bims-moremu 2025-04-06 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2025–04–06
29 papers selected by
Anna Vainshtein, Craft Science Inc.

Muscle fiber Myc is dispensable for muscle growth and its forced expression severely perturbs homeostasis.
Effects of aging on calcium channels in skeletal muscle.
Creation of knockin mice for the fluorescence protein based in vivo identification of skeletal myofiber types.
Neural stimulation suppresses mTORC1-mediated protein synthesis in skeletal muscle.
Muscle wasting in cancer cachexia: Mechanisms and the role of exercise.
Mg2+ influx mediated by TRPM7 triggers the initiation of muscle stem cell activation.
Mitophagy-mediated S1P facilitates muscle adaptive responses to endurance exercise through SPHK1-S1PR1/S1PR2 in slow-twitch myofibers.
Androgens as the "old age stick" in skeletal muscle.
Human skeletal muscle possesses both reversible proteomic signatures and a retained proteomic memory after repeated resistance training.
Resistance Exercise and Mechanical Overload Upregulate Vimentin for Skeletal Muscle Remodeling.
Three-Dimensional Analysis of Skeletal Muscle Stem Cell Niche Following Tissue Clearing.
Human Skeletal Muscle Niche Formation and Analysis with Spatial RNA Sequencing.
Muscle-specific increased expression of JAG1 improves skeletal muscle phenotype in dystrophin-deficient mice.
A History of Omics Discoveries Reveals the Correlates and Mechanisms of Loading-Induced Hypertrophy in Adult Skeletal Muscle.
Time Release Ion Matrix Regenerates Dystrophic Skeletal Muscle.
Muscle-specific Ryanodine receptor 1 properties underlie limb-girdle muscular dystrophy 2B/R2 progression.
DNM1L-mediated fission governs mitophagy & mitochondrial biogenesis during myogenic differentiation.
Nestin Regulates Autophagy-Dependent Ferroptosis Mediated Skeletal Muscle Atrophy by Ubiquitinating MAP 1LC3B.
Rapamycin does not compromise physical performance or muscle hypertrophy after PoWeR while intermittent rapamycin alleviates glucose disruptions by frequent rapamycin.
Proteomic profiling uncovers sexual dimorphism in the muscle response to wheel running exercise in the FLExDUX4 murine model of facioscapulohumeral muscular dystrophy.
Pan-PTM profiling identifies post-translational modifications associated with exceptional longevity and preservation of skeletal muscle function in Drosophila.
Multi-scale modeling and simulation of skeletal muscles with different fatigue degrees based on microphysiology.
Transcriptional Co-Activator With PDZ Binding Motif (TAZ) Inhibits Dexamethasone-Induced Muscle Atrophy via mTOR Signalling.
Leucine Supplementation Counteracts the Atrophic Effects of HDAC4 in Rat Skeletal Muscle Submitted to Hindlimb Immobilization.
Calcium Handling Machinery and Sarcomere Assembly are Impaired Through Multipronged Mechanisms in Cancer Cytokine-Induced Cachexia.
Mesenchymal stem cell-specific Sirt1 overexpression prevents sarcopenia induced by 1,25-dihydroxyvitamin D deficiency.
Small nucleolar RNAs promote the restoration of muscle differentiation defects in cells from myotonic dystrophy type 1.
The role of inner nuclear membrane protein emerin in myogenesis.
The road towards AAV-mediated gene therapy of Duchenne muscular dystrophy.

Nat Commun. 2025 Apr 03. 16(1): 3190

Muscle fiber Myc is dispensable for muscle growth and its forced expression severely perturbs homeostasis.

Daniel J Ham, Michelangelo Semeraro, Bianca M Berger, Timothy J McGowan, Shuo Lin, Eleonora Maino, Filippo Oliveri, Markus A Rüegg.

The oncogenic transcription factor Myc stimulates many growth processes including cell cycle progression and ribosome biogenesis. Myc expression is low in adult skeletal muscle, but is upregulated upon growth stimuli. Furthermore, muscle fiber Myc overexpression recapitulates many aspects of growth-related gene expression, leading to the hypothesis that Myc mediates pro-growth responses to anabolic stimuli, such as exercise. Here, we test this hypothesis by examining mouse models in which Myc is specifically eliminated or overexpressed in skeletal muscle fibers or muscle stem cells (MuSC). While muscle fiber Myc expression increased during muscle growth and Myc expression in MuSCs was required for successful muscle regeneration, muscle fiber Myc expression was dispensable for post-natal, mechanical overload or PKBα/Akt1-induced muscle growth in mice. Similarly, constitutive Myc expression did not promote skeletal muscle hypertrophy, but instead impaired muscle fiber structure and function within days. These data question the role of Myc in skeletal muscle growth.

DOI: https://doi.org/10.1038/s41467-025-58542-7
Front Mol Biosci. 2025 ;12 1558456

Effects of aging on calcium channels in skeletal muscle.

Mingyi Dong, Andrés Daniel Maturana.

  In skeletal muscle, calcium is not only essential to stimulate and sustain their contractions but also for muscle embryogenesis, regeneration, energy production in mitochondria, and fusion. Different ion channels contribute to achieving the various functions of calcium in skeletal muscles. Muscle contraction is initiated by releasing calcium from the sarcoplasmic reticulum through the ryanodine receptor channels gated mechanically by four dihydropyridine receptors of T-tubules. The calcium influx through store-operated calcium channels sustains the contraction and stimulates muscle regeneration. Mitochondrial calcium uniporter allows the calcium entry into mitochondria to stimulate oxidative phosphorylation. Aging alters the expression and activity of these different calcium channels, resulting in a reduction of skeletal muscle force generation and regeneration capacity. Regular physical training and bioactive molecules from nutrients can prevent the effects of aging on calcium channels. This review focuses on the current knowledge of the effects of aging on skeletal muscles' calcium channels.

Keywords:  aging; calcium; ion channels; sarcopenia; skeletal muscle

DOI:  https://doi.org/10.3389/fmolb.2025.1558456
Sci Rep. 2025 Apr 03. 15(1): 11389

Creation of knockin mice for the fluorescence protein based in vivo identification of skeletal myofiber types.

Shuuichi Mori, Takuya Omura, Mako Kono, Taichi Fukunaga, Haruhiko Koseki, Kazuhiro Shigemoto.

