bims-moremu 2025-03-09 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2025–03–09
thirty-one papers selected by
Anna Vainshtein, Craft Science Inc.

A satellite cell-dependent epigenetic fingerprint in skeletal muscle identity genes after lifelong physical activity.
The role of oxidative stress-mediated fibro-adipogenic progenitor senescence in skeletal muscle regeneration and repair.
Single-nuclei sequencing of skeletal muscle reveals subsynaptic-specific transcripts involved in neuromuscular junction maintenance.
3D Mechanical Confinement Directs Muscle Stem Cell Fate and Function.
Dysregulated ATX-LPA and YAP/TAZ signaling in dystrophic Sgcd-/- mice with early fibrosis and inflammation.
Skeletal Muscle: A Critical Organ for Survival and Recovery in Critical Illness.
Male mouse skeletal muscle lacking HuR shows enhanced glucose disposal at a young age.
Elevated levels of S100A8 and S100A9 exacerbate muscle mitochondrial fragmentation in sepsis-induced muscle atrophy.
O-GlcNAcylation modification of MyoD regulates skeletal muscle fiber differentiation by antagonizing the UPF1 pathway.
Functions and Therapeutic Potentials of Long Noncoding RNA in Skeletal Muscle Atrophy and Dystrophy.
Immunomodulatory role of the stem cell circadian clock in muscle repair.
Cellular and molecular contractile function in aged human skeletal muscle is altered by phosphate and acidosis and partially reversed with an ATP analog.
Metabolic dysregulation contributes to the development of dysferlinopathy.
The role of AGEs in muscle ageing and sarcopenia.
Metformin ablates high fat diet-induced skeletal muscle hypertrophy and elevation of sarcolemmal GLUT4 when feeding is initiated in young adult male mice.
Development and characterization of an Sf-1-Flp mouse model.
Deubiquitinating Enzymes Regulate Skeletal Muscle Mitochondrial Quality Control and Insulin Sensitivity in Patients With Type 2 Diabetes.
Fiber Type-Specific Proteomic Alterations in R349P Desminopathy Mice.
Zinc Alleviates Diabetic Muscle Atrophy via Modulation of the SIRT1/FoxO1 Autophagy Pathway Through GPR39.
The effect of IL-1β inhibitor canakinumab (Ilaris®) on IL-6 production in human skeletal muscle cells.
Immunosenescence in skeletal muscle: The role-play in cancer cachexia chessboard.
OBSCN undergoes extensive alternative splicing during human cardiac and skeletal muscle development.
Periarticular myositis and muscle fibrosis are cytokine dependent complications of inflammatory arthritis.
Myostatin Knockout Mice Have Larger Muscle Fibers With Normal Function and Morphology.
Testosterone Modulation of Muscle Transcriptomic Profile During Lifestyle Therapy in Older Men with Obesity and Hypogonadism.
Sex differences in absolute and relative changes in muscle size following resistance training in healthy adults: a systematic review with Bayesian meta-analysis.
Specific muscle targeted delivery of miR-130a loaded lipid nanoparticles: a novel approach to inhibit lipid accumulation in skeletal muscle and obesity.
Application of CIBERSORTx and BayesPrism to deconvolution of bulk RNA-seq data from human myocardium and skeletal muscle.
New selective androgen receptor modulator TEI-SARM2 improves muscle function in a Duchenne muscular dystrophy rat model.
Enhanced expression of dystrophin, IGF-1, CD44 and MYH3 in plasma and skeletal muscles including diaphragm of mdx mice after oral administration of Neu REFIX beta 1,3-1,6 glucan.
The Roles of myomiRs in the Pathogenesis of Sarcopenia: From Literature to In Silico Analysis.

FASEB J. 2025 Mar 15. 39(5): e70435

A satellite cell-dependent epigenetic fingerprint in skeletal muscle identity genes after lifelong physical activity.

Kevin A Murach, Davis A Englund, Toby L Chambers, Cory M Dungan, Hunter L Porter, Jonathan D Wren, Willard M Freeman, Esther E Dupont-Versteegden, Yuan Wen.

  Satellite cells comprise a small proportion of mononuclear cells in adult skeletal muscle. Despite their relative rarity, satellite cells have critical functions in muscle adaptation, particularly during prolonged exercise training. The mechanisms by which satellite cells mediate skeletal muscle responsiveness to physical activity throughout the lifespan are still being defined, but epigenetic regulation may play a role. To explore this possibility, we analyzed global DNA methylation patterns in muscle tissue from female mice that engaged in lifelong voluntary unweighted wheel running with or without satellite cells. Satellite cells were ablated in adulthood using the tamoxifen-inducible Pax7-DTA model. Compared to sedentary mice, wheel running for 13 months caused muscle DNA methylation differences in the promoter regions of numerous muscle fiber-enriched genes-Cacgn1, Dnm2, Mlip, Myl1, Myom2, Mstn, Sgca, Sgcg, Tnnc1, Tnni2, Tpm1, and Ttn-only when satellite cells were present. These genes relate to muscle fiber identity, cytoarchitecture, and size as well as overall muscle function. Epigenetic alterations to such genes are consistent with previously observed histological and in vivo impairments to running adaptation after satellite cell depletion in these same mice. Musk promoter region methylation was affected only in the absence of satellite cells with lifelong running relative to sedentary; this dovetails with work showing that satellite cells influence skeletal muscle innervation. Defining the epigenetic effects of satellite cells on identity genes in muscle fibers after lifelong physical activity provides new directions for how these rare stem cells can promote muscle adaptation and function throughout the lifespan.

Keywords:  DNA methylation; methylome; stem cells; wheel running

DOI:  https://doi.org/10.1096/fj.202500177R
Stem Cell Res Ther. 2025 Mar 01. 16(1): 104

The role of oxidative stress-mediated fibro-adipogenic progenitor senescence in skeletal muscle regeneration and repair.

Yuqing Yao, Yusheng Luo, Xiaomei Liang, Li Zhong, Yannan Wang, Zhengchao Hong, Chao Song, Zeyu Xu, Jiancheng Wang, Miao Zhang.

   BACKGROUND: Stem cells play a pivotal role in tissue regeneration and repair. Skeletal muscle comprises two main stem cells: muscle stem cells (MuSCs) and fibro-adipogenic progenitors (FAPs). FAPs are essential for maintaining the regenerative milieu of muscle tissue and modulating the activation of muscle satellite cells. However, during acute skeletal muscle injury, the alterations and mechanisms of action of FAPs remain unclear.
METHODS: we employed the GEO database for bioinformatics analysis of skeletal muscle injury. A skeletal muscle injury model was established through cardiotoxin (CTX, 10µM, 50µL) injection into the tibialis anterior (TA) of C57BL/6 mice. Three days post-injury, we extracted the TA, isolated FAPs (CD31-CD45-PDGFRα+Sca-1+), and assessed the senescence phenotype through SA-β-Gal staining and Western blot. Additionally, we established a co-culture system to evaluate the capacity of FAPs to facilitate MuSCs differentiation. Finally, we alleviated the senescent of FAPs through in vitro (100 µM melatonin, 5 days) and in vivo (20 mg/kg/day melatonin, 15 days) administration experiments, confirming melatonin's pivotal role in the regeneration and repair processes of skeletal muscle.
RESULTS: In single-cell RNA sequencing analysis, we discovered the upregulation of senescence-related pathways in FAPs following injury. Immunofluorescence staining revealed the co-localization of FAPs and senescent markers in injured muscles. We established the CTX injury model and observed a reduction in the number of FAPs post-injury, accompanied by the manifestation of a senescent phenotype. Melatonin treatment was found to attenuate the injury-induced senescence of FAPs. Further co-culture experiments revealed that melatonin facilitated the restoration of FAPs' capacity to promote myoblast differentiation. Through GO and KEGG analysis, we found that the administration of melatonin led to the upregulation of AMPK pathway in FAPs, a pathway associated with antioxidant stress response. Finally, drug administration experiments corroborated that melatonin enhances skeletal muscle regeneration and repair by alleviating FAP senescence in vivo.
CONCLUSION: In this study, we first found FAPs underwent senescence and redox homeostasis imbalance after injury. Next, we utilized melatonin to enhance FAPs regenerative and repair capabilities by activating AMPK signaling pathway. Taken together, this work provides a novel theoretical foundation for treating skeletal muscle injury.

Keywords:  FAPs; Melatonin; Senescence; Skeletal muscle injury

DOI:  https://doi.org/10.1186/s13287-025-04242-4
Nat Commun. 2025 Mar 05. 16(1): 2220

Single-nuclei sequencing of skeletal muscle reveals subsynaptic-specific transcripts involved in neuromuscular junction maintenance.

Alexander S Ham, Shuo Lin, Alice Tse, Marco Thürkauf, Timothy J McGowan, Lena Jörin, Filippo Oliveri, Markus A Rüegg.

