bims-moremu 2025-12-28 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2025–12–28
nineteen papers selected by
Anna Vainshtein, Craft Science Inc.

The Cell Polarity Protein Scribble Is Involved in Maintaining the Structure of Neuromuscular Junctions, the Expression of Myosin Heavy Chain Genes, and Endocytic Recycling in Adult Skeletal Muscle Fibers.
Identification of myokines associated with the pathological stress response in the mdx mouse model of Duchenne muscular dystrophy.
β-Hydroxy-β-Methylbutyrate enhances fast-twitch muscle and mitochondrial function, histopathology, and mTORC1 signalling in the mdx dystrophic mouse.
Decoding muscle-resident Schwann cell dynamics during neuromuscular junction remodeling.
Exercise-Induced Biomarker Modulation in Sarcopenia: From Inflamm-Aging to Muscle Regeneration.
Mitochondrial proteostasis regulated by CRL5Ozz and Alix modulates skeletal muscle metabolism and fiber type.
Vitamin C is essential for proper myogenic differentiation.
An orally active estrogen receptor-related receptor agonist, SLU-PP-915, enhances aerobic exercise capacity.
Aging-Induced Dysfunction of Adipose Tissue and Skeletal Muscle and its link to Insulin Resistance.
Statins, skeletal muscle, and ryanodine receptor activation: resolving a 30-year mystery behind statin myotoxicity.
Angiogenesis-independent VEGF signaling enhances exercise capacity by increasing fat oxidation in mice fed sulfur amino acid-restricted diets.
Spatially Resolved Profiling of Compartmentalized Muscle and Brain Inflammation.
RUNX2 Activation in Fibro/Adipogenic Progenitors Promotes Muscle Fibrosis in Muscular Dystrophy.
3'UTR shortening alleviates miRNA repression of mRNAs critical for muscle stem cell differentiation.
Body mass shapes mitochondrial NADH and NADPH sources in mammalian skeletal muscle.
Transient muscle expression of mitoARCUS in mice leads to a sustained reduction in pathogenic mtDNA content and improves muscle function.
Padua Days on Muscle and Mobility Medicine, March 3-6, 2026: Call for oral presentations.
Single-cell sequencing reveals APOE deletion alleviates adipose wasting in cancer cachexia via macrophage repolarization.
Perspective Review: Advancing toward the diagnosis of sarcopenia in the pediatric population.

Cells. 2025 Dec 16. pii: 2005. [Epub ahead of print]14(24):

The Cell Polarity Protein Scribble Is Involved in Maintaining the Structure of Neuromuscular Junctions, the Expression of Myosin Heavy Chain Genes, and Endocytic Recycling in Adult Skeletal Muscle Fibers.

Lea Gessler, Yongzhi Jian, Nam Anh Ngo, Said Hashemolhosseini.

  The role of LAP proteins expressed in skeletal muscles (ERBIN, LANO, and SCRIBBLE) and at neuromuscular junctions (NMJs) remains largely unknown. Our previous data demonstrate that LAP proteins are differentially expressed in muscle cells, nerve endings, and terminal Schwann cells, though they are all expressed in myofibers and accumulate at NMJs. ERBIN and SCRIBBLE align with acetylcholine receptor clusters (CHRNs) at the NMJ. In vivo ablation of Erbin is associated with smaller CHRN and upregulation of Lano and Scribble. However, SCRIBBLE was also shown to influence the fate decision of muscle stem cells. Here, we investigated how the absence of SCRIBBLE in skeletal muscle cells might impair skeletal muscle fibers or NMJs. Although conditional Scribble knockout mice did not exhibit changes in weight or viability, force per weight decreased slightly. This was supported by compromised neuromuscular transmission and increased NMJ fragmentation. Moreover, Scribble knockout muscles transcribe less myosin heavy chain genes. Here, we also showed that RAB5, an effector of endocytic recycling, interacts with all LAP proteins, but in Scribble knockout muscles, reduced interaction was detected with ERBIN and LANO. These data suggest that a delicate signaling network employing LAP proteins is necessary for skeletal muscle fibers and NMJs.

Keywords:  Erbin; LAP; Lano; Scrib; Scribble; neuromuscular junction; skeletal muscle

DOI:  https://doi.org/10.3390/cells14242005
J Neuromuscul Dis. 2025 Dec 23. 22143602251409302

Identification of myokines associated with the pathological stress response in the mdx mouse model of Duchenne muscular dystrophy.

Erynn E Johnson, Jacob Powers, James M Ervasti.

