rik Gijsbers.

   BACKGROUND: Cystinosis is a rare multisystem, autosomal recessive disease caused by dysfunction or loss of cystinosin (CTNS), which results in lysosomal cystine accumulation, primarily affecting the kidneys. Advances in renal transplantation, cysteamine treatment and improved medical care have increased life expectancy, revealing additional systemic phenotypes like myopathy later in life. Muscle weakness is a major concern leading to life-threatening events in patients, and yet the aetiology of cystinosis myopathy remains to be elucidated.
METHODS: We generated human muscle cell-based models using CRISPR technology to explore the pathophysiology of cystinosis myopathy with the potential to develop new therapies. We used a 4-day differentiation protocol of myoblasts into myotubes to study the effect of CTNS loss in key regulators of myogenic differentiation using western blot analysis. Afterwards, we used lentiviral (LV)-mediated CTNSWT cDNA addition in CTNS-/- cells to corroborate the CTNS-specific effect. As a next step, we performed multiomic analysis (proteomics, transcriptomics and metabolomics) to gain in-depth knowledge of affected mechanisms.
RESULTS: The polyclonal, isogenic human CTNS knock-out (KO; CTNS-/-) myoblasts exhibited unaltered growth characteristics and accumulated cystine. Early-stage differentiation of myoblasts into myotubes showed a mild reduction in the fusion index of CTNS-/- myotubes. Upon examination of several key regulators of myogenic differentiation, we observed significantly decreased myosin heavy chain (MyHC) and ryanodine receptor (RyR) protein levels in CTNS-/- myotubes compared to WT cells. Complementation with CTNSWT cDNA addition in CTNS-/- cells rescued the fusion index, cystine and altered protein levels to WT. In addition, proteomic analysis showed no differences at myoblast level upon the loss of CTNS, but following myotube differentiation, CTNS deletion led to an increase of five protein groups mainly involved in oxidative stress pathways, and a decrease of 18 protein groups biologically connected in myofibril assembly and muscle cell differentiation processes. Importantly, LV-mediated CTNS addback reverted protein levels to WT levels. Moreover, metabolomics revealed a distinct clustering resulting from CTNS loss.
CONCLUSIONS: Muscle-specific complications are often overlooked in systemic cystinosis treatment. We show that defective CTNS function impairs effective cystine mobilization from lysosomes, thereby affecting the protein levels of myogenic regulators. A deeper understanding of the molecular mechanisms underlying cystinosis myopathy holds promise for the development of targeted, personalized therapies to improve the quality of life for patients living with cystinosis.

Keywords:  CTNS; cystinosis; gene therapy; multiomics; myopathy; viral vectors

DOI:  https://doi.org/10.1002/jcsm.70116
Am J Physiol Cell Physiol. 2025 Nov 12.

Pediatric CHOP Chemotherapy Acutely Disrupts Satellite‑Cell Dynamics and Blunts Muscle Mass in a Sex‑Specific Manner.

Jainil Daredia, Marc A Magaña, Carla Manuela Crispim Nascimento, Jaden M Wells, Nicholas T Thomas, Yuan Wen, Savannah Rauschendorfer, Cory M Dungan, Michael P Wiggs.

  Pediatric cancer survival now exceeds 85 percent owing, in part, advances and use of combination chemotherapy treatments such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone). Despite its efficacy, CHOP may cause off-target effects during critical pediatric development periods such as impairments of skeletal muscle. We evaluated the acute effects of a CHOP administered to C57Bl/6J mice from postnatal day 28 to 48. CHOP slowed body-weight gain and led to smaller gastrocnemius fiber cross-sectional area by approximately 25% in both sexes (n=11-12 males; n=8-9 females). RNA sequencing detected 214 differentially expressed genes in males and 217 in females relative to controls, yet only 29 transcripts overlapped. Males exhibited downregulation of myogenic regulators, indicating impaired progenitor maintenance, whereas females showed an upregulation of extracellular-matrix and translational machinery genes plus cell-cycle regulators. Using immunohistochemistry to assess satellite cell abundance, there were 60% fewer satellite cells in males and a 40% fewer in females, which supported our transcriptional findings. These results demonstrate that pediatric CHOP acutely disrupts muscle stem-cell dynamics via sex-specific molecular programs and identify satellite cells as a potential target for preserving muscle health in pediatric cancer survivors.