The neuromuscular junction (NMJ) is the synapse formed between motor neurons and skeletal muscle fibers. Its stability relies on the continued expression of genes in a subset of myonuclei, called NMJ myonuclei. Here, we use single-nuclei RNA-sequencing (snRNA-seq) to identify numerous NMJ-specific transcripts. To elucidate how the NMJ transcriptome is regulated, we also performed snRNA-seq on sciatic nerve transected, botulinum toxin injected, and Musk knockout muscles. The data show that NMJ gene expression is not only driven by agrin-Lrp4/MuSK signaling but is also affected by electrical activity and trophic factors other than agrin. By selecting the three NMJ genes Etv4, Lrtm1, and Pdzrn4, we further characterize novel contributors to NMJ stability and function. AAV-mediated overexpression shows that Etv4 is sufficient to upregulate the expression of -50% of the NMJ genes in non-synaptic myonuclei, while AAV-CRISPR/Cas9-mediated muscle-specific knockout of Pdzrn4 induces NMJ fragmentation. Further investigation of Pdzrn4 revealed that it localizes to the Golgi apparatus and interacts with MuSK protein. Collectively, our data provide a rich resource of NMJ transcripts, highlight the importance of ETS transcription factors at the NMJ, and suggest a novel pathway for NMJ post-translational modifications.

DOI: https://doi.org/10.1038/s41467-025-57487-1
Adv Biol (Weinh). 2025 Mar 04. e2400717

3D Mechanical Confinement Directs Muscle Stem Cell Fate and Function.

GaYoung Park, Josh A Grey, Foteini Mourkioti, Woojin M Han.

  Muscle stem cells (MuSCs) play a crucial role in skeletal muscle regeneration, residing in a niche that undergoes dimensional and mechanical changes throughout the regeneration process. This study investigates how 3D confinement and stiffness encountered by MuSCs during the later stages of regeneration regulate their function, including stemness, activation, proliferation, and differentiation. An asymmetric 3D hydrogel bilayer platform is engineered with tunable physical constraints to mimic the regenerating MuSC niche. These results demonstrate that increased 3D confinement maintains Pax7 expression, reduces MuSC activation and proliferation, inhibits differentiation, and is associated with smaller nuclear size and decreased H4K16ac levels, suggesting that mechanical confinement modulates both nuclear architecture and epigenetic regulation. MuSCs in unconfined 2D environments exhibit larger nuclei and higher H4K16ac expression compared to those in more confined 3D conditions, leading to progressive activation, expansion, and myogenic commitment. This study highlights the importance of 3D mechanical cues in MuSC fate regulation, with 3D confinement acting as a mechanical brake on myogenic commitment, offering novel insights into the mechano-epigenetic mechanisms that govern MuSC behavior during muscle regeneration.

Keywords:  3D confinement; hydrogels; mechanobiology; mechano‐epigenetics; muscle stem cells; skeletal muscle

DOI:  https://doi.org/10.1002/adbi.202400717
Skelet Muscle. 2025 Mar 06. 15(1): 6

Dysregulated ATX-LPA and YAP/TAZ signaling in dystrophic Sgcd-/- mice with early fibrosis and inflammation.

Cristian Gutiérrez-Rojas, Adriana Córdova-Casanova, Jennifer Faundez-Contreras, Meilyn Cruz-Soca, Felipe S Gallardo, Alexia Bock-Pereda, Juan Carlos Casar, Elisabeth R Barton, Enrique Brandan.

   BACKGROUND: Sarcoglycanopathies are muscle dystrophies caused by mutations in the genes encoding sarcoglycans (α, β, γ, and δ) that can destabilize the dystrophin-associated glycoprotein complex at the sarcolemma, leaving muscle fibers vulnerable to damage after contraction, followed by inflammatory and fibrotic responses and resulting in muscle weakness and atrophy. Two signaling pathways have been implicated in fibrosis and inflammation in various tissues: autotaxin/lysophosphatidic acid (ATX-LPA) and yes-associated protein 1/transcriptional co-activator with PDZ-binding motif (YAP/TAZ). LPA, synthesized by ATX, can act as a pleiotropic molecule due to its multiple receptors. Two Hippo pathway effectors, YAP/TAZ, can be dephosphorylated by LPA and translocated to the nucleus. They induce several target genes, such as CCN2/CTGF, involved in fibrosis and inflammation. However, no detailed characterization of these processes or whether these pathways change early in the development of sarcoglycanopathy has been evaluated in skeletal muscle.
METHODS: Using the δ-sarcoglycan knockout mouse model (Sgcd-/-), we investigated components of these pathways, inflammatory and fibrotic markers, and contractile properties of different skeletal muscles (triceps-TR, gastrocnemius-GST, diaphragm-DFG, tibialis anterior-TA, and extensor digitorum longus-EDL) at one and two months of age.
RESULTS: We found that Sgcd-/- mice show early dystrophic features (fiber damage/necrosis, centrally nucleated fibers, inflammatory infiltrate, and regenerated fibers) followed by later fiber size reduction in TR, GST, and DFG. These changes are concomitant with an early inflammatory and fibrotic response in these muscles. Sgcd-/- mice also have early impaired force generation in the TA and EDL, and resistance to mechanical damage in the EDL. In addition, an early dysregulation of the ATX-LPA axis and the YAP/TAZ signaling pathway in the TR, GST, and DFG was observed in these mice.
CONCLUSIONS: The ATX-LPA axis and the YAP/TAZ signaling pathway, which are involved in inflammation and fibrosis, are dysregulated in skeletal muscle from an early age in Sgcd-/- mice. These changes are concomitant with a fibrotic and inflammatory response in these mice. Unraveling the role of the LPA axis and YAP/TAZ in sarcoglycanopathy holds great promise for improving our understanding of disease pathogenesis and identifying novel therapeutic targets for this currently incurable group of muscle disorders.

Keywords:  Autotaxin; Fibrosis; Inflammation; Lysophosphatidic acid; Muscle mechanics; Muscle regeneration; YAP/TAZ; δ Sarcoglycanopathy

DOI:  https://doi.org/10.1186/s13395-025-00375-5
Crit Care Clin. 2025 Apr;pii: S0749-0704(24)00084-8. [Epub ahead of print]41(2): 299-312

Skeletal Muscle: A Critical Organ for Survival and Recovery in Critical Illness.

Matthew J Lees, Carla M Prado, Paul E Wischmeyer, Stuart M Phillips.

  The intensive care unit (ICU) environment is one of the most challenging for skeletal muscle health. Atrophy associated with clinical care is distinct from that seen with inactivity or immobilization in the absence of disease and is exacerbated by aging. The substantial muscle loss in the ICU is likely due to the presence of inflammation, elevated proteolysis, bedrest, and undernutrition. Skeletal muscle parameters at admission are predictive of mortality and other clinically important outcomes. Treatment goals to mitigate muscle loss are early mobilization and adequate nutrient supply, especially protein, using an individualized approach to support skeletal muscle maintenance and recovery.

Keywords:  Amino acids; Atrophy; Bed rest; Immobilization; Intensive care unit; Skeletal muscle

DOI:  https://doi.org/10.1016/j.ccc.2024.08.011
Front Physiol. 2024 ;15 1468369

Male mouse skeletal muscle lacking HuR shows enhanced glucose disposal at a young age.

Robert C Noland, Sujoy Ghosh, Carlos J Crisanto, Antonio Aleman, McKenna K Chaney, Maitri K Chauhan, Layla G Loftis, Ally C Goad, Christin F Rickman, Samuel E Velasquez, Jaycob D Warfel.

   Introduction: Metabolic flexibility is the ability of a system to switch between metabolic substrates. Human and murine skeletal muscle tissues and cells with decreased activity of the regulatory RNA-binding protein, human antigen R (HuR), have decreased capacity for fat oxidation, and thus decreased metabolic flexibility. In this study, we aimed to assess the preference for carbohydrates in mice lacking HuR in skeletal muscle.
Methods: Experiments were performed on weight-matched control and HuR knockout mice of both sexes. Palmitate and pyruvate oxidation were performed in mouse muscle following the release of 14CO2. In vivo glucose and lipid uptake were assayed in mouse tissue following nonmetabolizable 3H-2-deoxyglucose or 14C-bromopalmitate injection. Transcriptomic analyses were performed in the skeletal muscle of all mice, followed by qPCR validation of select genes. Serum lactate and glucose levels were measured in mice via tail nick, and the muscle glycogen level was measured through colorimetric assay. Indirect calorimetry was used to measure respiratory exchange ratios.
Results: Male muscle-specific HuR knockout mice showed increased glucose uptake relative to controls, specifically in skeletal muscle, and have increased muscle glycogen content. These mice also displayed greater respiratory exchange ratios than controls. None of these differences were noted in females. Transcriptomics showed far more differences between male and female mice than between control and HuR knockout mice. However, differential gene expression between male and female mice was diminished by 50% following the removal of HuR. Male HuR knockout mouse skeletal muscle had increased glycolytic gene expression relative to controls but showed no difference relative to females of the same genotype. Both palmitate and pyruvate oxidation were decreased in the skeletal muscle of male HuR knockout mice relative to controls, and serum lactate levels were increased. No notable differences were seen in females between genotypes.
Discussion: The increase in the markers of glucose utilization with decreased HuR activity in male mice may indicate a switch toward glycolysis as compensation for decreased fat oxidation. These results continue to highlight a sex dependence on HuR as a driver of fat oxidation in mouse skeletal muscle while also indicating that muscle itself shows greater ambiguity between males and females following the removal of HuR.