   PURPOSE: Skeletal muscle constitutes 30-40% of total body mass and is now considered an endocrine organ, given its secretion of a variety proteins, metabolites, and cytokines. We have previously shown that the absence of dystrophin in skeletal muscle contributes to lethal systemic stress pathology in the mdx mouse model of Duchenne muscular dystrophy through a mechanism that remains to be identified. Here we searched for secreted protein signaling factors, or myokines, released from dystrophin-deficient skeletal muscle that influence the organism-wide integrated stress response. We performed skeletal muscle extracellular fluid extraction and discovery proteomics for wild-type, mdx, and transgenic mdx mice rescued by expression of a dystrophin construct, all analyzed under basal conditions and following brief scruff restraint stress that causes inactivity in mdx mice.
MAJOR FINDINGS: Our analysis demonstrated that skeletal muscle dystrophinopathy is associated with increased expression of numerous proteins in both intact mdx skeletal muscle and extracellular fluid compared to healthy mice. Brief scruff restraint revealed protein candidates with differential abundance in mdx extracellular fluid. Specifically, altered follistatin-like 1 protein and adiponectin secretion in response to scruff stress was shown to be dependent on skeletal muscle dystrophinopathy. The diverse signaling roles of follistatin-like 1 in the cardiovascular, musculoskeletal, and nervous system implicate it as a particularly intriguing myokine candidate regulating the mdx stress response.
CONCLUSIONS: Our current study informs on the skeletal muscle secretory profile in mdx following a stressful stimulus and provides new leads to elucidate the mechanism by which mdx skeletal muscle orchestrates inter-organ stress signaling.

Keywords:  duchenne muscular dystrophy; myokine; proteomics; skeletal muscle; stress physiology

DOI:  https://doi.org/10.1177/22143602251409302
Am J Physiol Cell Physiol. 2025 Dec 24.

β-Hydroxy-β-Methylbutyrate enhances fast-twitch muscle and mitochondrial function, histopathology, and mTORC1 signalling in the mdx dystrophic mouse.

Nicholas Giourmas, Hannah Lalunio, Chuhui Wu, Ryan Marko Bagaric, Memphis Calzoni, Craig A Goodman, Alan Hayes.

  Duchenne muscular dystrophy (DMD) is one of the most severe forms of inheritable muscular dystrophies, caused by a genetic mutation resulting in the loss of dystrophin. Dystrophin loss initiates a cascade of negative mechanistic changes in skeletal muscle, such as disrupted protein homeostasis and mitochondrial dysfunction. Recent evidence suggests the leucine metabolite, β-Hydroxy-β-methylbutyrate (HMB), may improve physical function in DMD boys and improve aspects of the dystrophic phenotype in preclinical mdx mice. HMB has been shown to modulate protein turnover and mitochondrial function, both of which are dysregulated in DMD. Therefore, this study examined the effect of 3-weeks of HMB supplementation (0.75mg/g/day via drinking water), starting at 3-weeks of age in mdx mice. HMB-treated mdx mice exhibited increased full body grip strength and holding impulse, compared to mdx controls. HMB treatment also increased normalised muscle mass of the fast-twitch extensor digitorum longus (EDL) muscle, which coincided with increased average fiber size and improved absolute/specific in vitro force production. Moreover, HMB-treated EDL muscles displayed increased mitochondrial complex II succinate dehydrogenase activity, alongside upregulated markers of mTORC1 signalling (p70S6K1 and 4EBP1 phosphorylation), suggestive of increased protein synthesis. Lastly, muscle fibers isolated from HMB-treated mdx mice showed improved mitochondrial efficiency that was associated with increased maximal respiration, spare respiratory capacity and ATP synthesis. This study is the first to show HMB-induced improvements on in vitro and in vivo measures of mdx skeletal muscle force production that are coupled with improved mitochondrial function, suggesting that HMB may be a viable treatment option for DMD.

Keywords:  Duchenne Muscular Dystrophy (DMD); Extensor Digitorum Longus (EDL); Histopathology; Mitochondria; β-Hydroxy-β-Methylbutyrate (HMB)

DOI:  https://doi.org/10.1152/ajpcell.00722.2025
JCI Insight. 2025 Dec 23. pii: e195917. [Epub ahead of print]

Decoding muscle-resident Schwann cell dynamics during neuromuscular junction remodeling.

Steve D Guzman, Ahmad Abu-Mahfouz, Carol S Davis, Lloyd P Ruiz, Peter Cd Macpherson, Susan V Brooks.