Keywords:  Cachexia; Pax7; myonuclear domain; sexual dimorphism; transcriptomics

DOI:  https://doi.org/10.1152/ajpcell.00758.2025
J Physiol Biochem. 2025 Nov 11.

Irisin ameliorates age-associated skeletal muscle atrophy in mice: potential involvement of iron overload and SIRT1/p53 pathway.

Yuxia Ma, Jiachuang Zheng, Yi Liu, Zhixia Zheng, Fengyun Yang, Mengyan Yu.

  Age-associated sarcopenia is characterized by progressive loss of skeletal muscle mass and function. Irisin, a myokine, has been shown to improve sarcopenia; however, the dosage-dependence of its effects and the underlying molecular mechanisms remain unclear. To investigate the effects of irisin on age-associated sarcopenia, 22-week-old mice were used. Recombinant irisin was administered via intraperitoneal injections at doses of 0.5, 1, and 2 mg/kg, three times per week, to evaluate potential dosage-dependent effects. Skeletal muscle function was assessed using hanging time, grip strength, and muscle mass measurements. Morphological changes in muscle tissue were examined through hematoxylin and eosin staining, and fibrosis was quantified using Masson staining. Serum irisin levels were measured via enzyme-linked immunosorbent assay, and protein expression was analyzed using Western blotting. Recombinant irisin treatment significantly increased serum irisin levels in aged mice and improved functional metrics, including hanging time, maximum speed, grip strength, and muscle mass, in a dosage-dependent manner. Histological analysis revealed improvements in muscle structure and a reduction in fibrosis following irisin treatment. Molecular analyses suggested that irisin may modulate iron homeostasis and restore key oxidative stress-related proteins such as GPX4 and SLC7A11. Further exploration revealed that irisin treatment restored sirtuin 1 (SIRT1) levels, leading to deacetylation of P53 and subsequent reduction in its expression. Irisin treatment ameliorates age-associated sarcopenia in a dosage-dependent manner, potentially involving iron overload and the SIRT1/P53 pathway. These findings provide insights into the therapeutic potential of irisin for age-related skeletal muscle atrophy.

Keywords:  Ferroptosis; Irisin; P53; SIRT1; Skeletal muscle atrophy

DOI:  https://doi.org/10.1007/s13105-025-01135-1
Cell Chem Biol. 2025 Nov 11. pii: S2451-9456(25)00344-7. [Epub ahead of print]

Lactylation of mTOR enhances autophagy in skeletal muscle during exercise.

Yan Li, Lamei Xue, Feijie Wang, Yu Wang, Yujie Sun, Zhoumin Niu, Shengnan Liu, Ying Yan, Siyi Shen, Kuiliang Zhang, Chenzhipeng Nie, Mingcong Fan, Mei Ma, Yuting Wu, Binrui Yang, Jun Du, Ben Zhou, Duo Zhang, Billy K C Chow, Li Zhang, Haifeng Qian, Liang Chen, Hao Ying, Li Wang.

  Emerging evidence suggests that autophagy is activated during exercise, mediating the benefits of exercise. However, the molecular mechanisms underlying the regulation of skeletal muscle autophagy during exercise are incompletely understood. Here, we show lactate severs as a positive regulator of autophagy in myocytes and its levels increase rapidly in response to a single bout of exercise. Mice with low lactate levels due to the lack of myocyte lactate dehydrogenase A exhibit significant abnormalities in skeletal muscle, including impaired autophagy. Our mechanistic study demonstrates that lactate enhances autophagy by inactivating mTOR complex 1 (mTORC1) through promoting mTOR lactylation at lysine 921 (K921) in myocytes. Accordingly, mutation of mTOR at K921 site causes sustained mTORC1 activation, leading to defects in skeletal muscle autophagy. Thus, our work uncovers a previously undescribed physiological action of lactate in the regulation of mTORC1-controlled skeletal muscle autophagy during acute exercise, which involves a lactylation-based post-translational modification mechanism.

Keywords:  autophagy; exercise; lactylation; mTOR; skeletal muscle

DOI:  https://doi.org/10.1016/j.chembiol.2025.10.007
Int J Mol Sci. 2025 Oct 24. pii: 10370. [Epub ahead of print]26(21):

Redox Homeostasis in Metabolic Syndrome and Type II Diabetes: Role of Skeletal Muscle and Impact of Gold-Standard Treatments.