  Skeletal muscles of the mammalian trunk and limbs comprise myofibers that express four types of myosin heavy-chain (MyHC) isoforms, each with distinct contractile and metabolic properties. Despite histochemical and immunohistochemical staining to identify myofiber types, all myofiber types cannot be identified simultaneously in vivo. In this study, we generated a novel knock-in mouse model, termed "MusColor," that enables the simultaneous identification of individual MyHC isoforms through the expression of four fluorescent proteins. The identification of fibre types by fluorescent expression in MusColor mice was consistent with that achieved by immunostaining and had higher sensitivity. By studying the aging-associated changes in myofiber types using the MusColor mice, we were able to identify changes in hybrid myofibers that simultaneously express multiple MyHCs. Furthermore, by culturing satellite cells isolated from MusColor mice and treatment of thyroid hormone or rapamycin, changes in myofiber type and metabolic function could be analysed in living cells. The MusColor mouse proved useful for elucidating the mechanisms of muscle fibre changes caused by diseases such as sarcopenia, neuromuscular and metabolic diseases, as well as by exercise and nutritional environments.

Keywords:  Aging; Knock-in mouse; Metabolism; Myofiber type; Myosin heavy chain; Satellite cell

DOI:  https://doi.org/10.1038/s41598-025-96118-z
Sci Adv. 2025 Apr 04. 11(14): eadt4955

Neural stimulation suppresses mTORC1-mediated protein synthesis in skeletal muscle.

Ana G Dumitras, Giorgia Piccoli, Frederik Tellkamp, Lena Keufgens, Martina Baraldo, Sabrina Zorzato, Laura Cussonneau, Leonardo Nogara, Marcus Krüger, Bert Blaauw.

Skeletal muscle fibers are classified as glycolytic or oxidative, with differing susceptibilities to muscle wasting. However, the intracellular signaling pathways regulating fiber-specific muscle trophism remain unclear because of a lack of experimental models measuring protein synthesis. We developed a mouse model overexpressing a mutated transfer RNA synthetase in muscle fibers, enabling specific protein labeling using an artificial methionine substitute, which can be revealed through click chemistry. This model revealed that denervation increases protein labeling in oxidative muscle fibers through mammalian target of rapamycin complex 1 (mTORC1) activation, while deleting the mTORC1 scaffold protein Raptor reduces labeling in glycolytic fibers. On the other hand, increased muscle activity acutely decreases protein synthesis, accompanied by reduced mTORC1 signaling, glycogen depletion, and adenosine 5'-monophosphate kinase activation. Our findings identify nerve activity as an inhibitory signal for mTORC1-dependent protein synthesis in skeletal muscle, enhancing the understanding of fiber-specific responses to exercise and pathological conditions.

DOI: https://doi.org/10.1126/sciadv.adt4955
Exp Physiol. 2025 Mar 30.

Muscle wasting in cancer cachexia: Mechanisms and the role of exercise.

Zoe P Libramento, Louisa Tichy, Traci L Parry.

  Cancer cachexia (CC) is a multifactorial disease marked by a severe and progressive loss of lean muscle mass and characterized further by inflammation and a negative energy/protein balance, ultimately leading to muscle atrophy and loss of muscle tissue. As a result, patients experiencing cachexia have reduced muscle function and thus less independence and a lower quality of life. CC progresses through stages of increasing severity: pre-cachexia, cachexia and refractory cachexia. Two proposed underlying mechanisms that drive cancer-induced muscle wasting are the autophagy-lysosome and ubiquitin-proteasome systems. An increase in autophagic flux and proteolytic activity leads to atrophy of both cardiac and skeletal muscle, ultimately mediated by tumour or immune-secreted inflammatory cytokines. These pathways occur at a basal level to maintain cellular homeostasis; therefore, it is the overactivation of the pathways that leads to muscle atrophy. Recent evidence demonstrates the ability of aerobic and resistance training to restore these pathways to their basal levels. The mechanism is not yet understood, and more research is needed to determine exactly how exercise influences each pathway. However, exercise has great promise as a therapeutic strategy for CC because of the evidence for it preserving muscle mass and function, and attenuating protein degradative pathways. The extent to which exercise affects the ubiquitin-proteasome and autophagy-lysosome systems is determined by the frequency, intensity and duration of the exercise protocol. As such, an ideal exercise prescription is lacking for individuals with CC.

Keywords:  atrophy; cancer cachexia; exercise

DOI:  https://doi.org/10.1113/EP092544
Sci Adv. 2025 Apr 04. 11(14): eadu0601

Mg2+ influx mediated by TRPM7 triggers the initiation of muscle stem cell activation.

Kotaro Hirano, Chika Nakabayashi, Mao Sasaki, Miki Suzuki, Yuta Aoyagi, Kaori Tanaka, Akira Murakami, Masaki Tsuchiya, Eiji Umemoto, Shuji Takabayashi, Yasuo Kitajima, Yusuke Ono, Takehisa Matsukawa, Masayuki Matsushita, Yasuyuki Ohkawa, Yasuo Mori, Yuji Hara.

Muscle satellite cells (MuSCs) respond immediately to environmental cues upon skeletal muscle injuries. Despite decades of research into muscle regeneration, the specific molecular factors that trigger the transition of MuSCs from a quiescent to an active state remain largely unidentified. Here, we identify transient receptor potential melastatin 7 (TRPM7), an Mg2+-permeable ion channel, as a critical regulator of MuSC activation. Trpm7 deletion in MuSCs reduced Mg2+ influx, impairing myofiber regeneration and leading to decreased MuSC numbers and cell cycle arrest during regeneration. These changes were linked to disrupted mTOR signaling, which drives the transition of MuSCs from G0 to GAlert phase. In addition, Trpm7-deficient MuSCs exhibited impaired early responses, including quiescent projection retraction and AP-1 induction. Mg2+ supplementation rescued these defects, restoring normal MuSC activation. Our findings reveal a previously unrecognized mechanism where Mg2+ permeation through TRPM7 is essential for MuSC activation and efficient skeletal muscle regeneration, highlighting TRPM7 as a critical regulator of muscle repair.

DOI: https://doi.org/10.1126/sciadv.adu0601
Autophagy. 2025 Apr 03.

