bims-moremu 2025-12-14 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2025–12–14
thirty-one papers selected by
Anna Vainshtein, Craft Science Inc.

Skeletal Muscle Methylome-Transcriptome Disruptions During the Onset and Progression of Colorectal Cancer-Induced Cachexia.
STIM1 Reduction Prevents Tubular Aggregate Formation and Compromises Muscle Performance in Ageing Mice.
Expression of concern "Immunosenescence in skeletal muscle: The role-play in cancer cachexia chessboard" [Semin. Cancer Biol. 111 (2025) 48-59].
Integrative Multi-Omics and Network Analyses Reveal Pathogenic and Protective Pathways in Centronuclear Myopathies.
The Role of Mammalian Target of Rapamycin (mTOR) and Adenosine Monophosphate-Activated Protein Kinase (AMPK) Signaling in Skeletal Muscle Hypertrophy: A Literature Review With Implications for Health and Disease.
Impact of rAAV-shRNA treatment targeting mechanosensitive Ilk1 and Fermt2 in a mouse model of sepsis-induced muscle weakness.
N-acetylglucosamine facilitates coordinated flow-like movement of myoblasts, forming a foundation for efficient myogenesis.
NAD+ Enhanced Mesenchymal Stromal Cells Effect on Muscle Atrophy by Improving SIRT1-Mediated Mitochondrial Function via NAMPT.
RIPK3 deficiency ameliorates diabetic sarcopenia through proteostasis regulation by suppressing inflammatory signaling and cellular stress pathways.
Transcytotic transportation of size-controlled nanocarriers into dystrophic skeletal muscle leads to therapeutic outcome in mice.
Molecular Insights into Central Core Disease: Proteomic Signatures and Potential Therapeutic Biomarkers in RYR1 I4895T Mice.
Liver before muscle: Tissue-specific glycogen recovery, with a view toward sex differences and hormonal regulation.
Concurrent training with long-interval HIIT does not impair skeletal muscle protein synthesis or hypertrophy: Little evidence of an 'interference effect'.
Explore sirtuin family: SIRT5 as a ticket for the entrance of the TBK1-RelA axis to skeletal muscle rejuvenation.
Glutamine Promotes Myogenesis in Myoblasts Through Glutaminolysis-Mediated Histone H3 Acetylation That Enhances Myogenin Transcription.
Mechanisms of Testosterone's Anabolic Effects on Muscle and Function: Controversies and New Insights.
Resistance exercise training attenuates skeletal muscle atrophy in experimental pulmonary arterial hypertension.
Implications for myofibrillar protein translation due to high-intensity muscle contraction via a rapamycin-insensitive mechanism.
MBNL loss of function in smooth muscle as a model for myotonic dystrophy associated gastrointestinal dysmotility.
Five days of physical inactivity induced by dry immersion alter skeletal muscle metabolism and whole-body glucose tolerance in healthy men.
Carbohydrate ingestion during prolonged exercise and net skeletal muscle glycogen utilization: A meta-analysis.
Assessing the involvement of tumor-secreted factors in the inhibition of muscle differentiation.
MCARE enhances SERCA1 activity in fast-twitch muscle to maintain calcium handling and muscle integrity.
Genetic and functional analysis of ZMIZ1 in neurodevelopmental disorder with dysmorphic facies and distal skeletal anomalies (NEDDFSA): insights from muscle cells and signaling pathways.
A-to-I RNA editing impairs miR-376b-3p repression of RYBP in skeletal muscle satellite cells.
IGFBP2: A Factor That Negatively Regulates Muscle Development and Growth.
Comprehensive transcriptomic profiling reveals lncRNA-miRNA-mRNA regulatory networks in skeletal muscle aging of mice.
Exercise attenuates the hallmarks of aging: Novel perspectives.
Glucagon-like peptide-1 receptor (GLP-1R) agonists prevent tributyltin-induced muscle atrophy/wasting via restoring GLP-1R signaling in vitro and in mice.
GLP-1 agonists and exercise: the future of lifestyle prioritization.
Muscle matters: Transforming the care of intensive care unit acquired sarcopenia and myosteatosis.

Am J Physiol Cell Physiol. 2025 Dec 12.

Skeletal Muscle Methylome-Transcriptome Disruptions During the Onset and Progression of Colorectal Cancer-Induced Cachexia.

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

  Cancer cachexia is a wasting condition, primarily affecting skeletal muscle, impairing patients' quality of life, prognosis, and survival. The molecular triggers are incompletely defined but given prior evidence for epigenetic plasticity in muscle, we speculate dysregulated DNA methylation plays a role in muscle transcriptional alterations mediating cachexia severity. We aimed to describe and integrate the cachexia methylome and transcriptome. We used a time course approach in a mild cachexia model (Colon-26, C26) coupled with a severe cachexia genetic model (ApcMin/+) in both biological sexes to assess the methylome across degrees of cachexia pathology. The muscle methylome and transcriptome were analyzed separately and subsequently integrated using a computational technique to infer epigenetic control of gene expression. Male mice exhibited widespread disruptions to the transcriptome across time points while females were more protected; in severe pathophysiologic phenotypes, the magnitude of change was similar between sexes. A conserved set of inflammation-related genes were dysregulated across cachexia progression and sex, including Osmr, Stat3, and Serpina3n. Epigenetic alterations in both sexes emerged in promoter regions as early as 10 days post tumor implant in C26 despite a lack of physiologic phenotype and prior to the transcriptome disruptions. Our integration analysis suggests methylome alterations as a mechanism of cachexia pathophysiology in severe phenotypes. A conserved feature across -omics layers, sexes, and conditions was dysregulated Runx1 and neurodegeneration-related pathways, which may indicate cachexia-mediated denervation. Overall, we provide evidence for the role of epigenetics in cachexia progression and severity and a valuable resource to the cachexia research communities.

Keywords:  Biological sex; Epigenetics; Molecular signatures; Omics integration; Runx1

DOI:  https://doi.org/10.1152/ajpcell.00751.2025
J Cachexia Sarcopenia Muscle. 2025 Dec;16(6): e70151

STIM1 Reduction Prevents Tubular Aggregate Formation and Compromises Muscle Performance in Ageing Mice.

Laura Pérez-Guàrdia, Roberto Silva-Rojas, Jocelyn Laporte, Johann Böhm.

   BACKGROUND: Ageing is an irreversible process involving the gradual decline of cellular functions in all tissues. In male mice, age-related loss of muscle force is accompanied by the formation of tubular aggregates, which are honeycomb-like structures composed of membrane tubules, proteins and Ca2+ deposits. Tubular aggregates are also found in tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK), two clinically overlapping human disorders affecting skeletal muscle, bones, skin, spleen and platelets. TAM/STRMK is caused by gain-of-function mutations in the ubiquitously expressed Ca2+ sensor STIM1 and results in excessive extracellular Ca2+ entry and the dysregulation of Ca2+ homeostasis.
METHODS: To understand the correlation between ageing, tubular aggregate formation, Ca2+ and STIM1, we conducted comparative analyses of WT and Stim1+/- male mice until 18 months of age. We examined growth, general and specific muscle force, fatigability and muscle structure.
RESULTS: Stim1+/- mice were born with the expected Mendelian ratio and showed unremarkable postnatal development with normal body and organ weight. However, at 18 months, Stim1+/- mice manifested delayed muscle contraction (Δ = 28%, p < 0.05) and relaxation (Δ = 40%, p < 0.01) kinetics as well as exacerbated fatigue (Δ = 28%, p < 0.05) compared with age-matched controls. Morphological investigations of Stim1+/- muscle sections by light and electron microscopy uncovered a shift towards slow myofibres and mitochondrial proliferation accompanied by enhanced SDH activity (Δ = 27%, p < 0.0001), an almost twofold increase in ROS production (p < 0.05), and signs of mitophagy-all representing histopathological hallmarks of age-related deterioration of muscle function known as sarcopenia. Strikingly, tubular aggregates-though abundant in WT muscles at 18 months-were absent in Stim1+/- mice.
CONCLUSIONS: Taken together, STIM1 depletion by 50% had no discernible effect on muscle function in young adult male mice, but compromised muscle performance and resistance to fatigue at later life stages. These findings highlight a critical role of STIM1 and Ca2+ balance in the maintenance of muscle physiology, fibre type composition and mitochondrial bioenergetics. The absence of tubular aggregates in Stim1+/- mice indicates that tubular aggregates possibly play a protective role and may contribute to the prevention of age-related muscle alterations.