  This investigation leverages single-cell RNA sequencing (scRNA-Seq) to delineate the contributions of muscle-resident Schwann cells to neuromuscular junction (NMJ) remodeling by comparing a model of stable innervation with models of reinnervation following partial or complete denervation. The study discovered multiple distinct Schwann cell subtypes, including a novel terminal Schwann cell (tSC) subtype integral to the denervation-reinnervation cycle, identified by a transcriptomic signature indicative of cell migration and polarization. The data also characterizes three myelin Schwann cell subtypes, which are distinguished based on enrichment of genes associated with myelin production, mesenchymal differentiation or collagen synthesis. Importantly, SPP1 signaling emerges as a pivotal regulator of NMJ dynamics, promoting Schwann cell proliferation and muscle reinnervation across nerve injury models. These findings advance our understanding of NMJ maintenance and regeneration and underscore the therapeutic potential of targeting specific molecular pathways to treat neuromuscular and neurodegenerative disorders.

Keywords:  Cell biology; Muscle biology; Skeletal muscle; Synapses; Transcriptomics

DOI:  https://doi.org/10.1172/jci.insight.195917
Sports (Basel). 2025 Dec 09. pii: 444. [Epub ahead of print]13(12):

Exercise-Induced Biomarker Modulation in Sarcopenia: From Inflamm-Aging to Muscle Regeneration.

Federica Marmondi, Vittoria Ferrando, Luca Filipas, Roberto Codella, Piero Ruggeri, Antonio La Torre, Emanuela Luisa Faelli, Matteo Bonato.

  Sarcopenia is a progressive, age-related loss of skeletal muscle mass, strength, and function, strongly associated with frailty, disability, and chronic disease. Its pathogenesis involves chronic low-grade inflammation, hormonal imbalance, and impaired anabolic signaling, making biomarkers essential for diagnosis, prognosis, and intervention monitoring. This review systematically analyzes randomized controlled trials (RCTs) evaluating the impact of physical exercise on biomarkers relevant to sarcopenia. Exercise modulates both pro-inflammatory markers (e.g., IL-6, TNF-α, CRP) and anti-inflammatory cytokines (e.g., IL-10, IL-15), while also affecting growth factors like IGF-1, myostatin, and follistatin. These changes support muscle anabolism, reduce catabolic signaling, and improve physical performance. In addition, we highlight a growing class of emerging exerkines, including irisin, apelin, beta-aminoisobutyric acid (BAIBA), decorin, brain-derived neurotrophic factor (BDNF), and meteorin-like factor (Metrnl). These molecules exhibit promising roles in mitochondrial health, lipid metabolism, muscle regeneration, and immune modulation, key processes in combating inflamm-aging and sarcopenic decline. Despite encouraging findings, biomarker responses remain heterogeneous across studies, limiting translational application. The integration of biomarker profiling with exercise prescription holds the potential to personalize interventions and guide precision medicine approaches in sarcopenia management. Future large-scale, standardized trials are needed to validate these biomarkers and optimize exercise protocols for aging populations.

Keywords:  exerkines; inflamm-aging; muscle wasting

DOI:  https://doi.org/10.3390/sports13120444
Commun Biol. 2025 Dec 22.

Mitochondrial proteostasis regulated by CRL5Ozz and Alix modulates skeletal muscle metabolism and fiber type.

Yvan Campos, Gustavo Palacios, Elida Gomero, Diantha van de Vlekkert, Krishnan Venkataraman, Jaison John, Jason Andrew Weesner, Randall Wakefield, Xiaohui Qiu, Ricardo Rodriguez-Enriquez, Stephanie Rockfield, Jeroen Demmers, Joseph T Opferman, Cam Robinson, Khaled Khairy, Tulio Bertorini, Gerard C Grosveld, Alessandra d'Azzo.

High-energy-demanding tissues, such as skeletal muscle, rely on mitochondrial proteostasis for proper function. Two key quality-control mechanisms -the ubiquitin proteasome system (UPS) and the release of mitochondria-derived vesicles- help maintain mitochondrial proteostasis, but whether these processes interact remains unclear. Here, we show that CRL5Ozz and its substrate, Alix, localize to mitochondria and together regulate the levels and distribution of the mitochondrial solute carrier Slc25A4, which is essential for ATP production. In Ozz-/- or Alix-/- mice, skeletal muscle mitochondria exhibit similar morphological abnormalities, including swelling and dysmorphism, along with partially overlapping metabolomic alterations. We demonstrate that CRL5Ozz ubiquitinates Slc25A4, targeting it for proteasomal degradation, while Alix facilitates Slc25A4 loading into exosomes for lysosomal degradation. Loss of Ozz or Alix in vivo disrupts the steady-state levels of Slc25A4, impairing mitochondrial metabolism and triggering a switch in muscle fiber composition from oxidative, mitochondria-rich slow to glycolytic fast fibers.