Keywords:  RNA-binding proteins; carbohydrate oxidation; fat oxidation; human antigen R; metabolic flexibility

DOI:  https://doi.org/10.3389/fphys.2024.1468369
Commun Biol. 2025 Feb 28. 8(1): 338

Elevated levels of S100A8 and S100A9 exacerbate muscle mitochondrial fragmentation in sepsis-induced muscle atrophy.

Dongqin Huang, Yang Li, Yuqian Guo, Mengcao Weng, Hui Ye, Yan Zhang, Fei Lin, Kai Zhang, Xiangming Fang.

Sepsis-induced skeletal muscle atrophy is common in septic patients with the increases risk of mortality and is associated with myocellular mitochondrial dysfunction. Nevertheless, the specific mechanism of sepsis muscle atrophy remains unclear. Here we conducted a clinical retrospective analysis and observed the elevation of skeletal muscle index (ΔSMI) was an independent risk factor for 60-day mortality in septic patients. Moreover, in mouse model of sepsis, the skeletal muscle atrophy was also observed, which was associated with the upregulation of S100a8/a9-mediated mitochondrial dysfunction. Inhibition of S100a8/a9 significantly improved mitochondrial function and alleviated muscle atrophy. Conversely, administration of recombinant S100a8/a9 protein exacerbated mitochondrial energy exhaustion and myocyte atrophy. Mechanistically, S100a8/a9 binding to RAGE induced Drp1 phosphorylation and mitochondrial fragmentation, resulting in muscle atrophy. Additionally, RAGE ablation or administration of Drp1 inhibitor significantly reduced Drp1-mediated mitochondrial fission, improved mitochondrial morphology and function. Our findings indicated the pivotal role of S100a8/a9 in driving the mitochondrial fragmentation in septic muscle atrophy. Targeting S100a8/a9-RAGE-initiated mitochondrial fission might offer a promising therapeutic intervention against septic muscle atrophy.

DOI: https://doi.org/10.1038/s42003-025-07654-3
J Biol Chem. 2025 Feb 27. pii: S0021-9258(25)00213-3. [Epub ahead of print] 108364

O-GlcNAcylation modification of MyoD regulates skeletal muscle fiber differentiation by antagonizing the UPF1 pathway.

Lele Kou, Meng Zhang, Xiaoshuang Li, Ziyang Zhang, Wenjin Guo, Boxi Zhang, Peisong Yang, Yuxin Xia, Huijie Wang, Bin Xu, Shize Li.

  Skeletal muscle is an essential tissue for maintaining the body's basic functions. The basic structural unit of skeletal muscle is the muscle fiber, and its type is the main factor that determines the athletic ability of animals. The O-linked N-acetylglucosamine (O-GlcNAc) modification, a reversible protein post-translational modification, is involved in many important biological processes such as gene transcription, signal transduction, cell growth, and differentiation. Myogenic differentiation factor (MyoD), the first discovered myogenic regulatory factor, facilitates the transformation of fibroblasts into skeletal muscle cells. In early laboratory studies, MyoD was found to be modified by O-GlcNAcylation. However, the regulatory effects and mechanisms of O-GlcNAcylation modification on MyoD in skeletal muscle development and differentiation remain unclear.Therefore, our research was aimed at exploring the mechanism of MyoD in skeletal muscle differentiation under the influence of O-GlcNAcylation modification, through O-linked N-acetyl glucosamine transferase (OGT) or O-N-acetylaminoglucosidase (OGA) manipulation, as well as MyoD supplementation. During the differentiation of C2C12 cells, O-GlcNAcylation of MyoD was found to be mediated by OGT, through its interaction with MyoD. Additionally, OGT was found to antagonize with UPF1 in inhibiting the ubiquitination-mediated degradation of MyoD via the K48 site, thereby regulating myotube formation. In mouse skeletal muscle tissue, Ogt gene deletion led to the differentiation of mouse skeletal muscle fibers from fast-twitch muscle fibers to slow-twitch muscle fibers, whereas this effect was mitigated by supplementation with exogenous MyoD. These results enhance understanding of the regulatory mechanisms of O-GlcNAcylation modification of MyoD in muscle development and differentiation. Our findings also indicate potential therapeutic targets for muscle and metabolism-related diseases.

Keywords:  Muscle fiber differentiation; MyoD; O-GlcNAcylation modification; Skeletal muscle

DOI:  https://doi.org/10.1016/j.jbc.2025.108364
J Cachexia Sarcopenia Muscle. 2025 Apr;16(2): e13747

Functions and Therapeutic Potentials of Long Noncoding RNA in Skeletal Muscle Atrophy and Dystrophy.

Yidi Zhang, Teng Wang, Ziang Wang, Xin'e Shi, Jianjun Jin.

  Skeletal muscle is the most abundant tissue in the human body and is responsible for movement, metabolism, energy production and longevity. Muscle atrophy is a frequent complication of several diseases and occurs when protein degradation exceeds protein synthesis. Genetics, ageing, nerve injury, weightlessness, cancer, chronic diseases, the accumulation of metabolic byproducts and other stimuli can lead to muscle atrophy. Muscular dystrophy is a neuromuscular disorder, part of which is caused by the deficiency of dystrophin protein and is mostly related to genetics. Muscle atrophy and muscular dystrophy are accompanied by dynamic changes in transcriptomic, translational and epigenetic regulation. Multiple signalling pathways, such as the transforming growth factor-β (TGF-β) signalling pathway, the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) pathway, inflammatory signalling pathways, neuromechanical signalling pathways, endoplasmic reticulum stress and glucocorticoids signalling pathways, regulate muscle atrophy. A large number of long noncoding RNAs (lncRNAs) have been found to be abnormally expressed in atrophic muscles and dystrophic muscles and regulate the balance of muscle protein synthesis and degradation or dystrophin protein expression. These lncRNAs may serve as potential targets for treating muscle atrophy and muscular dystrophy. In this review, we summarized the known lncRNAs related to muscular dystrophy and muscle atrophy induced by denervation, ageing, weightlessness, cachexia and abnormal myogenesis, along with their molecular mechanisms. Finally, we explored the potential of using these lncRNAs as therapeutic targets for muscle atrophy and muscular dystrophy, including the methods of discovery and clinical application prospects for functional lncRNAs.

Keywords:  long noncoding RNAs; muscle atrophy; muscular dystrophy; protein synthesis and degradation; therapeutic implications

DOI:  https://doi.org/10.1002/jcsm.13747
Sci Adv. 2025 Mar 07. 11(10): eadq8538

Immunomodulatory role of the stem cell circadian clock in muscle repair.

Pei Zhu, Eric M Pfrender, Adam W T Steffeck, Colleen R Reczek, Yalu Zhou, Abhishek Vijay Thakkar, Neha R Gupta, Ariana Kupai, Amber Willbanks, Richard L Lieber, Ishan Roy, Navdeep S Chandel, Clara B Peek.

Circadian rhythms orchestrate physiological processes such as metabolism, immune function, and tissue regeneration, aligning them with the optimal time of day (TOD). This study identifies an interplay between the circadian clock within muscle stem cells (SCs) and their capacity to modulate the immune microenvironment during muscle regeneration. We reveal that the SC clock triggers TOD-dependent inflammatory gene transcription after injury, particularly genes related to neutrophil activity and chemotaxis. These responses are driven by cytosolic regeneration of the signaling metabolite nicotinamide adenine dinucleotide (oxidized form) (NAD+), as enhancing cytosolic NAD+ regeneration in SCs is sufficient to induce inflammatory responses that influence muscle regeneration. Mononuclear single-cell sequencing of the regenerating muscle niche further implicates the cytokine CCL2 in mediating SC-neutrophil cross-talk in a TOD-dependent manner. Our findings highlight the intersection between SC metabolic shifts and immune responses within the muscle microenvironment, dictated by circadian rhythms, and underscore the potential for targeting circadian and metabolic pathways to enhance tissue regeneration.