Keywords:  STIM1; ageing; calcium; muscle; tubular aggregates

DOI:  https://doi.org/10.1002/jcsm.70151
Semin Cancer Biol. 2025 12;pii: S1044-579X(25)00141-5. [Epub ahead of print]117 111

Expression of concern "Immunosenescence in skeletal muscle: The role-play in cancer cachexia chessboard" [Semin. Cancer Biol. 111 (2025) 48-59].

DOI: https://doi.org/10.1016/j.semcancer.2025.11.004
Int J Mol Sci. 2025 Nov 28. pii: 11572. [Epub ahead of print]26(23):

Integrative Multi-Omics and Network Analyses Reveal Pathogenic and Protective Pathways in Centronuclear Myopathies.

Alix Simon, Charlotte Gineste, David Reiss, Julie D Thompson, Jocelyn Laporte.

  Centronuclear and myotubular myopathies (CNMs) are rare, inherited muscle disorders characterized by muscle atrophy, weakness, and altered muscle fiber structure, primarily caused by mutations in MTM1, DNM2, or BIN1. The molecular mechanisms driving CNM are only partially understood, and no curative therapies are available. To elucidate molecular pathways involved in CNMs, we present an integrative multi-omics analysis across several CNM mouse models untreated or treated with pre-clinical strategies, combining transcriptomic, proteomic, and metabolomic datasets with curated interaction, metabolic, tissue, and phenotype knowledge using network-based approaches. Weighted Gene Co-expression Network Analysis (WGCNA) identified gene modules commonly altered in three CNM genetic forms. Modules correlated with improved muscle function were enriched for processes such as muscle contraction, RNA metabolism, and oxidative phosphorylation, whereas modules linked to disease severity were enriched for immune response, innervation, vascularization, and fatty acid oxidation. We further integrated transcriptomic, proteomic, and metabolomic data from the Mtm1-/y mouse model with public knowledge bases into a multilayer network, and explored it using a random walk with restart approach. These analyses highlighted metabolites closely connected to CNM phenotypes, some of which may represent candidates for nutritional or pharmacological modulation. Our findings illustrate how integrative multi-omics and network analyses reveal both pathogenic and protective pathways in CNM and provide a foundation for identifying novel therapeutic opportunities.

Keywords:  biomarker; centronuclear myopathy; congenital myopathy; gene co-expression; myotubular myopathy; network-based analysis; omics; skeletal muscle; systems biology; therapeutic target

DOI:  https://doi.org/10.3390/ijms262311572
Cureus. 2025 Nov;17(11): e96018

The Role of Mammalian Target of Rapamycin (mTOR) and Adenosine Monophosphate-Activated Protein Kinase (AMPK) Signaling in Skeletal Muscle Hypertrophy: A Literature Review With Implications for Health and Disease.

Seon Yeop Jeong.

  Maintaining skeletal muscle mass is fundamental not only for strength and mobility but also for metabolic health, disease prevention, and healthy aging. Skeletal muscle functions as a dynamic metabolic organ, and its maintenance depends on the delicate equilibrium between mammalian target of rapamycin (mTOR), which drives anabolic processes, such as protein synthesis and hypertrophy, and adenosine monophosphate-activated protein kinase (AMPK), which promotes catabolic renewal through mitochondrial biogenesis, autophagy, and energy conservation. Sustained mTOR hyperactivation contributes to obesity, insulin resistance, neurodegeneration, and cancer, while AMPK activation counterbalances these effects by restoring cellular energy balance and enhancing metabolic resilience. Thus, optimal muscle and metabolic health depend not on dominance of one pathway, but on the strategic balance between mTOR and AMPK activity. Human trials and meta-analyses show that for individuals engaged in resistance training, a total protein intake of approximately 1.6 g/kg/day effectively maximizes muscle protein synthesis, with diminishing returns beyond that level. Distributing protein evenly across meals enhances anabolic efficiency, about 0.25 g/kg per meal in younger adults and 0.40 g/kg per meal in older adults, which helps overcome age-related anabolic resistance. Protein quality is equally critical: leucine-rich, rapidly absorbed sources such as whey elicit the most robust mTOR activation and muscle-building response. Exercise mode and energy timing further shape this anabolic-catabolic balance. Concurrent endurance and resistance training may attenuate hypertrophy depending on session order, intensity, and training status, whereas intermittent fasting and time-restricted feeding improve body composition and cardiometabolic health when total energy and protein needs are still met. Together, these findings suggest that integrating structured resistance exercise, well-distributed, high-quality protein intake, and periodic AMPK activation through fasting or aerobic training provides a practical framework for sustaining muscle mass, optimizing metabolic function, and promoting longevity.

Keywords:  amino acids; ampk; autophagy; fasting; mitochondrial biogenesis; mtor; muscle hypertrophy; protein synthesis; resistance exercise

DOI:  https://doi.org/10.7759/cureus.96018
PLoS One. 2025 ;20(12): e0338338

Impact of rAAV-shRNA treatment targeting mechanosensitive Ilk1 and Fermt2 in a mouse model of sepsis-induced muscle weakness.

Alexander Pacolet, Inge Derese, Lies Pauwels, Sarah Vander Perre, Maxime Smits, Chris Van den Haute, Sarah Derde, Katrien Koppo, Rik Gijsbers, Lies Langouche.

INTRODUCTION: Intensive-care-unit-acquired-muscle-weakness is a debilitating complication of sepsis, characterized by loss of muscle mass and functionality. Immobilization is an important trigger, but the role of disturbed mechanical signaling is incompletely understood. In health, the integrin-receptor-complex with key components Kindlin2 (KIND2/Fermt2) and integrin-linked-kinase (ILK/Ilk1) converses mechanical forces into biochemical signals to regulate muscle mass. We hypothesize that this complex, through key elements KIND2 and ILK, plays a role in sepsis-induced-muscle-weakness.
METHODS: AAV2/9-vectors expressing shRNA-sequences against Ilk1, Fermt2 or noncoding-control-gene were injected in tibialis anterior (TA) muscles of 24w-old male C57BL/6J mice. Two-weeks-post-injection, after knockdown validation, mice were made septic by cecal ligation and puncture. Five-days-post-sepsis muscle force, mass and fiber size were quantified and expression of mechanosensitive elements and downstream pathways of the integrin-receptor-complex was assessed.
RESULTS: Two-weeks-post-injection the respective sh-targets were strongly suppressed (mRNA Ilk1-44%, Fermt2-76%, protein ILK -34%, KIND2-70%). In rAAV-sh-controls, sepsis induced upregulation across TA and EDL muscle of Ilk1 and Fermt2 and integrin-receptor-complex-related genes Itga7, ItgB1, Tln1, Lims1, Lims2, Parva (P < 0.001), whereas in SOL muscle Lims1, Lims2 and Fermt2 were not and Vcl1 (P < 0.001) was upregulated. In TA and EDL, but not in SOL, rAAV-shIlk1 and rAAV-shFermt2 attenuated upregulation of respective targets down to healthy controls, but without affecting expression of other integrin-receptor-complex-related genes. TA muscle force or weight were not affected by rAAV-shIlk1 or rAAV-shFermt2 (P > 0.05), whereas muscle fiber size reduction (-20.7% in Sepsis shControl) was attenuated up to -13.4% (Sepsis shIlk1, P < 0.001) and -12.3% (Sepsis shFermt2, P < 0.001). Sepsis or sh-treatment did not shift TA fiber types. Expression of markers of atrophy, inflammation, autophagy, protein synthesis and regeneration were affected by sepsis, but not by sh-treatment. Only markers of metabolism Slc2a4 (P < 0.05) and Rac1 (P < 0.01) were further affected by sh-treatment.
CONCLUSIONS: Sepsis induced upregulation of integrin-receptor-complex-related genes but attenuating the upregulation of Ilk1 or Fermt2 did not affect the development of muscle weakness, although muscle fiber size was better preserved, arguing against a key role for Ilk1 or Fermt2.

DOI: https://doi.org/10.1371/journal.pone.0338338
Skelet Muscle. 2025 Dec 12.