Mitophagy-mediated S1P facilitates muscle adaptive responses to endurance exercise through SPHK1-S1PR1/S1PR2 in slow-twitch myofibers.

Minghong Leng, Fenghe Yang, Junhui Zhao, Yufei Xiong, Yiqing Zhou, Mingyang Zhao, Shi Jia, Limei Liu, Qiaoxia Zheng, Lebin Gan, Jingjing Ye, Ming Zheng.

  Endurance exercise triggers adaptive responses especially in slow-twitch myofibers of skeletal muscles, leading to the remodeling of myofiber structure and the mitochondrial network. However, molecular mechanisms underlying these adaptive responses, with a focus on the fiber type-specific perspective, remains largely unknown. In this study we analyzed the alterations of transcriptomics and metabolomics in distinct skeletal myofibers in response to endurance exercise. We determined that genes associated with sphingolipid metabolism, namely those encoding SPHK1, S1PR1, and S1PR2, are enriched in slow-twitch but not fast-twitch myofibers from both mouse and human skeletal muscles, and found that the SPHK1-S1PR pathway is essential for adaptive responses of slow-twitch to endurance exercise. Importantly, we demonstrate that endurance exercise causes the accumulation of ceramides on stressed mitochondria, and the mitophagic degradation of ceramides results in an increase of the sphingosine-1-phosphate (S1P) level. The elevated S1P thereby facilitates mitochondrial adaptation and enhances endurance capacity via the SPHK1-S1PR1/S1PR2 axis in slow-twitch muscles. Moreover, administration of S1P improves endurance performance in muscle atrophy mice by emulating these adaptive responses. Our findings reveal that the SPHK1-S1P-S1PR1/S1PR2 axis through mitophagic degradation of ceramides in slow-twitch myofibers is the central mediator to endurance exercise and highlight a potential therapeutic target for ameliorating muscle atrophy diseases.

Keywords:  Endurance exercise; mitochondrial biogenesis; mitophagy; skeletal muscle; sphingosine-1-phosphate

DOI:  https://doi.org/10.1080/15548627.2025.2488563
Cell Commun Signal. 2025 Apr 03. 23(1): 167

Androgens as the "old age stick" in skeletal muscle.

Gentile Giulia, De Stefano Ferdinando, Sorrentino Carmela, D'Angiolo Rosa, Lauretta Carmine, Giovannelli Pia, Migliaccio Antimo, Castoria Gabriella, Di Donato Marzia.

  Aging is associated with a reduction in skeletal muscle fiber size and number, leading to a decline in physical function and structural integrity-a condition known as sarcopenia. This syndrome is further characterized by elevated levels of inflammatory mediators that promote skeletal muscle catabolism and reduce anabolic signaling.Androgens are involved in various biological processes, including the maintenance, homeostasis and trophism of skeletal muscle mass. The decline in androgen levels contributes, indeed, to androgen deficiency in aging people. Such clinical syndrome exacerbates the muscle loss and fosters sarcopenia progression. Nevertheless, the mechanism(s) by which the reduction in androgen levels influences sarcopenia risk and progression remains debated and the therapeutic benefits of androgen-based interventions are still unclear. Given the significant societal and economic impacts of sarcopenia, investigating the androgen/androgen receptor axis in skeletal muscle function is essential to enhance treatment efficacy and reduce healthcare costs.This review summarizes current knowledge on the role of male hormones and their-dependent signaling pathways in sarcopenia. We also highlight the cellular and molecular features of this condition and discuss the mechanisms by which androgens preserve the muscle homeostasis. The pros and cons of clinical strategies and emerging therapies aimed at mitigating muscle degeneration and aging-related decline are also presented.

Keywords:  Aging; Androgen receptor; Androgens; Sarcopenia

DOI:  https://doi.org/10.1186/s12964-025-02163-6
J Physiol. 2025 Apr 04.

Human skeletal muscle possesses both reversible proteomic signatures and a retained proteomic memory after repeated resistance training.

Juha J Hulmi, Eeli J Halonen, Adam P Sharples, Thomas M O'Connell, Lauri Kuikka, Veli-Matti Lappi, Kari Salokas, Salla Keskitalo, Markku Varjosalo, Juha P Ahtiainen.

  Investigating repeated resistance training (RT) separated by a training break enables exploration of the potential for a proteomic memory of RT-induced skeletal muscle growth, i.e. retained protein adaptations from the previous RT. Our aim was to examine skeletal muscle proteome response to 10-week RT (RT1) followed by 10-week training cessation (i.e. detraining, DT), and finally, 10-week retraining (RT2). Thirty healthy, untrained participants conducted either periodic RT (RT1-DT-RT2, n = 17) or a 10-week no-training control period (n = 13) followed by 20 weeks of RT (n = 11). RT included twice-weekly supervised whole-body RT sessions, and resting vastus lateralis biopsies were obtained every 10 weeks for proteomics analysis using high-end dia-PASEF's mass spectrometry. The first RT period altered 150 proteins (93% increased) involved in, for example, energy metabolism and protein processing compared to minor changes during the control period. The proteome adaptations were similar after the second RT compared to baseline demonstrating reproducibility in proteome adaptations to RT. Many of the proteins induced by RT1 were reversed towards baseline after detraining and increased again after retraining. These reversible proteins were especially involved in aerobic energy metabolism. Interestingly, several proteins which increased after RT1 remain elevated (i.e. retained) after detraining, including carbonyl reductase 1 (CBR1) and proteins involved in muscle contraction, cytoskeleton and calcium binding. Among the latter, calcium-activated protease calpain-2 (CAPN2) has been recently identified as an epigenetic muscle memory gene. We show that resistance training evokes retained protein levels even after 2.5 months of no training, which demonstrates a potential proteomic memory of resistance training-induced muscle growth in human skeletal muscle. KEY POINTS: Repeated resistance training in humans separated by a training break (i.e. detraining) enables the identification of temporal protein signatures over the training, detraining and retraining periods, as well as studying reproducibility of protein changes to resistance training. Muscle proteome adaptations were similar after a second period of resistance training, demonstrating reproducibility in proteome adaptations to earlier resistance training. Many of the proteins induced by resistance training were reversed towards baseline after detraining and increased again after retraining. These reversible proteins were especially involved in aerobic energy metabolism. Several proteins increased after resistance training remain elevated (i.e. retained) after detraining, including carbonyl reductase 1 (CBR1) and calcium-binding proteins such as calpain-2 (CAPN2), a recently identified epigenetic muscle memory gene. Human skeletal muscle experiences retained protein changes following resistance training persisting over 2 months, demonstrating a potential proteomic memory of resistance training-induced muscle growth.