Mia S Wilkinson, Thomas A Rollin, Michelle Kuriakose, Roan A L Haggerty-Goede, Dalia M Miller, Kimberly J Dunham-Snary.

  Metabolic syndrome and type II diabetes pose a significant international health burden, with the latter characterized by insulin resistance. Patients must rely on therapies that maintain glucose homeostasis when endogenous systems become dysfunctional. Skeletal muscle, as the largest insulin-sensitive tissue in the body, plays a critical role in maintaining glucose homeostasis. During disease progression, chronic nutrient overload shifts redox balance to a pro-oxidant state, further exacerbating metabolic dysfunction. First-line treatments, such as metformin and insulin, along with newly adopted incretin-based therapies, modulate the redox state of skeletal muscle. This review explores how the redox state of healthy skeletal muscle is altered throughout metabolic disease progression and how these changes contribute to a worsening phenotype. We also highlight how each class of regularly prescribed medications targets redox-sensitive systems in skeletal muscle, identifying literature gaps and areas for future investigation.

Keywords:  diabetes pharmacotherapy; metabolic disease; redox homeostasis; skeletal muscle; type II diabetes

DOI:  https://doi.org/10.3390/ijms262110370
J Gen Physiol. 2026 Jan 05. pii: e202513800. [Epub ahead of print]158(1):

Mn quenching in activated zebrafish muscle fibers does not result from store-operated Ca entry.

Francisco Jaque-Fernandez, Léa Demesmay, Romane Idoux, Christine Berthier, Vincent Jacquemond, Bruno Allard.

In mammalian skeletal muscle fibers, transmembrane Ca2+ influx is known to occur at rest and to increase in response to depolarization. In parallel to the well-identified dihydropyridine receptor (DHPR) pathway underlying this depolarization-induced Ca2+ influx, a tubular Ca2+ entry pathway activated by sarcoplasmic reticulum (SR) Ca2+ depletion, named store-operated Ca2+ entry (SOCE), has been identified. The use of the Mn2+ quenching technique has been instrumental for the characterization of these Ca2+ influxes. But, because both should be activated by depolarization, it is difficult to discriminate between these two Ca2+ entry pathways. In that context, the zebrafish muscle fiber is an ideal model to determine whether or not SOCE develops in response to depolarization, because the zebrafish DHPR is not conductive to any divalent cation. Using the technique of Mn2+ quenching of fura-2 fluorescence in voltage-clamped zebrafish fast muscle fibers, we show that depolarization pulses evoke slow transient Mn2+ quenching signals that persist after washout of external Mn2+. The Mn2+ quenching signal displays rate of recovery and voltage dependence correlated to the rate of recovery and voltage dependence of SR Ca2+ release, respectively. Our data suggest that the voltage-evoked Mn2+ quenching signal of zebrafish muscle fibers does not result from a Mn2+ influx provoked by depletion of SR Ca2+ content but from a displacement of Mn2+ accumulated on intracellular Ca2+ buffers by Ca2+ released from the SR. These findings should encourage to consider that increase in Mn2+ quenching can result from changes in intracellular Ca2+ and not from SOCE.

DOI: https://doi.org/10.1085/jgp.202513800
J Appl Physiol (1985). 2025 Nov 14.

Donepezil treatment, alone or combined with exercise, enhances skeletal muscle function in healthy and advanced aging disease mouse models.

Nicholas J Ernst, Edziu Franczak, Julie Allen, Everett C Minchew, Andrew T Readyoff, Miles C Farlow, Espen E Spangenburg, Benjamin F Miller, Jill K Morris, Kartik Shankar, Mihaela E Sardiu, Hao Zhu, John A Stanford, John P Thyfault, Colin S McCoin.

  Reduced muscle mass and function are hallmarks of aging, increased frailty, and reduced resilience. There are no clinically-approved interventions besides exercise to improve muscle quality and function in the elderly. We recently found that older participants with mild cognitive impairment (MCI) who took the acetylcholinesterase inhibitor donepezil, (DON) had greater skeletal muscle mitochondrial respiratory capacity than non-treated counterparts. Here we tested if DON treatment or DON+exercise on treadmill (EX) improved muscle and mitochondrial function in male and female mice that were young adult wild-type (WT) or with an early aging phenotype (CDGH iron sulfur domain 2 (Cisd2) knockout mice (Cisd2KO; n=10-12 total mice/strain) from 4 to 15 weeks of age. In WT mice, DON improved screen hanging time at the midpoint and increased grip strength at the endpoint of the 11-week study. Further, DON increased non-resting energy expenditure and improved palmitate-dependent mitochondrial respiration in gastrocnemius muscle in WT while interacting with exercise to alter state 3 respiration in Cisd2KO gastrocnemius. DON+EX resulted in greater WT quadriceps mass and reduced endpoint beam walk slipping while DON increased midpoint screen hang time and reduced endpoint beam slips in the Cisd2KO. Overall, this study provides preliminary evidence that cholinesterase inhibition partially benefits skeletal muscle strength and quality in young healthy mice, changes that are associated with improvements in mitochondrial respiration. However, cholinesterase inhibition had minimal effects in a model of advanced aging. Further research is needed to determine if cholinesterase inhibitors can combat age-related muscle decline.