DOI: https://doi.org/10.1126/sciadv.adq8538
Am J Physiol Cell Physiol. 2025 Mar 06.

Cellular and molecular contractile function in aged human skeletal muscle is altered by phosphate and acidosis and partially reversed with an ATP analog.

Aurora D Foster, Chad R Straight, Philip C Woods, Christopher Lee, Jane A Kent, Stuart R Chipkin, Edward P Debold, Mark S Miller.

  Skeletal muscle fatigue occurs, in part, from accumulation of hydrogen (H+) and phosphate (Pi); however, the molecular basis through which these ions inhibit function is not fully understood. Therefore, we examined the effects of these metabolites on myosin-actin cross-bridge kinetics and mechanical properties in skeletal muscle fibers from older (65-75 years) adults. Slow-contracting myosin heavy chain (MHC) I and fast-contracting MHC IIA fibers were examined under control (5 mM Pi, pH 7.0) and fatigue (30 mM Pi, pH 6.2) conditions at maximal calcium-activation (5 mM ATP) and rigor (0 mM ATP). In MHC I and IIA fibers, fatigue decreased force per fiber size (23-37%), which was accompanied by reduced strongly bound myosin head characteristics (number and/or stiffness; 21-47%) and slower cross-bridge kinetics (longer myosin attachment times (22-46%) and reduced rates of force production (20-33%)) compared with control. MHC I myofilaments became stiffer with fatigue, a potential mechanism to increase force production. In rigor, which causes the myosin that can bind actin to be strongly bound, fatigue decreased force per fiber size (32-33%) in MHC I and IIA fibers, indicating less force was generated per cross-bridge. By replacing ATP with 2-deoxy-ATP (dATP), the fatigue-induced slowing of cross-bridge kinetics in MHC I and IIA fibers was reversed and reduced force production in MHC I fibers was partially improved, revealing potential mechanisms to help mitigate fatigue in older adults. Overall, our results identify novel fiber type-specific changes in cross-bridge kinetics, force per cross-bridge, and myofilament stiffness that help explain fatigue in older adults.

Keywords:  aging; dATP; fatigue; fiber; myosin heavy chain

DOI:  https://doi.org/10.1152/ajpcell.00332.2024
Life Sci Alliance. 2025 May;pii: e202402991. [Epub ahead of print]8(5):

Metabolic dysregulation contributes to the development of dysferlinopathy.

Regula Furrer, Sedat Dilbaz, Stefan A Steurer, Gesa Santos, Bettina Karrer-Cardel, Danilo Ritz, Michael Sinnreich, Christoph Handschin.

Dysferlin is a transmembrane protein that plays a prominent role in membrane repair of damaged muscle fibers. Accordingly, mutations in the dysferlin gene cause progressive muscular dystrophies, collectively referred to as dysferlinopathies for which no effective treatment exists. Unexpectedly, experimental approaches that successfully restore membrane repair fail to prevent a dystrophic phenotype, suggesting that additional, hitherto unknown dysferlin-dependent functions contribute to the development of the pathology. Our experiments revealed an altered metabolic phenotype in dysferlin-deficient muscles, characterized by (1) mitochondrial abnormalities and elevated death signaling and (2) increased glucose uptake, reduced glycolytic protein levels, and pronounced glycogen accumulation. Strikingly, elevating mitochondrial volume density and muscle glycogen accelerates disease progression; whereas, improvement of mitochondrial function and recruitment of muscle glycogen with exercise ameliorated functional parameters in a mouse model of dysferlinopathy. Collectively, our results not only shed light on a metabolic function of dysferlin but also imply new therapeutic avenues aimed at promoting mitochondrial function and normalizing muscle glycogen to ameliorate dysferlinopathies, complementing efforts that target membrane repair.

DOI: https://doi.org/10.26508/lsa.202402991
Bone Joint Res. 2025 Mar 04. 14(3): 185-198

The role of AGEs in muscle ageing and sarcopenia.

Zhaojing Guo, Hengzhen Li, Shide Jiang, Masoud Rahmati, Jingyue Su, Shengwu Yang, Yuxiang Wu, Yusheng Li, Zhenhan Deng.

Sarcopenia is an ageing-related disease featured by the loss of skeletal muscle quality and function. Advanced glycation end-products (AGEs) are a complex set of modified proteins or lipids by non-enzymatic glycosylation and oxidation. The formation of AGEs is irreversible, and they accumulate in tissues with increasing age. Currently, AGEs, as a biomarker of ageing, are viewed as a risk factor for sarcopenia. AGE accumulation could cause harmful effects in the human body such as elevated inflammation levels, enhanced oxidative stress, and targeted glycosylation of proteins inside and outside the cells. Several studies have illustrated the pathogenic role of AGEs in sarcopenia, which includes promoting skeletal muscle atrophy, impairing muscle regeneration, disrupting the normal structure of skeletal muscle extracellular matrix, and contributing to neuromuscular junction lesion and vascular disorders. This article reviews studies focused on the pathogenic role of AGEs in sarcopenia and the potential mechanisms of the detrimental effects, aiming to provide new insights into the pathogenesis of sarcopenia and develop novel methods for the prevention and therapy of sarcopenia.

DOI: https://doi.org/10.1302/2046-3758.143.BJR-2024-0252.R1
Connect Tissue Res. 2025 Mar 07. 1-15

Metformin ablates high fat diet-induced skeletal muscle hypertrophy and elevation of sarcolemmal GLUT4 when feeding is initiated in young adult male mice.

John M Lawler, Khaled Y Kamal, Rachel E Botchlett, Shih Lung Woo, Honggui Li, Jeff M Hord, James D Fluckey, Chaodong Wu.

  A high-fat diet (HFD) and metabolic disease can impair insulin signaling in skeletal muscle, including a reduction in IRS-1 and GLUT-4 at the cell membrane. Other sarcolemmal proteins (e.g. caveolin-3, nNOS) within the dystrophin-glycoprotein complex (DGC) are partially lost with Type II diabetes. Thus, we hypothesized that a HFD would cause a significant loss of sarcolemmal DGC proteins and GLUT4, and the anti-diabetic drug metformin would mitigate the disruption of the DGC and preserve sarcolemmal GLUT4 on the soleus muscle. Eight-week-old mice were fed a high-fat diet for 12 weeks. After 8 weeks, one-half of the HFD mice received metformin for the remaining 4 weeks. HFD caused a marked increase in soleus muscle mass and fiber cross-sectional area and elevated sarcolemmal GLUT4, even though systemic insulin resistance was greater. HFD-induced muscle hypertrophy and elevated membrane GLUT4 were unexpectedly attenuated by metformin. In addition, IRS-1 positive staining was not reduced by HFD but rather enhanced in the metformin mice fed a high-fat diet. Sarcolemmal staining of dystrophin and caveolin-3 was reduced by HFD but not in the metformin group, while nNOS intensity was unaffected by HFD and metformin. These findings suggest that skeletal muscles in young adult mice can compensate for a high-fat diet and insulin resistance, with a minor disruption of the DGC, by maintaining cell membrane nNOS and IRS-1 and elevating GLUT4. We postulate that a window of compensatory GLUT4 and nNOS signaling allows calorically dense food to enhance skeletal muscle fiber size when introduced in adolescence.

Keywords:  GLUT4; High‑fat diet; insulin resistance; metformin; nNOS

DOI:  https://doi.org/10.1080/03008207.2025.2471853
JCI Insight. 2025 Mar 04. pii: e190105. [Epub ahead of print]

Development and characterization of an Sf-1-Flp mouse model.

Marco Galvan, Mina Fujitani, Samuel R Heaselgrave, Shreya Thomas, Bandy Chen, Jenny J Lee, Steven C Wyler, Joel K Elmquist, Teppei Fujikawa.

  The use of genetically engineered tools, including combinations of Cre-LoxP and Flp-FRT systems, enable the interrogation of complex biology. Steroidogenic factor-1 (SF-1) is expressed in the ventromedial hypothalamic nucleus (VMH). Development of genetic tools, such as mice expressing Flp recombinase (Flp) in SF-1 neurons (Sf-1-Flp), will be useful for future studies that unravel the complex physiology regulated by the VMH. Here, we developed and characterized Sf-1-Flp mice and demonstrated its utility. Flp sequence was inserted into Sf-1 locus with P2A. This insertion did not affect Sf-1 mRNA expression levels and Sf-1-Flp mice do not have any visible phenotypes. They are fertile and metabolically comparable to wild-type littermate mice. Optogenetic stimulation using adeno-associated virus (AAV)-bearing Flp-dependent channelrhodopsin-2 (ChR2) increased blood glucose and skeletal muscle PGC-1α in Sf-1-Flp mice. This was similar to SF-1 neuronal activation using Sf-1-BAC-Cre and AAV-bearing Cre-dependent ChR2. Finally, we generated Sf-1-Flp mice that lack β2-adrenergic receptors (Adrβ2) only in skeletal muscle with a combination of Cre/LoxP technology (Sf-1-Flp::SKM∆Adrβ2). Optogenetic stimulation of SF-1 neurons failed to increase skeletal muscle PGC-1α in Sf-1-Flp::SKM∆Adrβ2 mice, suggesting that Adrβ2 in skeletal muscle is required for augmented skeletal muscle PGC-1α by SF-1 neuronal activation. Our data demonstrate that Sf-1-Flp mice are useful for interrogating complex physiology.