Keywords:  CAPN2; CBR1; calpain‐2; detraining; hypertrophy; muscle memory; proteomics

DOI:  https://doi.org/10.1113/JP288104
Am J Physiol Cell Physiol. 2025 Apr 03.

Resistance Exercise and Mechanical Overload Upregulate Vimentin for Skeletal Muscle Remodeling.

Joshua S Godwin, J Max Michel, Cleiton A Libardi, Andreas N Kavazis, Christopher S Fry, Andrew D Frugé, Mariah McCashland, Ivan J Vechetti, John J McCarthy, C Brooks Mobley, Michael D Roberts.

  We adopted a proteomic and follow-through approach to investigate how mechanical overload (MOV) potentially affects novel targets in skeletal muscle, and how a perturbation in this response could potentially affect the adaptive response. First, we determined that 10 weeks of resistance training in 15 college-aged females increased sarcolemmal-associated protein content (+10.1%, p<0.05). Sarcolemmal protein isolates were then queried using mass spectrometry based proteomics, ~10% (38/387) of proteins putatively associated with the sarcolemma or extracellular matrix (ECM) were up-regulated (>1.5-fold, p<0.05), and one target (intermediate filament vimentin; VIM) warranted further investigation due to its correlation to myofiber hypertrophy (r=0.652, p=0.009). VIM expression was then examined in 4-month-old C57BL/6J mice following 10- and 20-days of plantaris MOV via synergist ablation. Relative to Sham (control) mice, VIM mRNA and protein content was significantly higher in MOV mice and immunohistochemistry indicated that VIM predominantly resided in the ECM. MOV experiments were replicated in Pax7-DTA (satellite cell depleted) mice, which reduced VIM in the ECM by ~74%. A third MOV experiment was performed in C57BL/6 mice intramuscularly injected with either AAV9-scrambled (control) or AAV9-VIM-shRNA. While VIM-shRNA mice possessed lower VIM in the ECM (~45%), plantaris masses in response to MOV were similar between groups. However, VIM-shRNA mice possessed smaller and more centrally nucleated MyHCemb-positive fibers in response to MOV. In summary, skeletal muscle VIM appears to be enriched in the ECM following MOV, satellite cells may regulate its expression, and a disruption in expression during MOV leads to an excessive regenerative phenotype.

Keywords:  cytoskeletal protein; extracellular matrix; mechanical overload; muscle protein synthesis; skeletal muscle hypertrophy

DOI:  https://doi.org/10.1152/ajpcell.01028.2024
Methods Mol Biol. 2025 Apr 05.

Three-Dimensional Analysis of Skeletal Muscle Stem Cell Niche Following Tissue Clearing.

Yoko Asakura, Smrithi Karthikeyan, Atsushi Asakura.

  Skeletal muscle is an intricately structured tissue made up of a complex framework of various cell types. The dynamic spatial and temporal relationships among these cells during both homeostasis and periods of injury contribute to the regenerative abilities of skeletal muscle. Currently, there is a deficiency in quantitative assessment, biological role, and the molecular mechanisms that could elucidate a possible juxtavascular niche for muscle satellite cells, a stem cell population for skeletal muscle regeneration. To fully comprehend the regeneration process by muscle satellite cells, a three-dimensional (3-D) imaging approach is essential. Confocal microscopy serves as an exceptional method for examining the spatial arrangement of cells within a specific tissue. In this protocol, we provide a detailed procedure for preparing optically transparent extensor digitorum longus (EDL) skeletal muscle specimens that are appropriate for confocal microscopy and computational 3-D assessment. We outline the steps for sample preparation, which include perfusion fixation and the tissue clearing process for rodent muscle specimens, as well as guidelines for image capture and computational evaluation featuring sample segmentation and 3-D visualization. This methodology can be utilized to characterize diverse cell types, such as muscle satellite cells and capillary endothelial cells found in rodent skeletal muscle.

Keywords:  3-D imaging; Angiogenesis; Endothelial cell; Muscle regeneration; Muscle stem cell; Muscular dystrophy; Myogenesis; Satellite cell; Skeletal muscle; Tissue clearing

DOI:  https://doi.org/10.1007/7651_2025_618
Methods Mol Biol. 2025 Apr 05.

Human Skeletal Muscle Niche Formation and Analysis with Spatial RNA Sequencing.

Ben Clock, Michael Hicks.

  Formation of the human skeletal muscle can be achieved through xenotransplant of human stem or progenitor cells into mice. Human cells, such as those derived from human pluripotent stem cells (hPSCs), are dissociated from in vitro culture conditions and injected into immune-compromised mice where human cells must form new myofibers and retain or replace the mouse muscle stem cell pool. Efforts to better understand niche interactions will lead to improved regenerative potential that could ameliorate a broad range of muscle diseases. Spatial RNA sequencing of xenografted tissues allows for precise transcriptomic profiling of human muscle stem and progenitor cells in relation to myofibers and their niche throughout the myogenic differentiation process. Herein, we describe the procedures of obtaining high yields of human xenografted transplants and compare the use of various spatial RNA sequencing platforms to uncover stem cell niche formation.

Keywords:  Engraftment; Niche formation; Skeletal muscle; Spatial transcriptomics; Stem cell

DOI:  https://doi.org/10.1007/7651_2025_619
bioRxiv. 2025 Mar 14. pii: 2025.03.12.642857. [Epub ahead of print]

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

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

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

Keywords:  Biological Sciences; Duchenne Muscular Dystrophy; Jagged-1; genetic modifier; mouse model; muscles; physiology

DOI:  https://doi.org/10.1101/2025.03.12.642857
Am J Physiol Cell Physiol. 2025 Apr 02.

A History of Omics Discoveries Reveals the Correlates and Mechanisms of Loading-Induced Hypertrophy in Adult Skeletal Muscle.

Toby L Chambers, Kevin A Murach.