DOI: https://doi.org/10.1038/s42003-025-09363-3
Arch Biochem Biophys. 2025 Dec 18. pii: S0003-9861(25)00418-7. [Epub ahead of print]776 110704

Vitamin C is essential for proper myogenic differentiation.

Yoshitaka Kondo, Ayami Sato, Noritsugu Osakabe, Tatsuki Minowa, Yung-Li Hung, Shuichi Machida, Akihito Ishigami.

   BACKGROUND: Vitamin C (VC) is naturally present in the blood and skeletal muscles. However, conventional myoblast culture media typically lack VC. Because VC exists in skeletal muscle, VC-supplemented media should better represent physiological conditions than VC-deficient media. Therefore, we used a VC-supplemented culture medium to examine the effects of VC deficiency on myogenic differentiation.
METHODS: Mouse C2C12 myoblasts were cultured in VC-supplemented or VC-free differentiation medium (DM), with the medium replaced every 24 h to preserve the efficacy of VC.
RESULTS: First, we confirmed that VC was reliably taken up by the C2C12 cells. We assessed the expression of muscle regulatory factors during myogenic differentiation. The expression levels of late-stage differentiation markers, including myogenin (MyoG), myomaker (Mymk), myosin heavy chain 1 (Myh1), and Myh4 were elevated in VC-free DM during the early stages of myogenic differentiation. In contrast, the expression levels of terminal myogenic markers in mature myofibrils, such as troponin I slow skeletal muscle (Tnni1) and troponin I fast skeletal muscle (Tnni2), increased in cells differentiated in VC-free DM but were lower than those in cells differentiated in VC-supplemented DM. The diameters of the differentiated myotubes were smaller in VC-free DM than in VC-supplemented DM. The levels of 5-hydroxymethylcytosine (5-hmC), a product of the VC-dependent DNA demethylation enzyme ten-eleven translocation (Tet), were markedly lower in VC-free DM.
CONCLUSION: These results suggest that VC modulates myogenic differentiation.

Keywords:  Ascorbic acid; C2C12 cells; DNA demethylation; Muscle regulatory factors; Myoblast; Myosin heavy chain; Skeletal muscle; Vitamin C

DOI:  https://doi.org/10.1016/j.abb.2025.110704
J Pharmacol Exp Ther. 2025 Dec 01. pii: S0022-3565(25)40300-0. [Epub ahead of print]393(1): 103787

An orally active estrogen receptor-related receptor agonist, SLU-PP-915, enhances aerobic exercise capacity.

Cyrielle Billon, Kevin Appourchaux, Isabelle Côté, Thomas P Burris.

  Estrogen receptor-related receptors (ERRα, ERRβ, and ERRγ) are orphan nuclear receptors that regulate genes involved in mitochondrial biogenesis, oxidative phosphorylation, fatty acid oxidation, and the Krebs cycle. ERRs are essential for skeletal muscle adaptation to aerobic exercise and represent promising targets for exercise mimetic therapeutics. We previously developed an ERR pan-agonist, SLU-PP-332 (332), which improves aerobic performance in mice but lacks oral bioavailability. Here, we characterize SLU-PP-915 (915), a chemically distinct ERR pan-agonist that is orally bioavailable and exhibits potent in vivo exercise mimetic activity. Compound 915 enhances aerobic exercise performance (distance and duration) to a similar extent as 332 when administered intraperitoneally and maintains comparable efficacy when administered orally, adjusted for systemic exposure. Both compounds robustly induce the expression of DNA damage-inducible transcript 4 (Ddit4), a gene induced by acute aerobic exercise, with levels matching or exceeding levels induced by treadmill running, depending on the muscle examined. Notably, 915 synergizes with exercise training to further enhance Ddit4 and mitochondrial gene expression. These findings position orally active ERR agonists such as 915 as promising agents for the treatment of metabolic disorders (eg, obesity, type 2 diabetes, and metabolic disease-associated steatohepatitis), cardiovascular disease (heart failure), and muscle-related pathologies, including sarcopenia and muscular dystrophies. SLU-PP-915 offers a valuable chemical tool for exploring the chronic therapeutic potential of ERR activation. SIGNIFICANCE STATEMENT: The nuclear receptor estrogen receptor-related receptor plays an important role in driving the physiological adaptations to exercise. The article describes the ability of a pan-estrogen receptor-related receptor agonist SLU-PP-915, which also displays oral bioavailability, to enhance exercise capacity.