Keywords:  aging; donepezil; exercise; mitochondrial function; skeletal muscle

DOI:  https://doi.org/10.1152/japplphysiol.00895.2024
Proteomics. 2025 Nov 11. e70073

Proteomic Profiling of Myofiber Repair Annexins and Their Role in Duchenne Muscular Dystrophy.

Paul Dowling, Dounia Bouragba, Elisa Negroni, Capucine Trollet, Margit Zweyer, Dieter Swandulla, Kay Ohlendieck.

  Myofiber regeneration and membrane repair play crucial roles in maintaining the continuous physiological functioning of the neuromuscular system. A swift and efficient repair mechanism enables the rapid restoration of sarcolemmal integrity following cellular impairment in damaged skeletal muscles. Members of the annexin family of proteins, which are characterized by the peripheral binding to acidic phospholipid membranes, are intrinsically involved in this myofiber repair process. The biochemical and proteomic profiling of dystrophinopathy, a severe and highly progressive neuromuscular disorder of early childhood, is outlined in this article with special focus on skeletal muscle-associated annexins and their role in membrane repair, myofiber regeneration and the cellular pathogenesis of Duchenne muscular dystrophy. Findings from comparative mass spectrometry-based surveys are described, and dystrophinopathy-related alterations in annexin expression patterns are discussed regarding the establishment of improved biomarker signatures of skeletal muscle wasting disorders. Mass spectrometry-based proteomic profiling is highly suitable for the systematic study of complex pathobiochemical alterations and inherent adaptations in dystrophinopathy. Disease-specific changes in annexins and related proteins of the membrane repair machinery can now be used to improve diagnosis, evaluation of disease severity, prognosis and therapeutic monitoring, and identify novel therapeutic targets to treat X-linked muscular dystrophy.

Keywords:  annexin; caveolin; dysferlin; dystrophin; myoferlin

DOI:  https://doi.org/10.1002/pmic.70073
Cells. 2025 Oct 22. pii: 1656. [Epub ahead of print]14(21):

Distinct Intramuscular Extracellular Matrix Protein Responses to Exercise Training in COPD and Healthy Adults and Their Association with Muscle Remodeling.

Davina C M Simoes, Efpraxia Kritikaki, Gerasimos Terzis, Ioannis Vogiatzis.

  Background: The skeletal muscle extracellular matrix (ECM) is critical for muscle force and the regulation of important physiological processes. A growing body of evidence demonstrates that in aging, altered ECM composition profoundly hinders the capacity for muscle adaptation in response to exercise training. We evaluated the pattern of ECM expression in response to exercise training between healthy young participants and patients with chronic obstructive pulmonary disease (COPD), to provide insight into how normal adaptive processes differ under conditions of chronic disease. Methods: Vastus lateralis muscle biopsies from 29 patients (mean ± SD FEV1: 43 ± 16% predicted) and 14 healthy subjects were analyzed before and after an interval exercise training program for myofiber distribution and size. A selection of ECM molecules was quantified using ELISA. Results: Compared to healthy participants, patients exhibited a lower capacity to increase myofiber type I distribution (by 4.7 ± 3.4 vs. 1.3 ± 2.2%) and mean fiber cross-sectional area (by 13.6 ± 3.2 vs. 9.1 ± 1.9%). Exercise training induced a diverse protein expression between the two cohorts in ECMs regulating tissue structure (collagens: up-regulated only in COPD), myogenesis (SPARC: up-regulated only in healthy), necroptosis (tenascin C: up-regulated only in COPD), adherence to muscle-cell precursors (Fibronectin: up-regulated only in healthy) and tissue integrity (biglycan: down-regulated only in COPD). Conclusions: Impaired ECM remodeling may underlie the reduced exercise training muscle adaptation observed in COPD patients.