  Since the early 2000s, omics approaches to study skeletal muscle hypertrophy consequent to loading (e.g. resistance exercise) have expanded dramatically. Beginning with genomics and transcriptomics, there are now omics datasets from hypertrophying skeletal muscle spanning methylomics, proteomics, and phosphoproteomics, with further integration of single cell/nucleus-specific omics, among others. The purpose of this review is to explore the history of leveraging omics to enable understanding and discovery with respect to loading-induced hypertrophy in adult skeletal muscle. We elaborate on key historical and contemporary studies and findings, highlight specific examples where omics discoveries led to mechanistic understanding of skeletal muscle growth, and provide background on established and emerging omic technologies. We focus on findings from human skeletal muscle tissue but also provide context and support from the rodent literature, including insights from gain- and loss-of-function experiments. Moving forward, the computational integration of omics datasets will provide unprecedented information and exciting new directions for studying how resistance exercise mediates skeletal muscle health. This information will help inform how to target key factors influencing muscle mass with a deep, comprehensive, and integrated multi-layered understanding of their molecular regulation.

Keywords:  RNA-sequencing; bioinformatics; phosphoproteomics; proteomics; single cell RNA-sequencing

DOI:  https://doi.org/10.1152/ajpcell.00968.2024
Res Sq. 2025 Mar 20. pii: rs.3.rs-5968078. [Epub ahead of print]

Time Release Ion Matrix Regenerates Dystrophic Skeletal Muscle.

Aaron Morton, Jacob Kendra, Alexandra Naman, Rebekah Blatt, Richard Brow, Steven Segal, Yava Jones-Hall, Carla Zingariello.

A time-release ion matrix (TRIM) restores damaged tissue following injury through local ion release to stimulate regenerative gene expression. Here we report the use of CoO-TRIM, an FDA-designated Rare Pediatric Disease Drug, to restore muscle function and structure in the context of debilitating muscle disease. We demonstrate in an established animal model of Duchenne Muscular Dystrophy (DMD), the D2.mdx mouse, that tibialis anterior (TA) muscles receiving a single injection of CoO-TRIM exhibit greater active force, myofiber size and regeneration through 70 days post-treatment compared to D2.mdx receiving vehicle alone. TRIM promoted upregulation of pro-angiogenic growth factor (vascular endothelial growth factor) and increased muscle microvasculature. These findings indicate that CoO-TRIM stimulates growth factors to promote the restoration of muscle structure and function of severely dystrophic mice in vivo without toxicity. We conclude that CoO-TRIM is a first-in-class therapeutic compound to combat soft tissue disease by restoring tissue integrity. Moreover, this novel treatment strategy could benefit both early and late-stage DMD patients.

DOI: https://doi.org/10.21203/rs.3.rs-5968078/v1
Nat Commun. 2025 Mar 28. 16(1): 3056

Muscle-specific Ryanodine receptor 1 properties underlie limb-girdle muscular dystrophy 2B/R2 progression.

Aldo Meizoso-Huesca, Cedric R Lamboley, James R Krycer, Mark P Hodson, James E Hudson, Bradley S Launikonis.

Ryanodine receptor 1 Ca2+ leak is a signal in skeletal muscle, but chronic leak can underlie pathology. Here we show that in healthy male mouse, limb-girdle muscle presents higher sympathetic input, elevated ryanodine receptor 1 basal phosphorylation, Ca2+ leak and mitochondrial Ca2+ content compared to distal leg muscles. These regional differences are consistent with heat generation in resting muscle to maintain core temperature. The dysferlin-null mouse develops severe pathology in the limb-girdle but not leg muscles. Absence of dysferlin disrupts dihydropyridine receptors' inhibitory control over ryanodine receptor 1 leak, synergistically increasing leak through the already phosphorylated channel of limb-girdle muscle. This alters Ca2+ handling and distribution leading to reactive oxygen species production prior to disease onset. With age, oxidation of Ca2+ -handling proteins in dysferlin-null limb-girdle muscle alters basal Ca2+ movements. Our results show that muscle-specific pathology in dysferlin-null mice is linked to increased ryanodine receptor 1 Ca2+ leak.

DOI: https://doi.org/10.1038/s41467-025-58393-2
Cell Commun Signal. 2025 Apr 01. 23(1): 158

DNM1L-mediated fission governs mitophagy & mitochondrial biogenesis during myogenic differentiation.

Fasih A Rahman, Jasmine M Friedrich Yap, Tyler M Joseph, Amanda M Adam, Sarah M Chapman, Joe Quadrilatero.

   BACKGROUND: Remodeling of the mitochondrial network is implicated in myogenesis. Remodeling processes including mitochondrial fission, mitophagy, and biogenesis are important as they finetune the mitochondrial network to meet the increased energetic demand of myotubes. Evidence suggests that mitochondrial fission governs other mitochondrial remodeling processes; however, this relationship is unclear in the context of myogenesis.
METHODS: We used C2C12 myoblasts to study changes in mitochondrial remodeling processes and their role in regulating myogenesis. To investigate this, we employed genetic manipulation with adenoviruses to modify the levels of key molecules involved in mitochondrial remodeling, including DNM1L, BNIP3, and PPARGC1A.
RESULTS: We demonstrate that overexpression of fission protein DNM1L accelerated mitophagic flux, but reduced myotube size without affecting mitochondrial biogenesis. Conversely, DNM1L knockdown reduced mitophagic flux, impaired myoblast differentiation, and suppressed mitochondrial biogenesis signaling. Additionally, DNM1L knockdown increased mitochondrial apoptotic signaling through CASP9 and CASP3 activation. Attempts to rescue myogenesis through overexpression of the mitophagy receptor BNIP3 or the biogenesis regulator PPARGC1A were unsuccessful in the absence of proper mitochondrial fission. Furthermore, DNM1L overexpression in BNIP3-deficient cells enhanced mitophagic flux, but did not promote myogenesis.
CONCLUSION: These results underscore the complex interdependencies among mitochondrial remodeling processes and highlight the necessity for sequential activation of mitochondrial fission, mitophagy, and biogenesis.

Keywords:  Apoptosis; Mitochondrial biogenesis; Mitochondrial fission; Mitophagy; Myogenesis; Skeletal muscle

DOI:  https://doi.org/10.1186/s12964-025-02142-x
J Cachexia Sarcopenia Muscle. 2025 Apr;16(2): e13779

Nestin Regulates Autophagy-Dependent Ferroptosis Mediated Skeletal Muscle Atrophy by Ubiquitinating MAP 1LC3B.