Keywords:  Aerobic exercise; Energetics; Exercise; Exercise mimetic; Nuclear receptor; Skeletal muscle

DOI:  https://doi.org/10.1016/j.jpet.2025.103787
J Biochem. 2025 Dec 24. pii: mvaf081. [Epub ahead of print]

Aging-Induced Dysfunction of Adipose Tissue and Skeletal Muscle and its link to Insulin Resistance.

Masaji Sakaguchi.

  The extension of the human lifespan has increased the incidence of age-related metabolic disorders, such as type 2 diabetes and sarcopenia, which markedly impair quality of life and reduce life expectancy in older adults. Aging and insulin resistance synergistically compromise the functional integrity of the adipose and skeletal muscles. During aging, the adipose tissue exhibits impaired progenitor differentiation, chronic inflammation, fibrotic remodeling, and loss of thermogenic capacity. Skeletal muscles also exhibit changes, including satellite cell decline, mitochondrial dysfunction, defective protein turnover, and progressive sarcopenia. These changes diminish tissue plasticity and endocrine function and exacerbate insulin resistance through disrupted intracellular signaling and accumulation of metabolic burden. Notably, the deterioration of adipose and muscle tissue functions is interconnected, further exacerbating systemic metabolic dysfunction. Recent studies have contributed to elucidating the physiopathological causes and mechanisms of age-dependent cellular and molecular alterations in adipose and muscle tissues. This review summarizes the current insights into the cellular and molecular mechanisms underlying age-related alterations in adipose and muscle tissues and discusses emerging therapeutic strategies, including lifestyle interventions, pharmacological agents, approaches targeting senescent cells, and inter-organ communication that aim to preserve metabolic health in aging populations.

Keywords:  aging; diabetes; insulin resistance; obesity; sarcopenia

DOI:  https://doi.org/10.1093/jb/mvaf081
Cardiovasc Diabetol Endocrinol Rep. 2025 Dec 23. 11(1): 51

Statins, skeletal muscle, and ryanodine receptor activation: resolving a 30-year mystery behind statin myotoxicity.

Gaetano Santulli.



Keywords:  Atorvastatin; Cryo-EM; Muscle toxicity; RyR1 activation; Ryanodine receptor; Statin intolerance; Statins; Structural biology

DOI:  https://doi.org/10.1186/s40842-025-00267-z
iScience. 2025 Dec 19. 28(12): 114148

Angiogenesis-independent VEGF signaling enhances exercise capacity by increasing fat oxidation in mice fed sulfur amino acid-restricted diets.

Charlotte G Mann, Michael R MacArthur, Jing Zhang, Songlin Gong, Jenna E AbuSalim, Craig J Hunter, Wenyun Lu, Thomas Agius, Alban Longchamp, Florent Allagnat, Joshua D Rabinowitz, James R Mitchell, Katrien De Bock, Sarah J Mitchell.

  Dietary restriction of the sulfur-containing amino acids methionine and cysteine (SAAR) has numerous metabolic benefits including enhanced body composition and insulin sensitivity. Many of these benefits parallel those associated with endurance exercise. How SAAR impacts skeletal muscle remains largely unexplored. Here, we demonstrate that one week of SAAR in sedentary young male mice increases endurance exercise capacity. SAAR increased lipid oxidation at rest, delaying the onset of carbohydrate utilization during exercise. SAAR increased expression of fatty acid catabolism genes, especially in glycolytic muscle, leading to increased fatty acid circulatory turnover flux and muscle β-oxidation. Reducing lipid uptake from circulation through endothelial-cell-specific CD36 deletion attenuated the running phenotype. Inhibition of VEGF signaling prevented improved exercise performance following SAAR, independent of angiogenesis. These results support a role for angiogenesis-independent VEGF signaling and endothelial cell CD36-dependent fatty acid transport in the regulation of endurance exercise capacity by mediating muscle substrate availability.

Keywords:  diet; metabolic flux analysis; metabolomics

DOI:  https://doi.org/10.1016/j.isci.2025.114148
Eur J Immunol. 2025 Dec;55(12): e70119

Spatially Resolved Profiling of Compartmentalized Muscle and Brain Inflammation.