Keywords:  COPD; ECM; SPARC; biglycan; collagen; exercise-training; fibronectin; healthy; pulmonary rehabilitation; skeletal muscle; tenascin C

DOI:  https://doi.org/10.3390/cells14211656
Sci Rep. 2025 Nov 14. 15(1): 39997

Circulating protein biomarkers identified in two independent clinical trial cohorts of glucocorticoid-naive Duchenne muscular dystrophy patients.

VBP15-004 investigators, CINRG DNHS investigators

  Blood-accessible biomarkers offer promising insights into the pathogenesis of Duchenne muscular dystrophy (DMD) and other muscle diseases. Here, we quantified the relative abundance of 7,289 serum proteins using SomaScan proteomics in pre-treatment samples from 51 boys with DMD (aged 4 to <7) and 13 healthy controls from the VISION DMD (VBP15-004) trial. An independent validation cohort of untreated DMD boys (aged 4 to <8) from the FOR-DMD trial was also analyzed. Of the proteins screened, 26% and 15% were significantly elevated and decreased, respectively, in the serum of young DMD boys compared to controls (adjusted p-value < 0.05). A high correlation (Spearman r = 0.85) in fold changes was observed between the two datasets. Many proteins with altered levels overlapped with known markers of muscle injury, inflammation, regeneration, and extracellular matrix remodeling. Selected biomarkers were queried in two published muscle mRNA and a muscle snRNAseq dataset in DMD biopsies. Novel factors involved in muscle regeneration and ECM remodeling were identified. This larger-scale, multi-clinical trial-based cohort study in untreated DMD boys substantially expands the catalog of circulating biomarkers, highlighting early-stage pathological processes. These findings can help identify new therapeutic targets and develop clinically actionable biomarkers to assess disease progression and response to therapies.

Keywords:  Biomarker discovery-validation; Duchenne muscular dystrophy; Proteomics, SomaScan; Serum-muscle omics integration

DOI:  https://doi.org/10.1038/s41598-025-23758-6
Exp Physiol. 2025 Nov 14.

Changes in motor unit conduction velocity after unilateral lower-limb suspension and active recovery are correlated with muscle ion channel gene expression.

Giacomo Valli, Fabio Sarto, Francesco Negro, Elena Monti, Giuseppe Sirago, Matteo Paganini, Sandra Zampieri, Martino V Franchi, Andrea Casolo, Julián Candia, Luigi Ferrucci, Marco V Narici, Giuseppe De Vito.

  The effects of muscle disuse on the propagation of action potentials along motor unit (MU) muscle fibres, a key process for effective muscle activation and force generation, remain poorly understood. The aim of this study was to investigate changes in action potential propagation and to identify biological factors influencing these changes following unilateral lower-limb suspension (ULLS) and active recovery (AR). Eleven young males underwent 10 days of ULLS followed by 21 days of AR involving resistance exercise. Maximal force of the knee extensors (MVC), high-density surface EMG recordings and muscle biopsies of the vastus lateralis muscle were collected before ULLS, after ULLS and after AR. EMG recordings collected during submaximal isometric contractions were decomposed to estimate single-MU conduction velocity (CV). Biopsies were used to measure muscle fibre diameters via histochemical analysis and ion channel transcriptomic profiles via mRNA sequencing. The MVC declined by 29% after ULLS and returned to baseline after AR. MU CV decreased after ULLS and recovered fully, even exceeding baseline values after AR. Muscle fibre diameters did not change across the interventions and showed no correlation with MU CV. Conversely, a feature importance analysis revealed that mRNA expression levels of specific ion channel genes, particularly those involved in K+ transport, were correlated with MU CV at baseline and across the interventions. This study highlights the crucial role of K+ ion channels in influencing MU CV in humans, offering new insights into MU CV modulation and the mechanisms of changes in muscle force after disuse and active recovery.

Keywords:  ion channel; mRNA sequencing; muscle fibre diameter; muscle unloading; neuromuscular impairment

DOI:  https://doi.org/10.1113/EP093065
Dev Med Child Neurol. 2025 Nov 09.

Microscopic and molecular aspects of skeletal muscle alterations in cerebral palsy.

Sebastian Edman, Oscar Horwath, Eva Pontén, Sudarshan Dayanidhi, Ferdinand von Walden.