Keywords:  Diabetes; Glucose metabolism; Metabolism; Neuroscience

DOI:  https://doi.org/10.1172/jci.insight.190105
J Cachexia Sarcopenia Muscle. 2025 Apr;16(2): e13763

Deubiquitinating Enzymes Regulate Skeletal Muscle Mitochondrial Quality Control and Insulin Sensitivity in Patients With Type 2 Diabetes.

Wagner S Dantas, Elizabeth C Heintz, Elizabeth R M Zunica, Jacob T Mey, Melissa L Erickson, Kathryn P Belmont, Analisa L Taylor, Gangarao Davuluri, Hisashi Fujioka, Ciarán E Fealy, Charles L Hoppel, Christopher L Axelrod, John P Kirwan.

   BACKGROUND: Activation of mitochondrial fission and quality control occur early in the onset of insulin resistance in human skeletal muscle. We hypothesized that differences in mitochondrial dynamics, structure and bioenergetics in humans would explain the onset and progression of type 2 diabetes (T2D).
METHODS: Fifty-eight sedentary adults (37 ± 12 years) were enrolled into one of three groups: (1) healthy weight (HW), (2) overweight and obesity (Ow/Ob), or (3) T2D. Body composition, aerobic capacity, and insulin sensitivity were assessed during a 3-day inpatient stay. A fasted skeletal muscle biopsy was obtained to assess mitochondrial functions. C2C12 myoblasts were transfected with FLAG-HA-USP15 and FLAG-HA-USP30 and harvested to assess mitochondrial dynamics and cellular insulin action.
RESULTS: Insulin sensitivity and aerobic capacity were lower in Ow/Ob (132% and 28%, respectively) and T2D (1024% and 83%, respectively) relative to HW. Patients with T2D presented with elevated skeletal muscle mitochondrial fission (3.2 fold relative to HW and Ow/Ob), decreased fusion, and impairments in quality control. Mitochondrial content was lower in Ow/Ob (26%) and T2D (56%). USP13 (84%), USP15 (96%) and USP30 (53%) expression were increased with decreased Parkin and Ub activation in T2D alone. USP15 (R2 = 0.55, p < 0.0001) and USP30 (R2 = 0.40, p < 0.0001) expression negatively correlated with peripheral insulin sensitivity. USP15 and USP30 overexpression activated DRP1 (3.6 and 3.7 fold, respectively) while inhibiting AKT (96% and 81%, respectively) and AS160 (2.1 and 3.5 fold, respectively) phosphorylation.
CONCLUSION: Mitochondrial fragmentation bypasses defects in mitophagy to sustain skeletal muscle quality control in patients with T2D.

Keywords:  bioenergetics; fission; fusion; mitochondria; obesity; quality control; type 2 diabetes

DOI:  https://doi.org/10.1002/jcsm.13763
Muscle Nerve. 2025 Mar 03.

Fiber Type-Specific Proteomic Alterations in R349P Desminopathy Mice.

Britta Eggers, Karin Schork, Michael Turewicz, Katalin Barkovits, Martin Eisenacher, Rolf Schröder, Christoph Stephan Clemen, Katrin Marcus.

   INTRODUCTION/AIMS: Desminopathies are a group of rare human myopathies and cardiomyopathies caused by pathogenic variants of the desmin gene. Here, we analyzed the effects of the R349P mutant desmin on the proteomic profiles of individual fiber types of murine skeletal muscle.
METHODS: Soleus and tibialis anterior muscles from hetero- and homozygous R349P desmin knock-in mice and wild-type siblings were used to collect fiber type-specific material by laser microdissection to determine their proteomic profiles.
RESULTS: Aberrant proteomic profiles were observed in all four fiber types of homozygous mice. Type I and IIa fibers from homozygous muscle showed an increased abundance of 15 fibrotic proteins, for example, collagens I, IV, and VI, and associated proteins. Filamin-C, xin actin-binding repeat-containing proteins 1 and 2, and Kelch-like protein 41 were more abundant in homozygous fibers. A high number of proteins associated with the mitochondrial complexes had markedly lower amounts in all types of homozygous and type IIb heterozygous fibers, whereby 20 proteins of complex I, 6 proteins of complex III, 7 proteins of complex IV, and 4 proteins of complex V were found to be decreased in homozygous mice in at least one fiber type. This reduction included all mtDNA-encoded proteins of complexes I and V, as well as ADP/ATP translocase 1 and 2.
DISCUSSION: Our proteomic findings highlight a more severe myodegenerative process in fibers derived from homozygous R349P desmin knock-in mice. R349P desmin altered the abundance of proteins of the sarcomeric and extrasarcomeric cytoskeleton, extracellular matrix, and mitochondrial energy metabolism.

Keywords:  desminopathy; fiber types; laser microdissection; proteomics; skeletal muscle

DOI:  https://doi.org/10.1002/mus.28379
J Cachexia Sarcopenia Muscle. 2025 Apr;16(2): e13771

Zinc Alleviates Diabetic Muscle Atrophy via Modulation of the SIRT1/FoxO1 Autophagy Pathway Through GPR39.

Xing Yu, Xiaojun Chen, Weibin Wu, Huibin Tang, Yunyun Su, Guili Lian, Yujie Zhang, Liangdi Xie.

   BACKGROUND: Muscle atrophy is a severe complication of diabetes, with autophagy playing a critical role in its progression. Zinc has been shown to alleviate hyperglycaemia and several diabetes-related complications, but its direct role in mediating diabetic muscle atrophy remains unclear. This study explores the potential role of zinc in the pathogenesis of diabetic muscle atrophy.
METHODS: In vivo, C57BL/6J mice were induced with diabetes by streptozotocin (STZ) and treated with ZnSO₄ (25 mg/kg/day) for six weeks. Gastrocnemius muscles were collected for histological analysis, including transmission electron microscopy (TEM). Serum zinc levels were measured by ICP-MS. Protein expression was evaluated using immunofluorescence (IF), immunohistochemistry (IHC) and Western blotting (WB). Bioinformatics analysis was used to identify key genes associated with muscle atrophy. In vitro, a high-glucose-induced diabetic C2C12 cell model was established and received ZnSO₄, rapamycin, SRT1720, TC-G-1008, or GPR39-CRISPR Cas9 intervention. Autophagy was observed by TEM, and protein expression was assessed by IF and WB. Intracellular zinc concentrations were measured using fluorescence resonance energy transfer (FRET).
RESULTS: In vivo, muscle atrophy, autophagy activation, and upregulation of SIRT1 and FoxO1, along with downregulation of GPR39, were confirmed in the T1D group. ZnSO₄ protected against muscle atrophy and inhibited autophagy (T1D + ZnSO₄ vs. T1D, all p < 0.0001), as evidenced by increased grip strength (212.40 ± 11.08 vs. 163.90 ± 10.95 gf), gastrocnemius muscle index (10.67 ± 0.44 vs. 8.80 ± 0.72 mg/g), muscle fibre cross-sectional area (978.20 ± 144.00 vs. 580.20 ± 103.30 μm2), and serum zinc levels (0.2335 ± 0.0227 vs. 0.1561 ± 0.0123 mg/L). ZnSO₄ down-regulated the expression of Atrogin-1 and MuRF1, and decreased the formation of autophagosomes in the gastrocnemius muscle of T1D mice (all p < 0.0001). RNA-seq analysis indicated activation of the SIRT1/FoxO1 signalling pathway in diabetic mice. ZnSO₄ down-regulated LC3B, SIRT1 and FoxO1, while upregulating P62 and GPR39 (all p < 0.05). In vitro, muscle atrophy, autophagy activation, and down-regulation of GPR39 were confirmed in the diabetic cell model (all p < 0.05). Both ZnSO₄ and TC-G-1008 down-regulated Atrogin-1, LC3B, SIRT1, and FoxO1, and up-regulated P62 and GPR39, inhibiting autophagy and improving muscle atrophy (all p < 0.05). The beneficial anti-atrophic effects of ZnSO₄ are diminished following treatment with SRT1720 or RAPA. Upon GPR39 knockout, SIRT1, FoxO1, and Atrogin-1 were upregulated, while P62 was downregulated. Intracellular zinc concentrations in ZnSO₄-treated group remained unchanged (p > 0.05), indicating that zinc supplementation did not affect zinc ion entry but acted through the cell surface receptor GPR39.
CONCLUSION: ZnSO4 inhibits excessive autophagy in skeletal muscle and alleviates muscle atrophy in diabetic mice via the GPR39-SIRT1/FoxO1 axis. These findings suggest that zinc supplementation may offer a potential therapeutic strategy for managing diabetic muscle atrophy.