N-acetylglucosamine facilitates coordinated flow-like movement of myoblasts, forming a foundation for efficient myogenesis.

Masahiko S Satoh, Ann Rancourt, Guillaume St-Pierre, Elizabeth Bouchard, Maude Fillion, Kana Hagiwara, Kazuki Nakajima, Sachiko Sato.

   BACKGROUND: Skeletal muscle comprises 30-40% of a mammal's body mass, maintaining its integrity through efficient muscle fiber regeneration, which involves myoblast differentiation into myotubes. Previously, we reported that N-acetylglucosamine (GlcNAc) promotes myogenesis in C2C12 cells, although the underlying processes remained unclear. GlcNAc's activated form, UDP-GlcNAc, is critical for the biosynthesis of highly branched (N-acetyllactosamine-rich) N-linked oligosaccharides, which are recognized by galectin-3 (Gal-3), a protein that facilitates dynamic cell-cell and cell-matrix interactions and modulating the motility dynamics of membrane-associated proteins.
METHODS: In this study, we used primary myoblasts from both wild-type and Gal-3 null (Gal-3KO) mice, observing myotube formation through long-term live-cell imaging and single-cell tracking to reveal the dynamic process that occurred during the myotube formation.
RESULTS: We found that GlcNAc enhances myoblast fusion in a dose-dependent manner, and that the addition of Gal-3 with GlcNAc leads to the formation of larger myotubes. Gal-3KO myoblasts exhibited a reduced capacity for myotube formation-a deficiency that was rectified by supplementing with GlcNAc and Gal-3. Our results highlight the role of Gal-3 interaction with oligosaccharides, whose synthesis is promoted by GlcNAc in facilitating myotube formation. Single-cell tracking revealed that GlcNAc and Gal-3 increase myoblast motility, leading to a faster, coordinated, flow-like movement-a collective behavior, along which myotubes form through cell fusion. Interestingly, myoblasts contributing to myotube formation were pre-positioned along the eventual shape of the myotubes before this flow-like movement was fully established. These myoblasts moved along the flow, paused, and even moved against it, suggesting that both coordinated flow and initial spatial positioning contribute to myoblast alignment along the axis of future myotubes.
CONCLUSION: Our findings suggest that GlcNAc, in conjunction with Gal-3, enhances myotube formation by fostering an environment conducive to myoblast positioning, establishing optimal coordinated flow-like movement, and facilitating fusion. This suggests potential therapeutic applications of GlcNAc in muscle repair and muscle disorders.

Keywords:  Coordinated flow-like movement.; Dynamic myotube formation process; Gal-3KO myoblasts; Galectin-3 (Gal-3); Myogenesis; N-acetylglucosamine (GlcNAc); Single-cell tracking; Wild-type myoblasts

DOI:  https://doi.org/10.1186/s13395-025-00404-3
J Cachexia Sarcopenia Muscle. 2025 Dec;16(6): e70142

NAD+ Enhanced Mesenchymal Stromal Cells Effect on Muscle Atrophy by Improving SIRT1-Mediated Mitochondrial Function via NAMPT.

Jia Song, Yuting Sun, Nan Zang, Xue Liu, Jiamu Chen, Kewei Wang, Longqing Xia, Jun Chen, Ruxing Zhao, Fuqiang Liu, Xinguo Hou, Li Chen, Jun Cheng, Wenjian Zhang.

   BACKGROUND: Sarcopenia contributes to all-cause mortality in the elderly; however, there is no specific treatment. Mesenchymal stromal cells (MSCs) ameliorate age-related muscle loss and dysfunction and are potential therapeutic candidates for sarcopenia. However, their activity is easily affected by the surrounding environment and they are prone to replicative senescence during in vitro culture. Therefore, a drug that delays aging and enhances its function is required. Here, we investigated whether nicotinamide adenine dinucleotide (NAD+) pretreatment enhances the therapeutic efficacy of MSCs on skeletal muscle atrophy and its underlying mechanism in a D-galactose (D-gal)-induced mouse model.
METHODS: The administration of D-gal to mice induces a range of age-associated characteristics and is commonly used in research on age-related muscle atrophy. Therefore, in this study, C57BL/6 J mice and C2C12-differentiated myotubes exposed to D-gal were used to explore the effects of MSCs/NAD+-MSCs on muscle atrophy. MSCs/NAD+-MSCs were injected into the skeletal muscles of the hind limbs every 7 days for six cycles. Treadmill running and grip strength tests were used to evaluate muscle strength. Muscle weight and fibre cross-sectional area (CSA) were used to measure muscle mass. Multiomics analysis of quadriceps and NAD+-pretreated MSCs (NAD+-MSCs), Western blotting of muscle atrophy signalling, including Atrogin 1 and MuRF1, the mitochondrial complex, fatty acid oxidation indicators and Seahorse analysis were performed to explore the underlying mechanisms.
RESULTS: MSCs increased grip strength (p = 0.0005), running endurance (p = 0.0006) and muscle mass (p = 0.0165 for tibialis anterior [TA] muscle, p = 0.0049 for soleus [SO] muscle) in D-gal-treated mice, with elevated muscle fibre CSA (p < 0.0001) and reduced Atrogin 1 (p = 0.0242) and MuRF1 expression (p = 0.0009). NAD+ pretreatment increased the effect of MSCs on muscle atrophy (p = 0.0009 for grip strength, p = 0.0169 for running endurance, p = 0.0506 for TA muscle weight, p = 0.0238 for SO muscle weight, p = 0.0014 for muscle fibre CSA, p = 0.0005 for Atrogin 1 expression and p = 0.0223 for MuRF1 expression). MSCs/NAD+-MSCs activated the SIRT1/PGC-1α signalling, enhanced mitochondrial function and fatty acid oxidation in D-gal-induced mice and C2C12 myotubes. SIRT1 knockdown weakened the beneficial effects of MSCs/NAD+-MSCs on muscle atrophy. RNA-seq of MSCs/NAD+-MSCs and proteomic analysis of their supernatants revealed that NAD+ enhanced the therapeutic effect of MSCs by promoting NAMPT secretion.
CONCLUSIONS: NAD+ enhances the therapeutic effect of MSCs on D-gal-induced muscle atrophy by promoting NAMPT secretion, which acts on the SIRT1 signaling pathway, and improves mitochondrial function and fatty acid oxidation in skeletal muscles. This study provides new insights and a theoretical basis for clinical treatment of sarcopenia.

Keywords:  NAD+‐MSCs; NAMPT; SIRT1/PGC‐1α; mitochondrial function; muscle atrophy

DOI:  https://doi.org/10.1002/jcsm.70142
Biochem Pharmacol. 2025 Dec 09. pii: S0006-2952(25)00892-5. [Epub ahead of print] 117627

RIPK3 deficiency ameliorates diabetic sarcopenia through proteostasis regulation by suppressing inflammatory signaling and cellular stress pathways.

Jia Yi, Jitai Zhang, Xingxing Fang, Jiacheng Sun, Yuntian Shen, Xia Li, Fei Xue, Tongxin Shang, Xinlei Yao, Bingqian Chen, Hualin Sun.

  Diabetic sarcopenia is a major complication of diabetes severely impacting patient quality of life and increasing mortality risk. Its pathogenesis remains incompletely understood and effective treatments are lacking. This study reveals the critical role and molecular mechanisms of Receptor-interacting protein kinase 3 (RIPK3) in skeletal muscle atrophy during type 1 diabetes mellitus (T1DM). Using RIPK3-knockout diabetic mice, we found that RIPK3 deficiency significantly ameliorated muscle atrophy, as evidenced by increased myofiber cross-sectional area, restored muscle mass, and enhanced exercise capacity.Mechanistically, RIPK3 deletion suppressed chronic inflammation, alleviated cellular stress responses, and improved mitochondrial function. Furthermore, RIPK3 deficiency bidirectionally regulated skeletal muscle proteostasis byinhibiting overactivation of both the ubiquitin-proteasome and autophagy-lysosome systems while promoting protein synthesis pathway.In vitro experiments confirmed that the RIPK3 inhibitor GSK872 mitigated high glucose-induced atrophy in C2C12 myotubes, supporting RIPK3's direct regulatory role in muscle cells.Collectively, this work elucidates how RIPK3 contributes to T1DM-associated sarcopenia through coordinated regulation of proteostasis, inflammatory signaling, and stress responses, providing a theoretical foundation for targeting RIPK3 in the treatment of diabetic sarcopenia.