Shunshun Han, Xiyu Zhao, Chunlin Yu, Can Cui, Yao Zhang, Qing Zhu, Mohan Qiu, Chaowu Yang, Huadong Yin.

   BACKGROUND: Programmed cell death plays a critical role in skeletal muscle atrophy. Ferroptosis, an iron-dependent form of programmed cell death driven by lipid peroxidation, has been implicated in various diseases, but its role in skeletal muscle atrophy remains unclear.
METHODS: Ferroptosis in skeletal muscle atrophy was investigated using two models: dexamethasone (Dex)-induced atrophy (n = 6 independent cell cultures per group) and simulated microgravity (n = 6 mice per group). Conditional Nestin knockout (KO) mice were generated using CRISPR/Cas9 (n = 6-8 mice per group), with wild-type (WT) controls (n = 6-8). Phenotypic analyses included histopathology (HE staining), functional assessments (muscle strength, weight analysis, treadmill), and dystrophy evaluation (dystrophin staining). Molecular analyses involved flow cytometry, ELISA, transmission electron microscopy, PI staining, and IP/MS to delineate Nestin-regulated ferroptosis pathways in skeletal muscle atrophy.
RESULTS: Ferroptosis was significantly activated in both atrophy models, with a 2.5-fold increase in lipid peroxidation (p < 0.01), a 2-fold accumulation of Fe2+ (p < 0.01) and a 50% reduction in Nestin expression (p < 0.001). Nestin KO mice exhibited exacerbated muscle atrophy, showing a 40% decrease in muscle weight (p < 0.01) and a 30% reduction in muscle strength (p < 0.05) compared to WT mice. Nestin overexpression mitigated Dex-induced ferroptosis, reducing lipid peroxidation by 40%, decreasing Fe2+ accumulation by 50% (p < 0.01), and improving muscle function by 30% (p < 0.05). Mechanistically, Nestin interacted with MAP 1LC3B (LC3B) to catalyse LC3B polyubiquitination at lysine-51, reducing LC3B availability for autophagy and inhibiting autophagy flux by 60% (p < 0.01), leading to a 50% reduction in ferroptosis (p < 0.001).
CONCLUSIONS: Our study identifies Nestin as a critical regulator of ferroptosis-autophagy crosstalk in skeletal muscle atrophy. Targeting Nestin-LC3B ubiquitination may offer novel therapeutic strategies for preventing muscle wasting in diseases such as cachexia and sarcopenia.

Keywords:  MAP 1LC3B; autophagy; ferroptosis; nestin; skeletal muscle atrophy

DOI:  https://doi.org/10.1002/jcsm.13779
bioRxiv. 2025 Mar 13. pii: 2025.03.10.642477. [Epub ahead of print]

Rapamycin does not compromise physical performance or muscle hypertrophy after PoWeR while intermittent rapamycin alleviates glucose disruptions by frequent rapamycin.

Christian J Elliehausen, Szczepan S Olszewski, Carolyn G Shult, Aditya R Ailiani, Michaela E Trautman, Reji Babygirija, Dudley W Lamming, Troy A Hornberger, Dennis M Minton, Adam R Konopka.

An increasing number of physically active adults are taking the mTOR inhibitor rapamycin off label with the goal of extending healthspan. However, frequent rapamycin dosing disrupts metabolic health during sedentary conditions and abates the anabolic response to exercise. Intermittent once weekly rapamycin dosing minimizes many negative metabolic side effects of frequent rapamycin in sedentary mice. However, it remains unknown how different rapamycin dosing schedules impact metabolic, physical, and skeletal muscle adaptations to voluntary exercise training. Therefore, we tested the hypothesis that intermittent rapamycin (2mg/kg; 1x/week) would avoid detrimental effects on adaptations to 8 weeks of progressive weighted wheel running (PoWeR) in adult female mice (5-month-old) by evading the sustained inhibitory effects on mTOR signaling by more frequent dosing schedules (2mg/kg; 3x/week). Frequent but not intermittent rapamycin suppressed skeletal muscle mTORC1 signaling in PoWeR trained mice. PoWeR improved maximal exercise capacity, absolute grip strength, and myofiber hypertrophy with no differences between vehicle or rapamycin treated mice. Conversely, frequent and intermittent rapamycin treated mice had impaired glucose tolerance and insulin sensitivity compared to vehicle treated mice after PoWeR; however, intermittent rapamycin reduced the impact on glucose intolerance versus frequent rapamycin. Collectively, these data in adult female mice suggest that 1) rapamycin is largely compatible with the physical and skeletal muscle benefits of PoWeR and 2) the detrimental effects of rapamycin on body composition and glucose metabolism in the context of voluntary exercise may be reduced by intermittent dosing.

DOI: https://doi.org/10.1101/2025.03.10.642477
bioRxiv. 2025 Mar 17. pii: 2025.03.15.639012. [Epub ahead of print]

Proteomic profiling uncovers sexual dimorphism in the muscle response to wheel running exercise in the FLExDUX4 murine model of facioscapulohumeral muscular dystrophy.

Yusuke Nishimura, Adam Bittel, Abhishek Jagan, Yi-Wen Chen, Jatin Burniston.