Keywords:  GPR39; SIRT1/FoxO1; autophagy; muscle atrophy; zinc

DOI:  https://doi.org/10.1002/jcsm.13771
PLoS One. 2025 ;20(3): e0316110

The effect of IL-1β inhibitor canakinumab (Ilaris®) on IL-6 production in human skeletal muscle cells.

Anna Cordeiro-Santanach, Fiorella Morales, Maria Del Carmen Parquet, Kitipong Uaesoontrachoon, Joyce Rowsell, Jordan Warford, Wilson Wu, Pia Elustondo, Eric P Hoffman, Kanneboyina Nagaraju.

Muscle inflammation is one of the hallmarks of Duchenne muscular dystrophy (DMD). Dystrophin-deficient skeletal muscle cells produce higher levels of pro-inflammatory cytokines such as interleukin 1β (IL-1β) in response to toll-like receptor stimulation compared to normal muscle skeletal cells. IL- 1β induces the human skeletal muscle secretion of the myokine Interleukin-6 (IL-6). Here, we evaluated the effect of a human IgG1κ monoclonal antibody (canakinumab (Ilaris®)) that specifically blocks the IL-1β effect on IL-6 secretion by human skeletal muscle cells. Canakinumab is an excellent candidate for therapeutic repositioning to treat DMD because it is an FDA-approved drug to treat periodic fever syndromes and systemic juvenile idiopathic arthritis. Unlike previous generations of IL-1 inhibitors, canakinumab is highly specific for the IL-1β ligand, has a longer half-life, and does not interfere with other IL-1-activated inflammatory pathways. Following cell culture optimization and viability assays to assess toxicity, skeletal muscle cells were stimulated with IL-1β (10 ng/mL) for 48 hours in the presence of nine concentrations of canakinumab ranging from 0.001 nM to 1000 nM, and IL-6 production was measured with an enzyme-linked immunosorbent assay. Pre-incubation of myoblasts with canakinumab before IL-1β-stimulation, significantly reduced IL-6 production at concentrations of 1, 10, 100, 250, and 1000 nM relative to controls, yielding an IC50 of 0.264 nM. On the other hand, co-incubation of canakinumab with IL-1β before addition to myoblasts resulted in a significant inhibition with the IC50 reducing to 0.126 nM, less than half of the previous method. Canakinumab also did not affect myotube viability at 10 nM and was also able to significantly reduce the production of IL-6, when the cells were stimulated with IL-1β (10 ng/ml). Taken together, our results show that canakinumab is a potent inhibitor of IL-1β signaling in muscle cells. These results align with previously published pre-clinical work with other IL-1 inhibitors in the mdx mouse model and support further investigation into the clinical utility of repositioning canakinumab to treat DMD.

DOI: https://doi.org/10.1371/journal.pone.0316110
Semin Cancer Biol. 2025 Feb 26. pii: S1044-579X(25)00040-9. [Epub ahead of print]111 48-59

Immunosenescence in skeletal muscle: The role-play in cancer cachexia chessboard.

Matteo Giovarelli, Emanuele Mocciaro, Carla Carnovale, Davide Cervia, Cristiana Perrotta, Emilio Clementi.

  With the increase in life expectancy, age-related conditions and diseases have become a widespread and relevant social burden. Among these, immunosenescence and cancer cachexia play a significant often intertwined role. Immunosenescence is the progressive aging decline of both the innate and adaptive immune systems leading to increased infection susceptibility, poor vaccination efficacy, autoimmune disease, and malignancies. Cancer cachexia affects elderly patients with cancer causing severe weight loss, muscle wasting, inflammation, and reduced response to therapies. Whereas the connections between immunosenescence and cancer cachexia have been raising attention, the molecular mechanisms still need to be completely elucidated. This review aims at providing the current knowledge about the interplay between immunosenescence, skeletal muscle, and cancer cachexia, analyzing the molecular pathways known so far to be involved. Finally, we highlight potential therapeutic strategies suited for elderly population aimed to block immunosenescence and to preserve muscle mass in cachexia, also presenting the analysis of the current state-of-the-art of related clinical trials.

Keywords:  Cancer cachexia; Immune system; Immunosenescence; Sarcopenia; Skeletal muscle

DOI:  https://doi.org/10.1016/j.semcancer.2025.02.012
Skelet Muscle. 2025 Mar 01. 15(1): 5

OBSCN undergoes extensive alternative splicing during human cardiac and skeletal muscle development.

Ali Oghabian, Per Harald Jonson, Swethaa Natraj Gayathri, Mridul Johari, Ella Nippala, David Gomez Andres, Francina Munell, Jessica Camacho Soriano, Maria Angeles Sanchez Duran, Juha Sinisalo, Heli Tolppanen, Johanna Tolva, Peter Hackman, Marco Savarese, Bjarne Udd.

   BACKGROUND: Highly expressed in skeletal muscles, the gene Obscurin (i.e. OBSCN) has 121 non-overlapping exons and codes for some of the largest known mRNAs in the human genome. Furthermore, it plays an essential role in muscle development and function. Mutations in OBSCN are associated with several hypertrophic cardiomyopathies and muscular disorders. OBSCN undergoes extensive and complex alternative splicing, which is the main reason that its splicing regulation associated with skeletal and cardiac muscle development has not previously been thoroughly studied.
METHODS: We analyzed RNA-Seq data from skeletal and cardiac muscles extracted from 44 postnatal individuals and six fetuses. We applied the intron/exon level splicing analysis software IntEREst to study the splicing of OBSCN in the studied samples. The differential splicing analysis was adjusted for batch effects. Our comparisons revealed the splicing variations in OBSCN between the human skeletal and cardiac muscle, as well as between post-natal muscle (skeletal and cardiac) and the pre-natal equivalent muscle.
RESULTS: We detected several splicing regulations located in the 5'end, 3' end, and the middle of OBSCN that are associated with human cardiac or skeletal muscle development. Many of these alternative splicing events have not previously been reported. Our results also suggest that many of these muscle-development associated splicing events may be regulated by BUB3.
CONCLUSIONS: We conclude that the splicing of OBSCN is extensively regulated during the human skeletal/cardiac muscle development. We developed an interactive visualization tool that can be used by clinicians and researchers to study the inclusion of specific OBSCN exons in pre- and postnatal cardiac and skeletal muscles and access the statistics for the differential inclusion of the exons across the studied sample groups. The OBSCN exon inclusion map related to the human cardiac and skeletal muscle development is available at http://psivis.it.helsinki.fi:3838/OBSCN_PSIVIS/ . These findings are essential for an accurate pre- and postnatal clinical interpretation of the OBSCN exonic variants.

Keywords:  Exon inclusion; Muscle development; Neuromuscular diseases; OBSCN/RNA splicing

DOI:  https://doi.org/10.1186/s13395-025-00374-6
JCI Insight. 2025 Mar 04. pii: e179928. [Epub ahead of print]

Periarticular myositis and muscle fibrosis are cytokine dependent complications of inflammatory arthritis.

Jessica Day, Cynthia Louis, Kristy Swiderski, Angus Stock, Huon Wong, Wentao Yao, Bonnia Liu, Suba Nadesapillai, Gordon S Lynch, Ian P Wicks.

  The deleterious consequences of chronic synovitis on cartilage, tendon and bone in rheumatoid arthritis (RA) are well-described. In contrast, its effects on periarticular skeletal muscle are under-studied. Further, while TNF inhibition is an effective therapy for RA synovitis, it exacerbates fibrosis in muscle injury models. We aimed to investigate whether myositis and muscle fibrosis are features of inflammatory arthritis and evaluate whether targeted RA therapies influence these disease features. Periarticular muscle was analysed in murine models of poly- and mono-articular inflammatory arthritis: serum transfer induced arthritis, collagen-induced arthritis, K/BxN, and antigen-induced arthritis (AIA). Periarticular myositis and an increase in muscle fibroadipocyte progenitor cells (FAPs) were observed in all models, despite diverse arthritogenic mechanisms. Periarticular muscle fibrosis was observed from day 15 in AIA. Neither etanercept nor baricitinib suppressed periarticular myositis or subsequent fibrosis compared to vehicle, despite reducing arthritis. Notably, etanercept failed to prevent muscle fibrosis even when initiated early, but this was not linked to increased FAPs survival or collagen production. Corroborating these data, radiographic and histological analyses revealed periarticular myositis in RA patients. We conclude that periarticular myositis and fibrosis are under-recognised features of inflammatory arthritis. Targeted RA therapies may not prevent periarticular muscle sequelae, despite controlling arthritis.