Keywords:  Chronic inflammation; Diabetic sarcopenia; Oxidative stress; Protein homeostasis; RIPK3

DOI:  https://doi.org/10.1016/j.bcp.2025.117627
Nat Commun. 2025 Dec 11.

Transcytotic transportation of size-controlled nanocarriers into dystrophic skeletal muscle leads to therapeutic outcome in mice.

Xiangsheng Liu, Michael R Hicks, Zhenhan Feng, Jinhong Jiang, Yuting Li, Courtney S Young, Tianyu Zhang, Kholoud Saleh, Michael R Emami, Yanyan Liu, Mengmeng Qin, Jiulong Li, Yile Zheng, Honghong Yang, Melissa J Spencer, April D Pyle, Huan Meng.

Duchenne Muscular Dystrophy (DMD) is a lethal muscle-wasting disorder with limited therapeutic options. Although nano drug delivery offers promise, the biodistribution and access routes to dystrophic muscle remain poorly understood. Here we show that intravenously administered mesoporous silica nanoparticle (MSNP) carriers exhibit striking size-dependent biodistribution in male DMD mice. Small nanocarriers (50~100 nm) efficiently accumulate in skeletal muscle while avoiding hepatic and splenic sequestration, outperforming larger particles (200~300 nm). Importantly, we uncover that endothelial transcytosis, not passive vascular leakage, is the dominant and previously unrecognized route by which nanocarriers access dystrophic muscles. Further, we encapsulate tamoxifen, a repurposed drug, into optimized MSNPs. This intervention increases utrophin expression, reduces fibrosis, and diminishes myofiber necrosis, resulting in improved muscle health and strength. Our results establish size-tuned, transcytosis-enabled nanocarriers as a transformative strategy for targeted drug delivery to dystrophic muscle, paving the way for nanomedicine-based therapies in DMD and potentially other muscle disorders.

DOI: https://doi.org/10.1038/s41467-025-66061-8
Int J Mol Sci. 2025 Nov 26. pii: 11451. [Epub ahead of print]26(23):

Molecular Insights into Central Core Disease: Proteomic Signatures and Potential Therapeutic Biomarkers in RYR1 I4895T Mice.

Lorenza Vantaggiato, Enxhi Shaba, Federica Fiore, Daniela Rossi, Vincenzo Sorrentino, Luca Bini, Claudia Landi.

  Central Core Disease (CCD) is a congenital myopathy predominantly caused by mutations in the gene encoding ryanodine receptor type-1 (RYR1), the intracellular Ca2+ release channel embedded in the skeletal muscle sarcoplasmic reticulum membrane. The I4898T mutation represents one of the most common RYR1 mutations associated with CCD. Unfortunately, there are no approved therapies for CCD or for other myopathies caused by mutations in this gene. This study aims to perform a top-down differential proteomic analysis on soleus muscle samples from wild-type mice (WT) and heterozygous knock-in mice carrying the I4895T (IT) mutation in RyR1, to investigate the pathogenic mechanisms and molecular pathways involved in this myopathy and to shed light on new potential biomarkers useful for future therapies. Proteomic analysis revealed 50 dysregulated protein species, and multivariate analysis showed that IT mice exhibit a distinct proteomic signature compared to WT mice, characterized by alterations in proteins associated with contractile and structural dysfunction, metabolism, and stress response. In particular, a significant increase in myosin fragments was observed in IT mice, likely due to muscle breakdown. In contrast, myotilin was downregulated, suggesting a weakening of the muscle cytoskeletal structure. There was a notable downregulation of proteins involved in glycolysis and the TCA cycle; conversely, there was an increase in proteins related to anaerobic glycolysis, suggesting a shift from aerobic to anaerobic glycolysis. Furthermore, proteins involved in fatty acid beta-oxidation and oxidative phosphorylation were also found to be upregulated in IT mice, indicating an attempt by the muscle to maximize energy production. Finally, we found a significant decrease in PGC1α, which could serve as potential therapy target and biomarker in CCD.

Keywords:  Central Core Disease; PGC1α; RYR1; glycolysis; oxidative phosphorylation; oxidative stress

DOI:  https://doi.org/10.3390/ijms262311451
J Physiol. 2025 Dec 12.

Liver before muscle: Tissue-specific glycogen recovery, with a view toward sex differences and hormonal regulation.

Tony Stickel, Charles Masters, Cesar A Carrera, Kenny Tang.



Keywords:  exercise; glycogen; liver; oestrogen; recovery; skeletal muscle

DOI:  https://doi.org/10.1113/JP290130
J Appl Physiol (1985). 2025 Dec 10.

Concurrent training with long-interval HIIT does not impair skeletal muscle protein synthesis or hypertrophy: Little evidence of an 'interference effect'.

Miguel Conceição, Felipe C Vechin, Guilherme Telles, Manoel Lixandrão, Natália Ribeiro, Luiz A Riani Costa, Victoria Hevia-Larraín, Maíra C Scarpelli, Felipe Damas, Cleiton A Libardi, Donny M Camera, John Alan Hawley, Carlos Ugrinowitsch.

  Concurrent training is commonly associated with blunted muscle hypertrophy compared to resistance training alone, but the underlying physiological mechanisms remain unclear. This study aimed to investigate the acute and chronic effects of concurrent versus resistance training on muscle protein synthesis, satellite cell dynamics, myonuclear content, myogenic regulatory factor expression, muscle fibre hypertrophy, strength, and aerobic capacity.
METHODS: Nineteen previously untrained young men were randomly assigned to either concurrent or resistance training for 16 weeks. Muscle biopsies were collected before and 48 hours after a standardized exercise session at weeks 4 and 16. Samples were analyzed for myofibrillar protein synthesis via deuterium oxide incorporation, satellite cell content, myonuclear number, and gene expression. Strength, aerobic capacity, and muscle fibre cross-sectional area were measured at baseline and post-intervention.
RESULTS: Muscle protein synthesis increased 48 hours post-exercise at both weeks 4 and 16 (P=0.0105), with no group differences. Satellite cell content increased over time in type II fibres only (P=0.0021). Myonuclear number increased in both fibre types (type I: P=0.0301; type II: P=0.0009), with higher values in type I fibres in the concurrent training group (P=0.0027). MYF5 and MYF6 expression increased over time (P=0.0141; P=0.034), and MYOD1 was elevated post-exercise only in concurrent training (P=0.0009). Type II fibre size increased (P = 0.016). Strength gains were greater in resistance training (P = 0.016), while aerobic capacity improved only in concurrent training (P<0.001).
CONCLUSION: Sixteen weeks of concurrent training did not inhibit molecular mechanisms associated with muscle hypertrophy in previously untrained individuals.

Keywords:  interference phenomenon; physical training; protein synthesis

DOI:  https://doi.org/10.1152/japplphysiol.00642.2025
Life Med. 2025 Oct;4(6): lnaf034

Explore sirtuin family: SIRT5 as a ticket for the entrance of the TBK1-RelA axis to skeletal muscle rejuvenation.

DOI: https://doi.org/10.1093/lifemedi/lnaf034
Nutrients. 2025 Nov 24. pii: 3673. [Epub ahead of print]17(23):

Glutamine Promotes Myogenesis in Myoblasts Through Glutaminolysis-Mediated Histone H3 Acetylation That Enhances Myogenin Transcription.

Masaru Takatoya, Tomoya Kasugai, Daichi Arai, Urara Kasuga, Chisato Miyaura, Michiko Hirata, Yoshifumi Itoh, Tsukasa Tominari, Yoshitsugu Aoki, Masaki Inada.