Thorge Dobbertin, Lucas Schirmer.

  Spatial omics technologies enable high-resolution mapping of transcriptomic, proteomic, and metabolic profiles within intact tissues, revealing how immune, stromal, and parenchymal cells interact in situ during inflammation. Chronic inflammation in skeletal muscle and the central nervous system is spatially organized within defined niches that shape disease progression and therapeutic response. In skeletal muscle, spatial analyses have uncovered fiber-type-specific vulnerability, regenerative trajectories, and immune-stromal crosstalk in disorders such as Duchenne muscular dystrophy and inclusion body myositis. In the central nervous system, these approaches have revealed compartmentalized neuroinflammation in multiple sclerosis, innate immune activation in amyotrophic lateral sclerosis, and immune evasion in glioma. Integration with single-cell gene expression enables inference of cell-cell communication networks and identification of spatial gradients of immune activation and tissue remodeling. Despite major advances, clinical translation remains limited by small cohorts, methodological variability, and insufficient functional validation. As spatial profiling becomes more accessible, standardized, and scalable, it promises to stratify inflammatory disease states, identify tissue-resident immune programs, and guide mechanism-based therapies. Hence, spatial omics provide an unprecedented opportunity to resolve the cellular architecture of inflammation, revealing not only where immune activity occurs, but how it is orchestrated within complex tissue microenvironments.

Keywords:  immunopathology; inflammation; neuroimmunology; proteomics; transcriptomics

DOI:  https://doi.org/10.1002/eji.70119
Adv Sci (Weinh). 2025 Dec 22. e10850

RUNX2 Activation in Fibro/Adipogenic Progenitors Promotes Muscle Fibrosis in Muscular Dystrophy.

Pengkai Wu, Zehua Zhang, Kai Zheng, Ziqi Zhu, Yong Zhu, Abdukahar Kiram, Lei Zhao, Huihui Chen, Zhu Xu, Xihua Li, Beicheng Sun, Zhijian Li, Dengqiu Xu.

  Clinical evidence indicates concurrent muscle inflammation and fibrosis in muscular dystrophies (MDs); however, the molecular mechanisms underlying inflammation-mediated fibrosis in skeletal muscle remain inadequately understood. This study revealed a molecular link between macrophages and fibro-adipogenic progenitors (FAPs) in both human subjects and mice via the transforming growth factor-beta (TGF-β)-RUNX family transcription factor-2 (RUNX2) axis. RUNX2 mRNA levels correlated positively with both the expression of fibrotic genes and the fibrosis area of MD patients. We demonstrated that specific ablation of RUNX2 in FAPs alleviated muscle fibrosis in an animal model of MD. Mechanistically, injured myofibers activated the transcription of chemokine genes, enhancing macrophage recruitment and the release of TGF-β, which subsequently triggered RUNX2-mediated transcription of fibrogenic genes in FAPs, promoting muscle fibrosis. Additionally, we demonstrated that CADD522, a RUNX2 inhibitor, protects against muscle fibrosis in both dystrophic and denervated mice. Importantly, the anti-inflammatory drug prednisolone alleviated muscle fibrosis in MD patients by inhibiting inflammatory cytokine-mediated RUNX2 activation. Collectively, our findings indicated that the TGF-β-RUNX2 axis is a viable target for alleviating muscle fibrosis and related diseases, highlighting potential future research directions.

Keywords:  FAPs; RUNX2; fibrosis; macrophages; muscular dystrophy

DOI:  https://doi.org/10.1002/advs.202510850
EMBO J. 2025 Dec 22.

3'UTR shortening alleviates miRNA repression of mRNAs critical for muscle stem cell differentiation.

Yi Zhu, Jianshu Wang, Deng Tong, Peixuan Jia, Suli Chen, Yangyang Li, Jiaying Fu, Qiming Li, Ping Hu, Yu Zhou, Hong Cheng.