Keywords:  Arthritis; Inflammation; Muscle biology; Rheumatology; Skeletal muscle

DOI:  https://doi.org/10.1172/jci.insight.179928
Muscle Nerve. 2025 Mar 03.

Myostatin Knockout Mice Have Larger Muscle Fibers With Normal Function and Morphology.

Hans Degens, Ketan Patel, A Matsakas.

   INTRODUCTION: We assessed whether muscle fibers in myostatin knockout (MSTN-/-) mice are just larger or also exhibit morphological, metabolic, and functional differences from MSTN+/+ mice.
METHODS: We compared single fiber contractile properties and histological fiber properties in muscles from MSTN-/- and MSTN+/+ mice.
RESULTS: Even though in permeabilized muscle fibers from the extensor digitorum longus and soleus muscle maximal force was higher (p < 0.001) there were no significant differences in specific power (power per unit volume), specific tension (force per cross-sectional area), maximal shortening velocity, or curvature of the force-velocity relationship between MSTN-/- and MSTN+/+ mice. In histological sections of the soleus muscle, fibers were larger (p < 0.001), but the succinate dehydrogenase staining intensity and capillary density did not differ significantly between MSTN-/- and MSTN+/+ mice, which was explicable by the larger number of capillaries around a fiber (p < 0.001). A model showed no significant differences in soleus muscle oxygenation.
DISCUSSION: The larger force-generating capacity of fibers from MSTN-/- mice is explicable by the larger fiber cross-sectional area. The data indicate that muscle fibers from MSTN-/- mice are quantitatively, but not qualitatively different from muscle fibers from MSTN+/+ mice. Myostatin inhibition may help increase muscle mass in conditions accompanied by muscle weakness without a detrimental impact on muscle quality, but systemic side effects need to be considered.

Keywords:  capillary; force; microcirculation; myostatin; oxidative capacity; oxygenation; power; single fiber

DOI:  https://doi.org/10.1002/mus.28389
J Cachexia Sarcopenia Muscle. 2025 Feb;16(1): e13697

Testosterone Modulation of Muscle Transcriptomic Profile During Lifestyle Therapy in Older Men with Obesity and Hypogonadism.

Viola Viola, Tagari Samanta, Maria Liza Duremdes Nava, Alessandra Celli, Reina Armamento-Villareal, Ngoc Ho Lam Nguyen, Georgia Colleluori, Yoann Barnouin, Nicola Napoli, Clifford Qualls, Benny Abraham Kaipparettu, Dennis T Villareal.

   BACKGROUND: Testosterone replacement therapy (TRT) added to lifestyle therapy can mitigate weight-loss-induced reduction of muscle mass and bone mineral density (BMD) in older men with obesity and hypogonadism.
OBJECTIVE: To investigate the molecular mechanisms underlying the attenuation of muscle and BMD loss in response to TRT during intensive lifestyle intervention in this high-risk older population.
METHODS: Among 83 older (≥ 65 years) men with obesity (BMI ≥ 30 kg/m2) and hypogonadism (early AM testosterone persistently < 300 ng/dL) associated with frailty (Modified Physical Performance Test score ≤ 31) randomized into 26-week lifestyle therapy plus testosterone (LT+TRT) or placebo (LT+Pbo) in the LITROS trial, 38 underwent serial muscle biopsies for the muscle transcriptomics substudy.
RESULTS: Despite similar ~10% weight loss, lean body mass and thigh muscle volume decreased less in LT+TRT than LT+Pbo (-2% vs. -4%, respectively; p = 0.04). Hip BMD was preserved in LT+TRT compared with LT+Pbo (0.4% vs. -1.3%; p = 0.03). Muscle strength increased similarly in LT+TRT and LT+Pbo (23% vs. 24%; p = 0.95). Total testosterone increased more in LT+TRT than LT+Pbo (133% vs. 32%; p = 0.005). Based on Next Generation Sequencing, of the 39 160 and 39 115 genes detected in LT+TRT and LT+Pbo, respectively, 195 were differentially expressed in LT+TRT and 158 in LT+Pbo. Gene Ontology enrichment analyses revealed that in LT+TRT, just four muscle-related pathways (muscle organ development, muscle organ morphogenesis, regulation of skeletal muscle contraction, muscle atrophy) were downregulated and one pathway (muscle system process) was upregulated. In contrast, in LT+Pbo, nine muscle-related pathways (muscle system process, muscle tissue development, muscle organ development, skeletal muscle tissue development, skeletal muscle organ development, skeletal muscle cell differentiation, muscle organ morphogenesis, response to stimuli involved in regulation of muscle adaptation, muscle atrophy) and one pathway related to bone (bone mineralization involved in bone maturation) were downregulated. Muscle system process was upregulated in LT+TRT but downregulated in LT+Pbo. RT-PCR analyses showed that LT+TRT resulted in a higher expression of MYOD1 (p = 0.02) and WNT4 (p = 0.02), key genes involved in muscle and bone metabolism, respectively, compared with LT+Pbo. We also observed significantly higher mRNA expression of MYBPH (p = 0.006), SCN3B (p = 0.02) and DSC2 (p = 0.01), genes involved in the muscle system process, in response to LT+TRT compared with LT+Pbo.
CONCLUSION: The addition of TRT to lifestyle therapy mitigates the weight-loss-induced reduction of muscle mass and BMD via countering the weight-loss-induced downregulation of genes involved in muscle and bone anabolism.

Keywords:  bone; lifestyle therapy; skeletal muscle; testosterone

DOI:  https://doi.org/10.1002/jcsm.13697
PeerJ. 2025 ;13 e19042

Sex differences in absolute and relative changes in muscle size following resistance training in healthy adults: a systematic review with Bayesian meta-analysis.

Martin C Refalo, Greg Nuckols, Andrew J Galpin, Iain J Gallagher, D Lee Hamilton, Jackson J Fyfe.

   Background: Muscle hypertrophy may be influenced by biological differences between males and females. This meta-analysis investigated absolute and relative changes in muscle size following resistance training (RT) between males and females and whether measures of muscle size, body region assessed, muscle fibre type, and RT experience moderate the results.
Methods: Studies were included if male and female participants were healthy (18-45 years old) adults that completed the same RT intervention, and a measure of pre- to post-intervention changes in muscle size was included. Out of 2,720 screened studies, 29 studies were included in the statistical analysis. Bayesian methods were used to estimate a standardised mean difference (SMD), log response ratio (lnRR) with exponentiated percentage change (Exp. % Change of lnRR), and probability of direction (pd) for each outcome.
Results: Absolute increases in muscle size slightly favoured males compared to females (SMD = 0.19 (95% HDI: 0.11 to 0.28); pd = 100%), however, relative increases in muscle size were similar between sexes (Exp. % Change of lnRR = 0.69% (95% HDI: -1.50% to 2.88%)). Outcomes were minimally influenced by the measure of muscle size and not influenced by RT experience of participants. Absolute hypertrophy of upper-body but not lower-body regions was favoured in males. Type I muscle fibre hypertrophy slightly favoured males, but Type II muscle fibre hypertrophy was similar between sexes.
Conclusion: Our findings strengthen the understanding that females have a similar potential to induce muscle hypertrophy as males (particularly when considering relative increases in muscle size from baseline) and findings of our secondary analyses should inform future research that investigates sex differences in highly trained participants and muscle fibre type-specific hypertrophy.

Keywords:  Gender difference; Muscle hypertrophy; Muscle size; Resistance training; Sex difference

DOI:  https://doi.org/10.7717/peerj.19042
J Nanobiotechnology. 2025 Mar 03. 23(1): 159

Specific muscle targeted delivery of miR-130a loaded lipid nanoparticles: a novel approach to inhibit lipid accumulation in skeletal muscle and obesity.

Yingqian Wang, Zeqiang Ma, Lehua Jiang, Nataraj Bojan, Yiwen Sha, Boyu Huang, Lianxi Ming, Junnan Shen, Weijun Pang.