  Background/Objectives: Plasma glutamine levels in skeletal muscle change in response to exercise intensity and duration, both in physiological and pathological states. Glutamine contributes to muscle differentiation and regeneration; however, the mechanisms underlying this process remain unclear. This study investigated the role of glutamine glutaminolysis in myogenic differentiation, with a focus on epigenetic regulation of myogenin gene expression. Methods: C2C12 myoblasts were differentiated into myotubes using media containing various concentrations of glutamine, glutamate, or dimethyl 2-oxoglutarate (DM-α-KG), a cell-permeable analog of α-ketoglutarate. Results: Glutamine, glutamate, and DM-α-KG promoted C2C12 myoblast differentiation in a concentration-dependent manner, whereas the glutaminase inhibitor CB-839 suppressed differentiation. 4 mM glutamine increased myogenin mRNA expression by about 5-fold. CB-839 also inhibited glutamine-induced expression of myogenin but did not influence the effects of glutamate or DM-α-KG. Furthermore, glutamine increased histone H3 lysine 27 acetylation (H3K27ac) by about two-fold, whereas CB-839 (200 nM) and A-485 (10 µM), a CBP/p300 histone acetyltransferase inhibitor, reduced H3K27ac levels by about half. These results indicate that glutamine not only serves as a structural amino acid for muscle formation but also enhances myogenin transcription through epigenetic mechanisms. Conclusions: This report demonstrates glutaminolysis-dependent histone H3 acetylation, which induces myogenin transcription in myoblasts. These results, connecting glutamine supplementation during resistance training, may make it an effective strategy to accelerate muscle regeneration.

Keywords:  C2C12 myoblast; epigenetic regulation; glutamine; glutaminolysis; histone H3 acetylation

DOI:  https://doi.org/10.3390/nu17233673
Endocr Rev. 2025 Dec 08. pii: bnaf041. [Epub ahead of print]

Mechanisms of Testosterone's Anabolic Effects on Muscle and Function: Controversies and New Insights.

Shalender Bhasin, Chengzhi Wang, Mohan S Chandra, Thiago Gagliano-Jucá, Ravi Jasuja.

  Testosterone treatment increases muscle mass, maximal voluntary muscle-strength, aerobic capacity, and some measures of physical function. Activational and epigenetic mechanisms by which androgens improve muscle mass and physical performance and how to apply these anabolic effects to treat functional limitations associated with aging and disease remain incompletely understood. Testosterone treatment induces hypertrophy of type 1 and 2 muscle fibers, and increases muscle progenitor cell numbers by promoting differentiation of mesenchymal progenitor cells into myogenic lineage by an androgen receptor (AR)-mediated pathway. Liganded AR binds to β-catenin, translocates into nucleus where it binds TCF4 and upregulates follistatin that blocks signaling through TGFβ-pathway to promote myogenesis and inhibit adipogenesis. Testosterone increases myoblast proliferation by stimulating polyamine biosynthesis. Stimulation of GH and IGF-1 secretion, intramuscular IGF1-receptor, and muscle protein synthesis, and inhibition of muscle atrophy genes further contribute to testosterone's anabolic effects. Testosterone improves muscle bioenergetics by increasing erythrocytes, oxygen availability, tissue blood flow, and mitochondrial mass and quality. Testosterone increases blood flow by nongenomic mechanisms involving NO production, and calcium and potassium channels in vascular smooth muscle. The conversion of testosterone to 5α-dihydrotestosterone is not required for mediating its anabolic effects. Mechanisms of testosterone's sexually-dimorphic epigenetic and tissue-specific activational effects; and roles of α-keto reductase and steroid 5α-reductase, one-carbon and polyamine metabolism in testosterone's actions remain poorly understood. Strategies to translate testosterone-induced muscle mass and strength gains into patient-important improvements in functional performance and health outcomes are needed to enable its clinical applications to treat functional limitations associated with aging and disease.

Keywords:  Testosterone; anabolic effects of testosterone; androgens; mechanisms of testosterone's action; myogenic differentiation; polyamines; testosterone's effects on muscle performance and physical function

DOI:  https://doi.org/10.1210/endrev/bnaf041
Pflugers Arch. 2025 Dec 09. 478(1): 3

Resistance exercise training attenuates skeletal muscle atrophy in experimental pulmonary arterial hypertension.

Sebastião Felipe Ferreira Costa, Luciano Bernardes Leite, Leôncio Lopes Soares, Sara Caco Dos Lúcio Generoso, Mirielly Alexia Miranda Xavier, Matheus Soares Faria, Arthur Eduardo de Carvalho Quintão, Luiz Otávio Guimarães Ervilha, Thainá Iasbik Lima, Bruno Rocha Avila Pelozin, Tiago Fernandes, Edilamar Menezes Oliveira, Mariana Machado Neves, Emily Correna Carlo Reis, Leandro Licursi Oliveira, Antônio José Natali.

  To evaluate the effects of a resistance training (RT) program applied during the development of MCT-induced pulmonary arterial hypertension (PAH) on skeletal muscle atrophy in rats. Twenty-one male Wistar rats were randomly distributed into three experimental groups (n = 7 per group): Sedentary Control (SC), Sedentary Hypertensive (SH), and Trained Hypertensive (TH). PAH was induced by a single intraperitoneal injection of monocrotaline (MCT; 60 mg/kg). Animals in the TH group underwent RT (vertical ladder; 15 climbs with 1-minute interval; 60% of the maximum load supported), 1 session/day, 5 days/week, for approximately 3 weeks. On the 24th day after injection, all animals were euthanized. Subsequently, the biceps brachii were removed, processed and destined for histological or biochemical analyses. RT increased the exercise tolerance (i.e., maximum load supported) in rats with PAH. In addition, RT prevented adverse remodeling in skeletal muscle by preserving the cross-sectional area of myocytes and attenuated total collagen deposition. Furthermore, RT reduced the gene expression of proteolytic agents (i.e., MuRF1, atrogin-1, and myostatin) and attenuated redox imbalance (i.e., CAT, NO, and CP). However, neither PAH nor RT influenced muscle hypertrophy pathways (i.e., Akt, phospo-Akt, eIF4E e phospo- eIF4E) in this model. The RT applied during the development of MCT-induced PAH protects against skeletal muscle atrophy, by mitigating adverse structural remodeling and atrophy through proteolysis modulation and attenuation of redox imbalance.

Keywords:  Atrophy; Exercise; Monocrotaline; Oxidative stress; Proteolysis

DOI:  https://doi.org/10.1007/s00424-025-03142-z
J Appl Physiol (1985). 2025 Dec 11.

Implications for myofibrillar protein translation due to high-intensity muscle contraction via a rapamycin-insensitive mechanism.

Taiga Mishima, Yuki Fujita, Tomoki Abe, Satoru Ato, Riki Ogasawara.

  Muscle protein metabolism is thought to regulate muscle mass. High-intensity muscle contraction (HiMC) increases muscle protein synthesis (MPS), resulting in muscle hypertrophy. Inhibiting the mechanistic target of rapamycin complex 1 (mTORC1) using rapamycin leads to partially inhibited mTORC1 activation, along with increased MPS, and muscle hypertrophy after HiMC. Therefore, we hypothesized that rapamycin-sensitive mTORC1 regulates myofibrillar protein translation, and the purpose of this study was to investigate this possibility. The right gastrocnemius muscle of male Sprague-Dawley rats was contracted isometrically via percutaneous electrical stimulation, and the left gastrocnemius muscle served as control. Vehicle or rapamycin were intraperitoneally injected 1 h before HiMC. Gastrocnemius muscles were collected at 6 h after a bout of HiMC and 48 h after chronic muscle contractions for 4 weeks (three HiMC per week). Rapamycin completely inhibited HiMC-induced activation of 70 kDa ribosomal protein S6 kinase, which is a rapamycin-sensitive mTORC1 substrate. However, rapamycin completely inhibited HiMC-induced the dissociation of eIF4E:4E-BP1 and the interaction of eIF4E:eIF4G, despite the HiMC-induced phosphorylation of 4E-BP1 (Thr37/46, Thr70, and Ser65) being unaffected by rapamycin. Importantly, HiMC-induced myofibrillar protein synthesis was not influenced by rapamycin. Changes in myosin and actin levels relative to muscle mass induced by chronic muscle contraction remained constant even under rapamycin administration. These results indicated that rapamycin-sensitive mTORC1 signaling is not fully responsible for contraction-induced increases in myofibrillar protein synthesis.

Keywords:  mechanistic target of rapamycin (mTOR); muscle contraction; myofibrillar protein; translation initiation

DOI:  https://doi.org/10.1152/japplphysiol.00179.2025
Proc Natl Acad Sci U S A. 2025 Dec 16. 122(50): e2522788122

MBNL loss of function in smooth muscle as a model for myotonic dystrophy associated gastrointestinal dysmotility.