FLExDUX4 is a murine experimental model of facioscapulohumeral muscular dystrophy (FSHD) characterized by chronic, low levels of leaky expression of the human full-length double homeobox 4 gene (DUX4-fl). FLExDUX4 mice exhibit mild pathologies and functional deficits similar to people affected by FSHD. Proteomic studies in FSHD could offer new insights into disease mechanisms underpinned by post-transcriptional processes. We used mass spectrometry-based proteomics to quantify the abundance of 1322 proteins in triceps brachii muscle, encompassing both male and female mice in control and free voluntary wheel running (VWR) in Wild-type (n=3) and FLExDUX4 (n=3) genotypes. We report the triceps brachii proteome of FLExDUX4 mice recapitulates key skeletal muscle clinical characteristics of human FSHD, including alterations to mitochondria, RNA metabolism, oxidative stress, and apoptosis. RNA-binding proteins exhibit a sex-specific difference in FLExDUX4 mice. Sexual dimorphism of mitochondrial protein adaptation to exercise was uncovered specifically in FLExDUX4 mice, where females increased, but males decreased mitochondrial proteins after a 6-week of VWR. Our results highlight the importance of identifying sex-specific diagnostic biomarkers to enable more reliable monitoring of FSHD therapeutic targets. Our data provides a resource for the FSHD research community to explore the burgeoning aspect of sexual dimorphism in FSHD.
In Brief: Nishimura et al. conducted proteomic analysis of triceps brachii muscle in the FLExDUX4 murine model of FSHD and verified FLExDUX4 mice recapitulate key skeletal muscle clinical characteristics of human FSHD, including disruptions to the mitochondrial proteome and proteins associated with RNA metabolism, oxidative stress, and apoptosis. RNA-binding proteins and the mitochondrial proteome response to exercise exhibited sexual dimorphism in FLExDUX4 mice. Specifically, females exhibited increases, whereas males exhibited decreases in mitochondrial protein abundance after 6-weeks voluntary wheel running.
Highlights: FLExDUX4 muscle proteome mirrors pathophysiology of FSHD patient myoblastsMitochondrial proteins are more abundant in FLExDUX4 as compared to WT miceSeverity of proteome disruption is greater in male than female miceRNA-binding proteins exhibit a sex-specific difference in FLExDUX4 miceSex-specific mitochondrial proteome response to VWR in FLExDUX4 mice.

DOI: https://doi.org/10.1101/2025.03.15.639012
NPJ Aging. 2025 Mar 30. 11(1): 23

Pan-PTM profiling identifies post-translational modifications associated with exceptional longevity and preservation of skeletal muscle function in Drosophila.

Suresh Poudel, Chia-Lung Chuang, Him K Shrestha, Fabio Demontis.

Skeletal muscle weakness is a major component of age-associated frailty, but the underlying mechanisms are not completely understood. Drosophila has emerged as a useful model for studying skeletal muscle aging. In this organism, previous lab-based selection established strains with increased longevity and reduced age-associated muscle functional decline compared to a parental strain. Here, we have applied a computational pipeline (JUMPptm) for retrieving information on 8 post-translational modifications (PTMs) from the skeletal muscle proteomes of 2 long-lived strains and the corresponding parental strain in young and old age. This pan-PTM analysis identified 2470 modified sites (acetylation, carboxylation, deamidation, dihydroxylation, mono-methylation, oxidation, phosphorylation, and ubiquitination) in several classes of proteins, including evolutionarily conserved muscle contractile proteins and metabolic enzymes. PTM consensus sequences further highlight the amino acids that are enriched adjacent to the modified site, thus providing insight into the flanking residues that influence distinct PTMs. Altogether, these analyses identify PTMs associated with muscle functional decline during aging and that may underlie the longevity and negligible functional senescence of lab-evolved Drosophila strains.

DOI: https://doi.org/10.1038/s41514-025-00215-2
Sci Rep. 2025 Mar 31. 15(1): 11020

Multi-scale modeling and simulation of skeletal muscles with different fatigue degrees based on microphysiology.

Monan Wang, Daixin Jin, Haibin Wang, Xinyi Xu, Siyuan Zheng.

  The ability for skeletal muscle to constantly generate force is limited by the muscle fatigue. The calcium ion plays a significant role of the cross-bridge cycle under fatigue conditions in the force generation of skeletal muscle. To uncover complicated fatigue behavior, we conducted a multi-scale model of skeletal muscle based on cellular biochemical events. We also parameterized our model to obtain the characteristics of the change of concentration of phosphate ions and phosphate compounds in the myoplasm. The results provided evidence that under different fatigue levels, the peak of muscle strength decreases with the increase of muscle fatigue, which proves that the synergistic effect of muscle filaments and phosphate will affect the circulation of calcium ions, thereby affecting muscle fatigue and generation of muscle force. We used our modeling approach to bring new insights into the effect of phosphate ions and synergistic effect of myofilaments.

Keywords:  Calcium dynamics; Multi-scale; Phosphate dynamics; Skeletal muscle

DOI:  https://doi.org/10.1038/s41598-025-87443-4
J Cachexia Sarcopenia Muscle. 2025 Apr;16(2): e13790

Transcriptional Co-Activator With PDZ Binding Motif (TAZ) Inhibits Dexamethasone-Induced Muscle Atrophy via mTOR Signalling.

Kyung Min Kim, Ho Taek Oh, Youjin Do, Gi Don Yoo, Woong Heo, Jeekeon Park, Hyejin Yang, Suh Jin Yoon, Mi Ran Byun, Eun Sook Hwang, Jeong-Ho Hong.

   BACKGROUND: Glucocorticoid therapy has a beneficial effect in several diseases, but chronic treatment has adverse effects, including muscle atrophy, which refers to the gradual decrease in muscle mass, size and strength. It is important to know how the muscle atrophy occurs, but the underlying mechanism is not yet fully understood. This study shows that dexamethasone decreases levels of the transcriptional co-activator with PDZ binding motif (TAZ), which facilitates dexamethasone-induced muscle atrophy.
METHODS: To induce muscle atrophy, C2C12 myotubes were treated with dexamethasone, and mice were fed with water containing dexamethasone. Muscle atrophy was analysed for the expression of myosin heavy chain, MuRF1 and Atrogin-1 using immunofluorescence staining, immunoblot analysis and qRT-PCR. Muscle tissue was analysed by haematoxylin and eosin staining. Adeno-associated virus was used for overexpression of wild-type and mutant TAZ.
RESULTS: TAZ levels decrease in dexamethasone-treated mice (0.36-fold, p < 0.001) and C2C12 myotubes (0.44-fold, p = 0.024). Overexpression of the TAZ mutant, which resists its proteolytic degradation, inhibits dexamethasone-induced muscle atrophy. Atrogin-1 and MuRF1 interact with TAZ and facilitate its degradation in dexamethasone-treated C2C12 myotubes. TAZ mutant stimulates protein synthesis through activation of mTOR signalling via induction of RhebL1 (DEX; Con vs, TAZ4SA: 5.1-fold, p < 0.001) in dexamethasone-treated mice. Ginsenoside Rb3 increases TAZ levels in dexamethasone-treated mice (1.49-fold, p = 0.007) and C2C12 myotubes (1.63-fold, p = 0.01), which stimulates mTOR signalling and inhibits dexamethasone-induced muscle atrophy.
CONCLUSIONS: Our results demonstrate a novel regulatory mechanism of dexamethasone-induced muscle atrophy by TAZ, suggesting that stabilisation of TAZ in muscle cells ameliorates the muscle atrophy. These results suggest that TAZ may be a drug target for the dexamethasone-induced muscle atrophy.