Cerebral palsy (CP), the most prevalent childhood-onset motor disability, frequently entails progressive musculoskeletal complications. This comprehensive review synthesizes existing knowledge of microscopic and molecular alterations in CP skeletal muscle. Considerable methodological variability, heterogeneous patient cohorts, and inconsistent control groups significantly complicate comparative interpretations across studies. Nonetheless, some structural abnormalities consistently emerge, including increased variability in muscle fibre size, altered fibre type distribution, long sarcomeres at standardized joint positions, increased collagen content, disrupted neuromuscular junction integrity, reduced capillary density, and mitochondrial and satellite cell impairments. Investigations of satellite cell function in vitro further underscore potential mechanistic alterations, although findings remain inconsistent. Remarkably, few studies have systematically explored the cellular and molecular consequences of standard clinical interventions, revealing a notable research gap. In conclusion, the overall literature reveals considerable divergence in reported outcomes, reflecting the profound complexity of CP muscle biology. We believe that resolving this complexity will require more coordinated and collaborative research approaches.

DOI: https://doi.org/10.1111/dmcn.70044
Am J Pathol. 2025 Nov 06. pii: S0002-9440(25)00408-0. [Epub ahead of print]

PathViT: Automated disease classification from skeletal muscle histopathology.

Taymaz Akan, Sait Alp, Richa Aishwarya, Diensn G Xing, Destyn Dicharry, Md Shenuarin Bhuiyan, Mohammad A N Bhuiyan.

  Analyzing skeletal muscle pathology from histological images is a labor-intensive process prone to inter- and intra-user variability influencing diagnosis accuracy and consistency-conventional techniques, such as ImageJ-based tools, demand manual cell counting, segmentation, and thresholding. As a result, they are time-consuming and create different results. To address these difficulties, we developed PathViT, a transformer-based deep learning model for automated classification of pathological images. Skeletal muscle pathology is characterized by changes in myofiber cross-sectional area, increased central nuclei, and structural disruptions in sarcomeres. To investigate these changes in myofiber size, we utilized Wheat Germ Agglutinin (WGA) stained histopathological images of different skeletal muscles (quadriceps, gastrocnemius, tibialis anterior, extensor digitorum longus, and soleus) to classify amyotrophic lateral sclerosis (ALS), diabetes, and healthy controls. PathVit can automatically distinguish between healthy and diseased muscle fibers, reducing human intervention, minimizing subjectivity and variability, and significantly decreasing analysis time compared to traditional manual methods. We evaluated PathViT against state-of-the-art deep learning models using WGA-stained skeletal muscle images from wild-type and disease models (G93A*SOD1 for ALS and Akita for Type 1 diabetes). PathViT classified healthy and diseased muscle fibers with 96% accuracy, outperforming all other models. Compared to manual methods, PathVit reduces human intervention, subjectivity, variability, and analysis time. This approach enhances scalability, diagnostic accuracy, and variability, making PathViT a powerful biomedical research and clinical tool.

Keywords:  Deep learning; Skeletal Muscle; Transformers; WGA-stained; computational pathology

DOI:  https://doi.org/10.1016/j.ajpath.2025.10.009
Arch Gerontol Geriatr. 2025 Nov 07. pii: S0167-4943(25)00338-3. [Epub ahead of print] 106081

Reframing sarcopenia: the AWGS 2025 paradigm shift from disease to muscle health.

Liang-Kung Chen.



Keywords:  Healthy aging; Intrinsic capacity; Muscle health; Muscle-organ cross-talk; Sarcopenia

DOI:  https://doi.org/10.1016/j.archger.2025.106081
Cell Signal. 2025 Nov 07. pii: S0898-6568(25)00635-7. [Epub ahead of print] 112220

Akt-Axin1/TNKS-Tiam1-Rac1 mediates insulin-stimulated GLUT4 translocation in skeletal muscle cells.

Yingying Yue, Qiu Gu, Chang Zhang, Xiaoting Yu, Yajie Run, Yang Guo, Chunlei Zhou, Hong Mu, Wenyan Niu.