  Alternative polyadenylation (APA) modulates gene expression by altering 3' untranslated region (3'UTR) length. Although 3'UTR lengthening typically accompanies cell differentiation, we unexpectedly observed preferential APA-mediated 3'UTR shortening events during muscle stem cell (satellite cell, SC) differentiation, coinciding with increased muscle-specific miRNAs (myomiRs) targeting at alternative 3'UTRs. Mechanistically, this shortening primarily results from reduced cleavage factor I (CFI) expression and allows transcripts to escape repression by differentiation-induced myomiRs. Interestingly, perturbation of mRNA 3'UTR shortening of multiple genes impairs myogenic differentiation. Focusing on Matr3-a gene linked to muscle disorders-we demonstrate that its APA-miRNA regulatory balance is critical for efficient SC differentiation in vitro. Genetically mutating Matr3 proximal polyadenylation site (pA site) impaired mouse muscle regeneration in vivo. Together, our findings reveal that APA-mediated 3'UTR shortening counteracts miRNA repression to orchestrate the gene expression program essential for robust muscle regeneration.

Keywords:   Matr3 ; Alternative Polyadenylation; Muscle Regeneration; Myogenic Differentiation; miRNA

DOI:  https://doi.org/10.1038/s44318-025-00663-2
Comp Biochem Physiol A Mol Integr Physiol. 2026 Jan;pii: S1095-6433(25)00143-6. [Epub ahead of print]311 111944

Body mass shapes mitochondrial NADH and NADPH sources in mammalian skeletal muscle.

Mélanie Boël, Yann Voituron, Damien Roussel.

  Here, we investigate whether the elevated mitochondrial H2O2 release in small mammals arises from a tradeoff between NAD-dependent enzymes, which synthesizes NADH to support high oxidative phosphorylation, and NADP-dependent enzymes, which generates NADPH to detoxify H2O2 within the matrix. We measured the activities of NAD- and NADP-dependent enzymes in skeletal muscle mitochondria from mammal species ranging from 4 g to 600 kg. The activities of the two most active NADPH-producing enzymes increased, whereas NAD-dependent enzyme activities declined with body mass. Therefore, small mammals prioritize NADH synthesis at the expense of NADPH, increasing the oxidative cost of mitochondrial metabolism.

Keywords:  Allometry; Mammals; Mitochondria; NADPH; Skeletal muscle

DOI:  https://doi.org/10.1016/j.cbpa.2025.111944
Mol Ther. 2025 Dec 24. pii: S1525-0016(25)01064-0. [Epub ahead of print]

Transient muscle expression of mitoARCUS in mice leads to a sustained reduction in pathogenic mtDNA content and improves muscle function.

Sandra R Bacman, Wendy Shoop, C Spencer Henley-Beasley, Rhese Thompson, Jose Domingo Barrera-Paez, Lise-Michelle Theard, Monica Rodriguez-Silva, Cassandra Gorsuch, Elisabeth R Barton, Carlos T Moraes.

Mitochondrial myopathies are often caused by heteroplasmic mutations in the mitochondrial DNA (mtDNA). In muscle, biochemical, pathological, and clinical impairments are observed only when the ratios of mutant/wild-type mtDNA are high. Because reductions in mutant mtDNA loads are essentially permanent, we reasoned that transient expression of a therapeutic mitochondrial nuclease could be sufficient to permanently alter heteroplasmy. We expressed a mitochondrial targeted gene editing nuclease (mitoARCUS) via intramuscular injection of lipid nanoparticle (LNP)/mRNA complexes in a mouse model of mtDNA disease (m.5024C>T in the mt-tRNAAla gene). Transient expression of mitoARCUS in the tibialis anterior (TA) led to a robust decrease in mtDNA mutation load which was maintained up to forty-two weeks after injection. A molecular marker of the mitochondrial defect in this model, namely low levels of mt-tRNAAla, were markedly improved in treated muscles. Muscle force assessment in situ after repeated stimulation showed that fatigability was improved in the treated TA. Finally, we showed that multi-muscle injections can alter mtDNA heteroplasmy essentially in whole limbs. These results demonstrate that transient expression of mitoARCUS via LNP/mRNA intramuscular injections have long-lasting positive effects in muscles afflicted with mitochondrial myopathy.

DOI: https://doi.org/10.1016/j.ymthe.2025.12.041
Eur J Transl Myol. 2025 Dec 19. 35(4):

Padua Days on Muscle and Mobility Medicine, March 3-6, 2026: Call for oral presentations.

Ugo Carraro.