Janel A M Peterson, Jesus A Frias, Andrew N Miller, Krishnakant G Soni, Yi Zhang, Zheng Xia, John W Day, Geoffrey A Preidis, Thomas A Cooper.

  Myotonic dystrophy type 1 (DM1) is the most common adult-onset muscular dystrophy and severely affects multiple organ systems, including the brain, heart, skeletal muscle, and gastrointestinal (GI) tract. Despite 80% of individuals with DM1 experiencing GI dysfunction that affects their daily life, the mechanisms of GI dysmotility in DM1 remain an understudied aspect of the disease. DM1 is caused by a CTG repeat expansion in the DMPK gene that, when expressed as an expanded CUG repeat RNA, sequesters and reduces the activity of the muscleblind-like (MBNL) RNA-binding protein family. We developed a mouse line with conditional, smooth muscle-specific knockout of Mbnl1 and Mbnl2 to model and investigate myogenic mechanisms contributing to GI dysmotility in DM1. Mice with Mbnl knockout exhibited delayed GI transit of small and large bowel in vivo and increased smooth muscle contractile tone of jejunum and colon segments ex vivo. Smooth muscle from the jejunum and colon showed no histopathology suggesting an intrinsic defect and contained increased phosphorylation of the 20 kDa myosin light chain (Mlc20), consistent with increased contraction. RNA sequencing of mouse and human DM1 GI samples enriched for smooth muscle revealed conserved misregulated alternative splicing of transcripts associated with the regulation of Mlc20 phosphorylation and smooth muscle contraction. These findings demonstrate that Mbnl knockout disrupts the regulation of contraction dynamics and causes GI smooth muscle hyperactivity, suggesting that therapeutics that reduce GI contractile activity may improve DM1 GI symptoms.

Keywords:  alternative splicing; gastrointestinal dysmotility; muscleblind-like; myotonic dystrophy; smooth muscle

DOI:  https://doi.org/10.1073/pnas.2522788122
J Appl Physiol (1985). 2025 Dec 09.

Five days of physical inactivity induced by dry immersion alter skeletal muscle metabolism and whole-body glucose tolerance in healthy men.

Benjamin Lair, Elisa Le Roux, Isabelle de Glisezinski, Dominique Larrouy, Isabelle Harant, Marie-Pierre Bareille, Loïc Treffel, Guillemette Gauquelin-Koch, Cédric Moro, Chantal Simon, Claire Laurens, Audrey Bergouignan.

  Even brief periods of physical inactivity can induce metabolic disruptions; however, the underlying cellular and molecular mechanisms initiating these alterations remain unclear. We investigated whole-body and skeletal muscle-specific metabolic responses to short-term inactivity induced by dry immersion (DI), a model of rapid physical deconditioning. Eighteen healthy men (age=33.6 [SD 5.5] years, BMI=23.3 [1.8] kg/m²) underwent five days of DI in a longitudinal within-subject design, with each participant serving as his own control. DI-induced inactivity reduced VO2max (-7.4%, P=0.003), fat mass (-2.6%, P=0.002), fat-free mass (DXA, -2.6%, P<0.001), and quadriceps cross-sectional area (MRI, -2.8%, P<0.001). Fat content increased in the liver (MRI, +21%, P<0.001), but not in the muscles (MRI, +0.1%, P=0.218). Urinary nitrogen excretion rose (+28%, P<0.001), indicating increased whole-body protein catabolism. Fasting insulin (+46%, P=0.009) and triglycerides (+14%, P=0.013), as well as postprandial incremental glucose (+49%, P=0.002) and insulin (+90%, P<0.001) concentrations following a carbohydrate-rich meal were increased. Fasting and postprandial total lipid and carbohydrate oxidation measured by indirect calorimetry and adjusted for body composition remained unchanged (P>0.05 for all). In differentiated myotubes isolated from vastus lateralis biopsies, insulin-stimulated Akt Thr308 phosphorylation (P=0.03), in vitro glycogen synthesis assessed from U-14C glucose (P<0.01), and the ability to suppress in vitro palmitate oxidation (1- 14Cpalmitate) following incremental glucose concentrations were impaired (P=0.02). The ability to increase palmitate oxidation when palmitate availability rises remained preserved. These results suggest that early intrinsic skeletal muscle cell changes may contribute to the onset of whole-body metabolic disorders induced by physical inactivity.

Keywords:  dry immersion; fat oxidation; insulin sensivity; physical inactivity; skeletal muscle; substrate oxidation

DOI:  https://doi.org/10.1152/japplphysiol.00481.2025
J Appl Physiol (1985). 2025 Dec 09.

Carbohydrate ingestion during prolonged exercise and net skeletal muscle glycogen utilization: A meta-analysis.

Jeffrey A Rothschild, Harrison Dudley-Rode, Harriet Carpenter, Abbie Smith, Daniel J Plews, Ed Maunder.

  Background: While some studies report attenuated net muscle glycogenolysis with carbohydrate ingestion, others show no effect, possibly due to small sample sizes or methodological differences. Objective: To determine whether carbohydrate ingestion during endurance exercise reduces net skeletal muscle glycogen use, and to identify potential moderating factors. Methods: A meta-analysis was conducted using data from 31 studies which included 48 unique effect sizes derived from crossover trials comparing carbohydrate vs. placebo ingestion during prolonged endurance exercise. Standardized mean differences (SMDs) in net muscle glycogen utilization were calculated. A multilevel random-effects model accounted for repeated estimates within studies. Subgroup and meta-regression analyses tested potential moderators. Sensitivity analyses were conducted using a range of plausible pre/post correlation values. Results: Carbohydrate ingestion was associated with a small but statistically significant muscle glycogen-sparing effect (SMD = -0.16, 95% CI: -0.30 to -0.02, p = 0.021). Subgroup and moderator analyses revealed no significant effects of exercise mode, carbohydrate type, ingestion rate, or pre-exercise glycogen on the observed effect. Translating the standardized effect into absolute units, carbohydrate ingestion was estimated to spare ~24 mmol kg-1 dry weight (95% CI: 4 to 45 mmol kg -1) of muscle glycogen, relative to placebo, during ~100 min of exercise. Conclusion: Carbohydrate ingestion during endurance exercise leads to a small but statistically significant reduction in net skeletal muscle glycogen utilization. Although no consistent moderating variables were identified, the direction of effect was consistent across studies, and the absolute magnitude of sparing may be physiologically meaningful during prolonged or repeated efforts.

Keywords:  Exercise; Glycogenolysis; Metabolism; Nutrition; Skeletal muscle

DOI:  https://doi.org/10.1152/japplphysiol.00861.2025
Biochim Biophys Acta Mol Cell Res. 2025 Dec 04. pii: S0167-4889(25)00198-3. [Epub ahead of print] 120093

Assessing the involvement of tumor-secreted factors in the inhibition of muscle differentiation.

Miranda van der Ende, Xiaolin Li, Mieke Poland, Fleur Jansen, Jocelijn Meijerink, Jaap Keijer, Renger F Witkamp, Sander Grefte, Klaske van Norren.

  Cancer cachexia is a multifactorial syndrome characterized by involuntary and pathological weight loss, predominantly caused by muscle wasting. While tumors can elicit detrimental effects on skeletal muscle function, the contribution of specific tumor-derived mediators remains elusive. To explore this, we investigated the impact of conditioned media (CM) from four cachexia-inducing tumor cell lines (KPC, 4662, LLC, and C26) on muscle differentiation using C2C12 cells. Creatine kinase (CK) activity was measured as an indicator of muscle wasting, and global gene expression changes in C2C12 cells were analyzed via RNA sequencing. Cytokine profiling of the CM identified 111 immune factors, and mimic combinations of the most abundant cytokines from KPC CM were tested for their effects on CK activity. Additionally, the involvement of tumor-derived PGE2 was assessed via CRISPR/Cas9-mediated knockout of the Ptgs2 gene in KPC cells. CM from all tumor cell lines significantly reduced CK activity in C2C12 cells, consistent with downregulation of CKm gene expression. Global gene expression profiles revealed upregulation of immune-related pathways in C2C12 cells exposed to KPC CM. However, mixtures of the 14 most abundant cytokines in CM had minimal effects on CK activity, and tumor-derived PGE2 showed no significant effect on CK activity or muscle cell differentiation. These findings suggest that the observed muscle-wasting effects of cachexia-inducing tumor cells cannot be replicated by the most abundant cytokines present in CM alone, highlighting the need for further research to identify the key tumor-derived factors responsible for cancer-induced muscle wasting.