  It is known that insulin stimulates skeletal muscle glucose uptake via the InsR-IRS-PI3K pathway. The signaling downstream of PI3K is divided into the Akt-AS160-Rabs branch and the Rac1-actin cytoskeleton branches. These two signaling branches jointly mediate the effect of insulin to promote GLUT4 transporters to transport glucose into the cell. The scaffolding protein Axin1 plays a crucial role in maintaining glucose homeostasis and TNKS, a member of the PARP family, is involved in insulin-stimulated GLUT4 translocation. However, the specific roles of Axin1 and TNKS and their relationship are elusive in insulin-stimulated skeletal muscle cell glucose uptake. Here, we showed that insulin up-regulated the protein levels of Axin1 and TNKS in an Akt-dependent manner in C2C12 skeletal muscle cells. Knockdown of Axin1 inhibited insulin-stimulated GLUT4myc translocation in C2C12-GLUT4myc myotubes. Both over-expression Axin1 and TNKS activity inhibitor XAV939 enhanced insulin-stimulated GLUT4myc translocation. XAV939 up-regulated Axin1 and TNKS protein levels. Knockdown or over-expression of Axin1 down- or up-regulated the protein level of TNKS, respectively. Axin1 interacted with TNKS which was enhanced by insulin. Knockdown of Axin1 inhibited insulin-induced the phosphorylation of the Rac1 target protein PAK. Over-expression of Axin1 and XAV939 increased insulin-phosphorylated PAK. Up- and down-regulation of Axin1 and XAV939 had no effects on the phosphorylation of Akt and AS160. Insulin increased the Rac1-GEF Tiam1 protein levels. Knockdown of Tiam1 diminished insulin-stimulated PAK phosphorylation and GLUT4myc translocation. Knockdown of Axin1 inhibited insulin-induced Tiam1 expression, while over-expression of Axin1 and XAV939 had the opposite effect. In summary, our results suggest that an Akt-Axin1/TNKS-Tiam1-Rac1 signaling pathway mediates insulin-stimulated GLUT4 translocation in skeletal muscle cells.

Keywords:  Axin1; GLUT4; Insulin; Rac1; Skeletal muscle cells; TNKS

DOI:  https://doi.org/10.1016/j.cellsig.2025.112220
J Appl Physiol (1985). 2025 Nov 10.

Caffeine Decreases Mu scle and Tendon Protein Synthesis and Engineered Ligament Strength In Vitro and Attenuates Adaptation to Exercise in Mice.

Danielle Steffen, Kevin J M Paulussen, Ryman Crone, Benjamin Tucker, Suraj Pathak, Keith Baar.

  Caffeine is a well-known stimulant that is widely used to increase alertness and performance. However, there is little information on the effect of chronic caffeine consumption on exercise adaptations. We first sought to characterize the effect of caffeine on protein synthesis in vitro using immortalized C2C12 and TTD6 muscle and tendon cells. Total protein synthesis, as measured by puromycin incorporation, decreased 31% in TT-D6 cells with 4mM caffeine (p < 0.05) and 41% in C2C12 cells with 0.5 mM caffeine (p <0.01). The structure and function of in vitro engineered ligaments were also reduced with caffeine, including a 45% reduction in maximal tensile load (MTL) (p = 0.0128) and 30% reduction in collagen content (p = 0.0038) with 1 mM caffeine. To assess the effect of caffeine in vivo, sedentary and running mice were provided with a moderately high dose of caffeine (0.22 mg/mL, roughly equivalent to 5.7 mg/kg for a human) or water as a placebo control. Free access to a running wheel was effective in increasing gastrocnemius, soleus, and heart muscle mass relative to body weight, oxidative phosphorylation proteins, and Achilles tendon collagen concentration and Col1a1 gene expression. Mice that consumed caffeine while exercising did not gain skeletal muscle mass (gastrocnemius, soleus) to the same extent as the non-caffeinated exercising mice. Together, these data suggest that high caffeine consumption can dampen the molecular signals associated with protein synthesis and in excess may limit exercise-induced skeletal muscle adaptations.

Keywords:  caffeine; exercise; mice; muscle; tendon

DOI:  https://doi.org/10.1152/japplphysiol.00512.2025
Sci Rep. 2025 Nov 10. 15(1): 39359

Evaluating muscle aging during relaxed standing, squats and lunges through electrical bioimpedance.

Samaneh Zolfaghari, Abdelakram Hafid, Saad Abdullah, Annica Kristoffersson, Mia Folke.