  The Padova Muscle Days (PMD), an international congress on skeletal muscle, was founded in 1985 to provide consultancy on Translational Myology. Its goal has always been to translate the results of basic research into clinical trials. Indeed, function and mass of skeletal striated muscle are influenced by and affect central and peripheral neural pathologies, cardiac, pulmonary, hepatic, metabolic, and endocrine disorders, as well as lifestyle, aging, not to mention cancer. Over the years, PMD has led to innovative multidisciplinary results, so much so that it became natural to emphasize this with a neologism now included in the title of the congress series: "Padua Days on Muscle and Mobility Medicine (Pd3m)". Mobility Medicine is used to bring together knowledge currently dispersed across too many subspecialties. Medium-sized scientific conferences, held in hotels large enough to accommodate all participants, increase opportunities for constructive discussions during breaks and evenings, bringing together young and senior experts in basic sciences and clinical specialties. Extra-sessional discussions offer young scientists good opportunities for new collaborations and job offers. Since its inception, the PMD has offered these opportunities, leading to innovative multidisciplinary results published in high-level scientific journals. We hope that many more speakers will share our dreams and make them come true during the next conference in March 2026.

Keywords:  2026 Padua Days on Muscle and Mobility Medicine; Call for speakers; European Journal of Translational Myology

DOI:  https://doi.org/10.4081/ejtm.2025.14667
Clin Immunol. 2025 Dec 24. pii: S1521-6616(25)00235-9. [Epub ahead of print] 110660

Single-cell sequencing reveals APOE deletion alleviates adipose wasting in cancer cachexia via macrophage repolarization.

Jun Han, Qifeng Yao, Qiuyue Huang, Zuoyou Ding, Guohao Wu.

  Cancer cachexia involves severe skeletal muscle and adipose tissue loss. The role of Apolipoprotein E (ApoE) in adipose remodeling remains unclear. This study investigated ApoE's function in cancer cachexia. We found cachectic patients had decreased plasma ApoE but elevated expression in subcutaneous adipose. In vitro, ApoE knockdown in adipocytes downregulated both lipogenesis and lipolysis genes. In vivo, ApoE-/- mice were protected against adipose wasting in a cachexia model. Single-cell RNA sequencing revealed ApoE deficiency altered immune cell dynamics, increasing total macrophages and enriching a specific Cbr2+ macrophage subpopulation with an M2-like phenotype. This was confirmed by immunofluorescence showing enhanced M2 macrophage infiltration in adipose tissue. We conclude that ApoE is a critical regulator of adipose homeostasis and immune modulation in cancer cachexia, representing a promising diagnostic and therapeutic target.

Keywords:  APOE; Adipose tissue; Cancer cachexia; Macrophage; Single-cell RNA sequencing

DOI:  https://doi.org/10.1016/j.clim.2025.110660
Pediatr Res. 2025 Dec 26.

Perspective Review: Advancing toward the diagnosis of sarcopenia in the pediatric population.

Marcelo Flores-Opazo, Matías Monsalves-Álvarez, Carlos Sepúlveda-Guzmán, Sebastián Jannas-Vela, Paz Fernández Valero, Raquel Burrows, Paulina Correa-Burrows, Rodrigo Troncoso.

Sarcopenia is a muscle disorder characterized by the progressive loss of muscle mass and strength, leading to diminished physical performance. Although primarily associated with aging and chronic diseases, it is increasingly recognized in younger populations, particularly among those with chronic illnesses. Recent evidence suggests that muscle mass and strength deficits can manifest as early as childhood and adolescence, affecting three out of ten adolescents. Pediatric sarcopenia, while challenging to define due to the lack of standardized diagnostic criteria, presents significant health risks, including increased susceptibility to metabolic syndrome and chronic non-communicable diseases. Recent studies have attempted to establish normative values for muscle health in pediatric populations, yet many rely only on assessment of either muscle mass or strength, thus limiting the understanding of overall muscle health. In this context, the interaction between muscle mass, strength, and functionality, herein referred to as the muscle mass-strength-functionality triad (MSFt), is crucial for understanding the onset and progression of pediatric sarcopenia. The present review provides a perspective on concepts and operators defining pediatric sarcopenia and advocates for incorporating novel diagnostic criteria encompassing the MSFt. Furthermore, the importance of physical literacy and the acquisition of fundamental movement skills during childhood is highlighted, as these factors significantly influence long-term muscle health and physical activity levels. IMPACT: This perspective review provides an insightful view of muscle health in children and adolescents centered around the definition of pediatric sarcopenia. We discussed how to understand and describe sarcopenic-like deficits in pediatric populations. We propose the muscle mass-strength-functionality triad as an attribute that describes physical competence and is key to defining pediatric sarcopenia. We suggest the addition of physical literacy and movement competence assessment to the current diagnostic criteria of pediatric sarcopenia.

DOI: https://doi.org/10.1038/s41390-025-04716-4