Keywords:  C2C12 cells; Cancer cachexia; Creatine kinase; Cytokines; Muscle wasting; PGE2

DOI:  https://doi.org/10.1016/j.bbamcr.2025.120093
Nat Commun. 2025 Dec 10.

MCARE enhances SERCA1 activity in fast-twitch muscle to maintain calcium handling and muscle integrity.

Takashi Sasaki, Hayataka Takase, Michinori Koebis, Atsu Aiba, Yu Takahashi, Yoshio Yamauchi, Ryuichiro Sato.

The release of Ca2+ from the sarcoplasmic reticulum into the cytoplasm, followed by its reuptake by sarco/endoplasmic reticulum Ca2+ ATPase (SERCA), is critical for the muscle contraction-relaxation cycle. In this study, we identify a small transmembrane protein, predominantly expressed in fast-twitch muscles, which regulates SERCA1 activity. This protein, termed muscle-enriched Ca2+ regulator (MCARE), enhances SERCA1 function by competitively inhibiting myoregulin, a muscle-specific micropeptide that otherwise suppresses SERCA1 activity. By facilitating more efficient Ca2+ clearance from the cytoplasm, MCARE accelerates muscle relaxation. Mcare-deficient mice exhibit symptoms resembling muscular dystrophy, including progressive muscle wasting in fast-twitch muscles, reduced muscle strength, and increased susceptibility to exercise-induced muscle damage. Notably, these mice also present with distinctive rippling muscle contractions. Our findings establish MCARE as a key regulator of SERCA1 activity, essential for maintaining Ca2+ homeostasis and the functional integrity of fast-twitch muscle fibers.

DOI: https://doi.org/10.1038/s41467-025-67358-4
Pediatr Res. 2025 Dec 07.

Genetic and functional analysis of ZMIZ1 in neurodevelopmental disorder with dysmorphic facies and distal skeletal anomalies (NEDDFSA): insights from muscle cells and signaling pathways.

Shan Li, Dafei Zhou, Yuyang Han, Chao Feng, Xuemin Lv, Gang Fu, Xing Wei, Chengai Wu, Chaoji Yu, Zheng Yang.

BACKGROUND: Mutations in the ZMIZ1 gene have been implicated in neurodevelopmental disorder with dysmorphic facies and distal skeletal anomalies (NEDDFSA). However, the underlying cellular and physiological mechanisms remain poorly understood.
METHODS: Exome sequencing was performed to identify candidate variants. qPCR, Western blot, immunofluorescence, CCK-8, and wound-healing assays were employed to assess gene function in human skeletal muscle cells (HSkMCs). RNA-seq and co-immunoprecipitation coupled with mass spectrometry (Co-IP/MS) were used for transcriptomic and interactome profiling.
RESULTS: Here, we identified a novel de novo missense variant c.910G>C (p.A304P) in ZMIZ1 in a patient with NEDDFSA. The p.A304P variant significantly increased ZMIZ1 mRNA and protein expression levels and altered its subcellular localization. Functional assays demonstrated enhanced proliferation and migration in HSkMCs expressing the mutant ZMIZ1. qPCR validation revealed significant dysregulation of key genes in the TGF-β1 signaling pathway. Transcriptome analysis identified the cytokine-cytokine receptor interaction pathway as the most significantly enriched pathway. Additionally, we identified a novel interaction between ZMIZ1 and the transcription factor GTF2I.
CONCLUSION: Our study identifies a novel likely pathogenic variant in ZMIZ1 associated with NEDDFSA. These findings provide new insights into the cellular and physiological mechanisms underlying NEDDFSA, highlighting ZMIZ1's role as a regulatory hub in multiple signaling pathways.
IMPACT: Our study identifies a novel likely pathogenic variant in the ZMIZ1 gene associated with NEDDFSA, the second in China, and demonstrates its functional impact on cellular processes and signaling pathways, particularly in muscle cells. This finding expands the known ZMIZ1 mutation spectrum and provides the first functional evidence of its role in muscle cells, highlighting its potential as a regulatory hub in multiple pathways beyond the nervous system. These results offer new insights into the cellular mechanisms underlying NEDDFSA, especially in non-neurological tissues, and may facilitate the development of targeted therapies for related disorders.

DOI: https://doi.org/10.1038/s41390-025-04612-x
J Biol Chem. 2025 Dec 05. pii: S0021-9258(25)02858-3. [Epub ahead of print] 111006

A-to-I RNA editing impairs miR-376b-3p repression of RYBP in skeletal muscle satellite cells.

Xiaoli Xu, Chengqi Wei, Peijie Zeng, Siyuan Zhan, Dinghui Dai, Li Li, Hongping Zhang.

  Adenosine-to-inosine (A-to-I) RNA editing can affect microRNA (miRNA) activity, but its role in skeletal muscle development remains unclear. Here, we investigated miR-376b-3p in goat skeletal muscle satellite cells (MuSCs), which undergo ADAR1-mediated editing at the sixth nucleotide of its seed sequence. Although both isoforms were detected, the unedited miR-376b-3p (miR-WT) predominated over the edited form (miR-E) during skeletal muscle development and MuSC differentiation. Functional assays revealed that miR-WT, but not the miR-E type, enhanced MuSC proliferation and differentiation by upregulating Pax7, PCNA, MyoD, MyoG, and MyHC, and promoting myotube formation. Furthermore, we identified Ring1 and YY1 binding protein (RYBP), a repressor of myogenesis, as a direct target of miR-WT. Overexpression of RYBP inhibited MuSC differentiation, while miR-WT relieved this repression through direct binding to the RYBP 3'UTR. In contrast, miR-E failed to target RYBP and lacked pro-myogenic activity. These findings demonstrate that A-to-I editing attenuates the function of miR-376b-3p, highlighting its role as a post-transcriptional regulator of skeletal muscle development.

Keywords:  A-to-I editing; MuSCs; RYBP; differentiation; miR-376b-3p; proliferation

DOI:  https://doi.org/10.1016/j.jbc.2025.111006
FASEB J. 2025 Dec 15. 39(23): e71258

IGFBP2: A Factor That Negatively Regulates Muscle Development and Growth.

Zhipeng Liu, Yalong Su, Zhilin Liu, Jingxuan Li, Kaiping Deng, Zhen Zhang, Peiyong Chen, Shang Gao, Wurilege Wei, Wei Yi, Jianmin Zhu, Yixuan Fan, Yanli Zhang, Feng Wang.

  Livestock growth performance is pivotal to meat production and skeletal muscle development. Identifying key genetic variants associated with growth traits can facilitate the selection of superior breeding stock. However, the role of Insulin-like Growth Factor Binding Protein 2 (IGFBP2) in livestock muscle development remains controversial, particularly regarding its genetic regulation in goats. In this study, the whole-genome resequencing of Hainan Black goats (HNBGs) revealed a growth-associated insertion/insertion variant (P1-Del-8-bp) in IGFBP2 3' UTR. Notably, individuals with the DD genotype exhibited significantly impaired growth performance, lower GH levels, and higher IGFBP2 levels compared to other genotypes. Mechanistically, IGFBP2 knockdown significantly enhanced the proliferation and differentiation of goat primary myoblasts (GPMs) by targeting Transforming Growth Factor Beta 2 (TGFβ2). Additionally, reduced IGFBP2 promoted myogenic differentiation by stimulating mitochondrial biogenesis. These findings provide novel insights into the molecular mechanisms governing skeletal muscle development in goats and offer potential genetic targets for livestock molecular breeding strategies aimed at improving meat production efficiency.

Keywords:  Hainan Black Goat; IGFBP2; InDel; TGFβ2; growth; myoblast proliferation; myogenic differentiation

DOI:  https://doi.org/10.1096/fj.202501888RR
Gene. 2025 Dec 08. pii: S0378-1119(25)00736-X. [Epub ahead of print]979 149946

Comprehensive transcriptomic profiling reveals lncRNA-miRNA-mRNA regulatory networks in skeletal muscle aging of mice.

Jinrui Jia, Qingyan Wang, Xuanye Jiang, Hao Chen, Minwei Huang, Bing Ni, Huiying Zhang, Xin'e Shi, Jianjun Jin.