   BACKGROUND: Skeletal muscle lipid deposition is a key manifestation of obesity, often accompanied by decreased exercise capacity and muscle atrophy. Skeletal muscle as the largest organ in the body, makes it challenges for designing targeted drug delivery systems. Lipid nanoparticles (LNPs) are widely used as a safe and efficient delivery carrier, there is limited research on LNPs that specifically target skeletal muscle.
RESULTS: A LNP designed with five specific receptor complements on its surface, which specifically targets skeletal muscle in vivo in mice, without off-target effects on other tissues and organs. MiR-130a, a regulator of PPARG, which is a key factor in skeletal muscle lipid deposition, was encapsulated with LNP (LNP@miR-130a). In high-fat diet (HFD) mice, LNP@miR-130a effectively reduced skeletal muscle lipid deposition, increased exercise activity and enhanced muscle mass. Interestingly, the myokines in skeletal muscle have also changed which may leading to reduce the adipose tissue weight and liver lipid deposition in HFD mice.
CONCLUSIONS: These results indicated LNP@miR-130a is a promising inhibitor of skeletal muscle lipid deposition and may help alleviate obesity. This study provides new insights for obesity treatment and lays foundation for the development of targeted skeletal muscle therapeutics.

Keywords:  LNP@miR-130a; Lipid nanoparticle; Obesity; PPARG; Skeletal muscle lipid deposition

DOI:  https://doi.org/10.1186/s12951-025-03225-0
Heliyon. 2025 Feb 28. 11(4): e42499

Application of CIBERSORTx and BayesPrism to deconvolution of bulk RNA-seq data from human myocardium and skeletal muscle.

Marcella Conning-Rowland, Chew W Cheng, Oliver Brown, Marilena Giannoudi, Eylem Levelt, Lee D Roberts, Kathryn J Griffin, Richard M Cubbon.

  RNA-sequencing (RNA-seq) is an important tool to explore molecular mechanisms of disease. Technological advances mean this can be performed at the single-cell level, but the large sample sizes needed in clinical studies are currently prohibitively expensive and complex. Deconvolution of bulk RNA-seq offers an opportunity to bridge this gap by defining the cell lineage composition of samples. This approach is widely used in immunology studies, but currently there are no validated pipelines for researchers analysing human myocardium or skeletal muscle. Here, we describe the application and in silico validation of two pipelines to deconvolute human right atrium, left ventricle and skeletal muscle bulk RNA-seq data. Specifically, we have defined the major cell lineages of these tissues using single cell/nucleus RNA-seq data from the Heart Cell Atlas, which are then applied during deconvolution using the CIBERSORTx or BayesPrism deconvolution packages. Both pipelines gave robust estimates of the proportion of all major cell lineages in these tissues. We demonstrate their value in defining age- and sex-differences in tissue composition using bulk RNA-seq data from the GTEx consortium. Our validated pipelines can be rapidly applied by researchers working with existing or novel bulk RNA-seq of myocardium or skeletal muscle to gain novel insights.

Keywords:  Age; Deconvolution; Myocardium; RNA-Seq; Sex; Skeletal muscle

DOI:  https://doi.org/10.1016/j.heliyon.2025.e42499
Hum Mol Genet. 2025 Feb 28. pii: ddaf028. [Epub ahead of print]

New selective androgen receptor modulator TEI-SARM2 improves muscle function in a Duchenne muscular dystrophy rat model.

Katsuyuki Nakamura, Masanobu Kanou, Wataru Fujii, Karina Kouzaki, Toshie Jimbo, Keitaro Yamanouchi, Koichi Nakazato, Hiroshi Ueda, Jun Hirata, Kei Yamana.

  Duchenne muscular dystrophy (DMD) is a severe muscle wasting disease caused by a genetic mutation in the Dmd gene. Dystrophin mutant mice (mdx) have traditionally been used for DMD research as a disease model in the preclinical stage; however, mdx mice exhibit only very mild phenotypes to partially mimic muscle degeneration and regeneration. To overcome this limitation in preclinical studies, DMD mutant rats (DMD rats) generated by CRISPR/Cas were used as a DMD model to exhibit age-dependent progressive muscle degeneration and pathophysiological features similar to DMD patients and more severe than those displayed by mdx mice. TEI-SARM2 is a non-steroidal, orally available selective androgen receptor modulator (SARM) developed as a pharmaceutical candidate for the treatment of muscle wasting diseases based on its potent anabolic activity on skeletal muscle mass. In this study, long-term treatment of daily oral administration of TEI-SARM2 to DMD rats significantly improved muscle function (endurance and strength) assessed by grip and tetanic force measurements. TEI-SARM2 did not increase the muscle weight of hindlimbs in male DMD rats; moreover, long-term, weekly oral administration for 24 weeks improved muscle function with reduced side effects on the prostate and testes weight. Histological analysis showed that TEI-SARM2 significantly reduced adipose tissue infiltration in DMD muscle. In female DMD rats, both daily and weekly TEI-SARM2 treatment showed anabolic effects and enhanced muscle strength and endurance. Taken together, these results indicate that TEI-SARM2 has non-anabolic and anabolic effects that improve dystrophic muscle dysfunction and can be a supportive therapeutic option for DMD.

Keywords:  CRISPR/Cas9; DMD rats; Duchenne muscular dystrophy; selective androgen receptor agonist (SARM)

DOI:  https://doi.org/10.1093/hmg/ddaf028
Sci Rep. 2025 Feb 28. 15(1): 7232

Enhanced expression of dystrophin, IGF-1, CD44 and MYH3 in plasma and skeletal muscles including diaphragm of mdx mice after oral administration of Neu REFIX beta 1,3-1,6 glucan.

Senthilkumar Preethy, Shuji Sakamoto, Takuma Higuchi, Koji Ichiyama, Naoki Yamamoto, Nobunao Ikewaki, Masaru Iwasaki, Vidyasagar Devaprasad Dedeepiya, Subramaniam Srinivasan, Kadalraja Raghavan, Mathaiyan Rajmohan, Rajappa Senthilkumar, Samuel Jk Abraham.

  Duchenne muscular dystrophy (DMD) is a rare genetic disease, causing muscle degeneration due to lack of dystrophin with inadequate muscle regeneration culminating in muscle dysfunction. The N-163 strain of Aureobasidium Pullulans produced Beta-1,3 - 1,6-glucan (Neu REFIX) reported to be safe with anti-inflammatory and anti-fibrotic efficacy earlier, herein we evaluated its effects on muscle regeneration in mdx mice. Forty-five mice in three groups (n = 15 each): Group 1 (normal), Group 2 (mdx control), and Group 3 (mdx fed Neu REFIX) were evaluated for 45 days. IGF-1, Dystrophin, CD44 and MYH3 in diaphragm, plasma and skeletal muscle were evaluated by ELISA and immunohistochemistry. Mean IGF-1 expression was 20.32% and 16.27% higher in plasma (p = 0.03) and diaphragm respectively in Neu-REFIX group. Mean dystrophin was higher in Neu-REFIX group by 70.3% and 4.7% in diaphragm and plasma respectively than control. H-score intensity of CD44 + was > 2.0 with an MYH3-positivity 20% higher in Neu-REFIX than control. Oral administration of Neu REFIX was safe. Significantly enhanced plasma IGF-1 beside increased Dystrophin, MYH3 and CD44, proving a restoration of muscle regeneration and differentiation, especially in diaphragm, makes us recommend it as a disease modifying adjuvant in both early and advanced stages of DMD.

Keywords:   mdx mice; CD44; Duchenne muscular dystrophy (DMD); Dystrophin; IGF-1; MYH3; β-Glucan

DOI:  https://doi.org/10.1038/s41598-025-92258-4
Mol Biotechnol. 2025 Mar 01.

The Roles of myomiRs in the Pathogenesis of Sarcopenia: From Literature to In Silico Analysis.

Huanxia Jia, Nurgulsim Kaster, Rajwali Khan, Amel Ayari-Akkari.

  Senile sarcopenia is a condition of age-associated muscular disorder and is a significant health issue around the world. In the current review, we curated the information from the NCBI, PubMed, and Google Scholar literature and explored the non-genetic and genetic causes of senile sarcopenia. Interestingly, the myomiRs such as miR-1, miR-206, miR-133a, miR-133b, miR-208b, and miR-499 are skeletal muscle's critical structural and functional regulators. However, very scattered information is available regarding the roles of myomiRs in different skeletal muscle phenotypes through a diverse list of known target genes. Therefore, these pieces of information must be organized to focus on the conserved target genes and comparable effects of the myomiRs in regulating senile sarcopenia. Hence, in the present review, the roles of pathogenetic factors in regulating senile sarcopenia were highlighted. The literature was further curated for the roles of myomiRs such as hsa-miR-1-3p/206, hsa-miR-27-3p, hsa-miR-146-5p, and hsa-miR-499-5p and their target genes. Additionally, we used different bioinformatics tools and predicted target genes of the myomiRs and found the most critical target genes, shared pathways, and their standard functions in regulating muscle structure and functions. The information gathered in the current review will help the researchers to explore their possible therapeutic potential, especially the use of the myomiRs for the treatment of senile sarcopenia.

Keywords:  Causes of sarcopenia; MiRNAs in sarcopenia; Muscular atrophy; MyomiRs; Sarcopenia

DOI:  https://doi.org/10.1007/s12033-025-01373-0