  Electrical bioimpedance (EBI) is widely used for body composition analysis and shows promise for assessing muscle activation during physical activities (PAs), particularly in aging. This study investigated EBI's sensitivity to age-related changes in muscle function by analyzing data from 40 adult participants divided into young (20-29 years), middle-aged (32-60 years), and older (62-73 years) groups. EBI signals were recorded from the Quadriceps and Extensor Digitorum Longus (EDL) muscles during three PAs: relaxed standing position, squats, and lunges. Key features were extracted to identify age-related differences. Results revealed distinct muscle-specific patterns: In the relaxed standing position, the EDL muscle exhibited a consistent, monotonic decline in the PrePAmagnitude feature from young to old adults, while the Quadriceps muscle displayed greater variability and a non-monotonic trend. Among the dynamic activities, squats revealed the most pronounced age-related differences, with 62.5% of the features showing statistical significance, whereas fewer differences in the features (25%) where shown during lunges. The findings suggest that EBI can detect age-related reductions in muscle activation and neuromuscular coordination, supporting its potential as a non-invasive tool for functional muscle assessment in aging.

Keywords:  Electrical bioimpedance; Feature analysis; Muscle aging; Muscle function; Physical activities; Statistical analysis

DOI:  https://doi.org/10.1038/s41598-025-27187-3
J Cachexia Sarcopenia Muscle. 2025 Dec;16(6): e70109

Role of Peptides in Skeletal Muscle Wasting: A Scoping Review.

Petar Naumovski, Bart De Spiegeleer, Aster Wakjira, Christophe Van De Wiele, Vincent Mouly, Katarzyna Goljanek-Whysall, Kauê Santana da Costa, Ewerton Cristhian Lima de Oliveira, Evelien Wynendaele, Anton De Spiegeleer.

   BACKGROUND: Systemic muscle wasting is a prevalent condition that predicts adverse health outcomes in aging and disease. Despite its clinical relevance, the development of predictive biomarkers and effective pharmacological therapies remains limited. Peptides have recently gained attention for their diverse bioactive functions, positioning them as promising biomarkers and therapeutic agents for muscle wasting.
METHODS: This scoping review systematically identifies studies examining the direct association between well-defined peptides and clinical components of muscle wasting: muscle mass, strength and physical performance. The review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analysis for Scoping Reviews (PRISMA-ScR) guidelines. A comprehensive search of Embase, PubMed and Web of Science was conducted up to 31 October 2024, focusing on original human or animal studies. Studies involving congenital or inherited muscle disorders, inflammatory myopathies and neurodegenerative diseases, such as Parkinson's disease, were excluded. A snowball approach was used to synthesize the presumed cellular pathways of identified peptides.
RESULTS: A total of 126 studies were included: 71 (56.3%) focused on a single muscle wasting component (48 on mass, 16 on strength and 7 on performance), 31 (24.6%) examined two, 16 (12.7%) analysed all three separately, and 8 (6.3%) assessed sarcopenia as a categorical variable. Eighty-seven distinct peptides linked to muscle wasting were identified, ranging from collagen tripeptide (3 amino acids) to insulin (51 amino acids). The most studied peptides are ghrelin (14.3%), brain natriuretic peptide (BNP, 11.1%), C-peptide (11.1%), insulin (10.3%) and Szeto-Schiller 31 (SS-31, 6.3%). Most (62.1%) influence one or more of four key muscle homeostasis pathways (PI3K/Akt/mTOR, ActR/SMAD, IKK/NF-κB and AMPK/PGC1α), which regulate atrophy (via FOXO, NF-κB, SMAD2/3, glucocorticoid receptor and GSK-3β) and hypertrophy (via androgen receptors, PGC-1α and S6K). Flaws in study design and reporting were prevalent, hindering clinical translation. Sex bias was evident, with females comprising 23.9% of participants in human interventional studies and only 9.1% and 12.4% of mice and rats in rodent studies, respectively. Clinical, pre-analytical and analytical reporting gaps were common: 56.6% documented diurnal timing, food intake and activity around peptide collection; none specified storage-to-analysis duration; and only 11.5% reported detection limits for peptide measurements.
CONCLUSION: This scoping review highlights the potential of peptides as biomarkers and intervention targets for muscle wasting. It connects the cellular receptors and signaling pathways linking peptides with skeletal muscle wasting. Improving clinical translation requires addressing study design limitations, incorporating more representative study populations and adhering to standardized reporting guidelines. The application of machine learning can support the identification of novel bioactive peptides.

Keywords:  cachexia ; muscle wasting; peptides; sarcopenia

DOI:  https://doi.org/10.1002/jcsm.70109