   PURPOSE: As organisms age, physiological and pathological changes occur, with altered lncRNA expression playing a key role. However, their regulatory mechanisms in aging remain unclear. This study investigates the differential expression of lncRNAs between aged and young mice, and explores the lncRNA-miRNA-mRNA interplay to gain insights into the molecular basis of aging.
METHODS: We performed whole-transcriptome sequencing on tibialis anterior muscles from four aged (20-month-old) and four young (3-month-old) mice. Hub genes were identified via PPI and WGCNA analyses, followed by functional enrichment. Integrative analysis revealed interactions among differentially expressed lncRNAs, miRNAs, and mRNAs, leading to the construction of cis-/trans-regulatory and ceRNA networks.
RESULTS: Our results revealed 746 significantly differentially expressed known lncRNAs (465 upregulated, 281 downregulated) and 27 novel lncRNAs in aged mouse TA muscle, alongside 50 miRNAs and 1124 mRNAs. Based on lncRNA classification (antisense, intergenic, intronic), we constructed subtype-specific cis- and trans-regulatory networks. Hub genes were identified via PPI and WGCNA analyses to further refine these networks. Highly expressed and variable genes were also integrated into regulatory mapping. Enrichment analyses indicated involvement in extracellular matrix remodeling, epithelial cell migration, and immune response.
CONCLUSIONS: This study systematically profiled age-related changes in lncRNAs, miRNAs, and mRNAs in TA muscle, and constructed core regulatory networks based on lncRNA subtypes. This study systematically profiled age-related transcriptomic changes in mouse skeletal muscle and constructed lncRNA-miRNA-mRNA regulatory networks associated with aging. These results provide a valuable resource and generate hypotheses for future experimental validation of lncRNA-mediated regulatory mechanisms in muscle aging.

Keywords:  Aging; ceRNA; lncRNA; mRNA; miRNA

DOI:  https://doi.org/10.1016/j.gene.2025.149946
J Sport Health Sci. 2025 Dec 04. pii: S2095-2546(25)00116-4. [Epub ahead of print] 101108

Exercise attenuates the hallmarks of aging: Novel perspectives.

Yan Qiu, Benjamin Fernández-García, H Immo Lehmann, Guoping Li, Guido Kroemer, Carlos López-Otín, Junjie Xiao.

  The number and proportion of individuals aged 60 years and older are steadily increasing. However, increased life expectancy is accompanied by a decline in functional capacity and a heightened risk of age-related diseases, ultimately leading to reduced quality of life. Interventions that support physiological function in later life and hence extend healthspan are therefore of considerable importance. Among these, regular physical exercise is strongly associated with numerous health benefits and is recognized as a key strategy for promoting healthy aging and extending healthspan. In this review, we highlight the impact of an active lifestyle, particularly regular physical activity, on the major hallmarks of aging. These include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, impaired macroautophagy, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, changes in the extracellular matrix, stem cell exhaustion, altered intercellular communication, chronic inflammation, dysbiosis, and psychosocial isolation. A deeper understanding of the mechanisms by which exercise confers these benefits will aid in enhancing both physical and mental health in the elderly and in mitigating the onset of aging-associated diseases.

Keywords:  Exercise; Hallmarks of aging; Healthspan; Healthy aging

DOI:  https://doi.org/10.1016/j.jshs.2025.101108
Ecotoxicol Environ Saf. 2025 Dec 05. pii: S0147-6513(25)01868-8. [Epub ahead of print]309 119523

Glucagon-like peptide-1 receptor (GLP-1R) agonists prevent tributyltin-induced muscle atrophy/wasting via restoring GLP-1R signaling in vitro and in mice.

Rong-Sen Yang, Yuan-Cheng Lin, Kuo-Cheng Lan, Ching-Chia Wang, Huei-Ping Tzeng, Ting-Yu Chang, Ding-Cheng Chan, Shing-Hwa Liu.

  Tributyltin (TBT), an endocrine disruptor, has been shown to exert pathological effects on skeletal muscle, though the underlying mechanisms remain incompletely understood. This study investigated the role of glucagon-like peptide-1 receptor (GLP-1R) in TBT-induced myopathy both in vitro and in vivo. GLP-1R agonists (GLP-1RAs), exendin-4 (Ex-4) and liraglutide (Lira), were tested in C2C12 myotubes (25-500 nM) exposed to TBT (0.25 μM) and in mice orally administered TBT (25 μg/kg/day) with Ex-4 (2.5 μg/kg/day) for 8 weeks. In myotubes, TBT reduced cell viability and diameter and increased apoptosis- and atrophy-related proteins, effects that were significantly mitigated by either Ex-4 or Lira. Both agents shifted myotube diameter distributions toward larger sizes, indicating attenuation of atrophy. TBT decreased GLP-1R protein expression, which was restored by Ex-4. In mice, reduced soleus muscle mass, cross-sectional area, and hindlimb grip strength, increased apoptotic and atrophy markers, and suppressed ERK and FoxO1 phosphorylation; these effects were reversed by Ex-4. GLP-1R expression in soleus muscle, downregulated by TBT, was restored with Ex-4. These findings demonstrate that GLP-1RAs protect against TBT-induced muscle wasting in vitro, with Ex-4 showing in vivo efficacy through restoration of GLP-1R expression and normalization of apoptosis- and atrophy-related signaling.

Keywords:  Exendin-4; Glucagon-like peptide-1 receptor agonist; Skeletal muscle wasting; Tributyltin

DOI:  https://doi.org/10.1016/j.ecoenv.2025.119523
Front Clin Diabetes Healthc. 2025 ;6 1720794

GLP-1 agonists and exercise: the future of lifestyle prioritization.

Roberto Codella, Pamela Senesi, Livio Luzi.

  Recent literature shows that GLP-1 receptor agonists are highly effective for weight loss and improving metabolic and cardiovascular health, often surpassing the results of lifestyle interventions alone, such as exercise and diet modification. However, long-term weight maintenance is more successful when exercise is included, as stopping GLP-1 therapy alone often leads to weight regain, while exercise helps preserve muscle mass and sustain weight loss. Combining GLP-1 receptor agonists with structured lifestyle changes, especially increased protein intake and strength training, can mitigate muscle loss and enhance overall outcomes. As a result, future obesity management is likely to prioritize integrated approaches that combine pharmacotherapy with lifestyle interventions, rather than replacing lifestyle changes with medication alone.

Keywords:  exercise-as-a-medicine; health; metabolism; training; type 2 diabetes

DOI:  https://doi.org/10.3389/fcdhc.2025.1720794
World J Clin Cases. 2025 Nov 26. 13(33): 110976

Muscle matters: Transforming the care of intensive care unit acquired sarcopenia and myosteatosis.

Sahil Kataria, Saketh Vinjamuri, Deven Juneja.

  Intensive care unit (ICU) acquired sarcopenia and myosteatosis are increasingly recognized complications of critical illness, characterized by a rapid loss of skeletal muscle mass, quality, and function. These conditions result from a complex interplay of systemic inflammation, immobilization, catabolic stress, mitochondrial dysfunction, and immune dysregulation, often culminating in impaired recovery, prolonged hospitalization, and increased long-term mortality. First identified in survivors of sepsis and prolonged mechanical ventilation, these muscle abnormalities were initially described using computed tomography-based assessments of muscle area and density. Subsequent advances in imaging, biomarker discovery, and functional testing have enabled earlier detection and risk stratification across diverse ICU populations. While nutritional optimization and early mobilization form the cornerstone of current prevention and treatment strategies, the emergence of novel approaches, including automated artificial intelligence-based screening, neuromuscular electrical stimulation, and targeted pharmacologic therapies, has broadened the clinical scope of interventions. Despite their significant prognostic implications, ICU-acquired sarcopenia and myosteatosis remain under-recognized in routine critical care practice. This mini-review aims to synthesize current knowledge regarding their pathophysiology, available diagnostic modalities, prognostic relevance, and the evolving landscape of therapeutic strategies for long-term functional recovery in critically ill patients.

Keywords:  Intensive care unit acquired sarcopenia; Intensive care unit acquired weakness; Muscle atrophy; Muscle weakness; Myosteatosis

DOI:  https://doi.org/10.12998/wjcc.v13.i33.110976