Keywords:  dexamethasone; ginsenoside; mTOR; muscle atrophy

DOI:  https://doi.org/10.1002/jcsm.13790
Muscle Nerve. 2025 Apr 04.

Leucine Supplementation Counteracts the Atrophic Effects of HDAC4 in Rat Skeletal Muscle Submitted to Hindlimb Immobilization.

Paula K N Alves, André Cruz, William J Silva, Afonso M Melazzo, Siegfried Labeit, Volker Adams, Anselmo S Moriscot.

   INTRODUCTION/AIMS: We previously demonstrated that leucine supplementation significantly reduces histone deacetylase 4 (HDAC4) expression induced by hindlimb immobilization, thereby attenuating the increase in HDAC4 protein levels and nuclear accumulation. In this study, we investigated the impact of supraphysiological HDAC4 levels on skeletal muscle and the inhibitory potential of leucine in this scenario.
METHODS: A total of 64 male Wistar rats were used in this study and subjected to electroporation of the soleus muscle with or without a plasmid overexpressing HDAC4 mRNA, followed by hindlimb immobilization and leucine supplementation (1.35 g/kg) for 7 days.
RESULTS: Our findings revealed that HDAC4 overexpression alone led to soleus atrophy, resulting in a 23% decrease in mass, a 31% reduction in whole muscle cross-sectional area (CSA), and a 17% decrease in fiber CSA. These reductions were further exacerbated by hindlimb immobilization, with decreases of 50%, 46%, and 34%, respectively. Moreover, leucine supplementation protected against soleus atrophy and preserved soleus fiber CSA by 17%. This protective effect was accompanied by a 57% reduction in HDAC4-positive nuclear localization in immobilized rats overexpressing HDAC4.
DISCUSSION: Our results indicate that HDAC4 forced expression can alone induce skeletal muscle atrophy. In addition, our results indicate that leucine is dominant in blocking HDAC4 signaling and highlight the use of this amino acid as a therapeutic tool in conditions involving skeletal muscle atrophy.

Keywords:  HDAC4; hindlimb immobilization; leucine; rats; skeletal muscle

DOI:  https://doi.org/10.1002/mus.28411
J Cachexia Sarcopenia Muscle. 2025 Apr;16(2): e13776

Calcium Handling Machinery and Sarcomere Assembly are Impaired Through Multipronged Mechanisms in Cancer Cytokine-Induced Cachexia.

Luis Vincens Gand, Chiara Lanzuolo, Mugeng Li, Valentina Rosti, Natalie Weber, Dongchao Lu, Christian Bär, Thomas Thum, Andreas Pich, Theresia Kraft, Mamta Amrute-Nayak, Arnab Nayak.



Keywords:  RNA polymerase II; calcium homeostasis; cancer secreted pro‐inflammatory cytokine‐induced cachexia; chromatin organization; proteostasis; sarcoplasmic reticulum

DOI:  https://doi.org/10.1002/jcsm.13776
Aging (Albany NY). 2025 Mar 31. null

Mesenchymal stem cell-specific Sirt1 overexpression prevents sarcopenia induced by 1,25-dihydroxyvitamin D deficiency.

Haiyun Chen, Biqi Ren, Jing Wang, Xingchen Liu, Xiangjiao Yi, David Goltzman, Dengshun Miao.

  Sarcopenia, characterized by an age-related decline in skeletal muscle mass and function, is closely linked to vitamin D deficiency. This study examines the role of Sirtuin 1 (Sirt1) and its regulation by vitamin D in preventing sarcopenia. Utilizing wild-type, 1α-hydroxylase knockout (1α(OH)ase-/-), and Sirt1 transgenic (Sirt1Tg) 1α(OH)ase-/- mice, we investigated muscle Sirt1 levels, muscle mass, fiber type, and senescence markers. Our results demonstrated that 1,25-Dihydroxyvitamin D (1,25(OH)2D3) upregulated Sirt1 and myogenic factor MyoD1 expression in C2C12 myoblasts via VDR-mediated transcription. Sirt1 overexpression in mesenchymal stem cells (MSCs) significantly mitigated muscle mass reduction, improved fiber cross-sectional area, and increased type II fiber numbers in 1α(OH)ase-/- mice. Mechanistically, 1,25(OH)2D3 promoted muscle cell health by enhancing Sirt1 expression, which in turn reduced muscle cell senescence and the senescence-associated secretory phenotype (SASP) through decreased levels of acetylated nuclear p53 and p65, maintaining their cytoplasmic localization. Additionally, Sirt1 overexpression accelerated muscle regeneration post-injury by increasing embryonic myosin heavy chain expression and cell proliferation. These findings underscore the therapeutic potential of targeting vitamin D and Sirt1 pathways to prevent sarcopenia, suggesting that supplementation with active vitamin D and consequent Sirt1 activation could be effective strategies for managing age-related muscle wasting.

Keywords:  Myod1; Sirt1; active vitamin D; muscle regeneration; sarcopenia

DOI:  https://doi.org/10.18632/aging.206232
Nucleic Acids Res. 2025 Mar 20. pii: gkaf232. [Epub ahead of print]53(6):

Small nucleolar RNAs promote the restoration of muscle differentiation defects in cells from myotonic dystrophy type 1.

Baptiste Bogard, Hélène Bonnet, Ekaterina Boyarchuk, Gilles Tellier, Denis Furling, Vincent Mouly, Claire Francastel, Florent Hubé.

Recently, the repertoire of human small nucleolar noncoding RNAs (snoRNAs) and their potential functions has expanded with the discovery of new snoRNAs and messenger RNA (mRNA) targets, for which snoRNA-guided modifications may influence their stability, translatability, and splicing. We previously identified snoRNAs that are abundant in healthy human muscle progenitor cells. In this study, we demonstrated that SNORA40 and SNORA70 loss-of-function impairs myogenic differentiation. Interestingly, gain-of-function can rescue impaired differentiation muscle progenitor cells in myotonic dystrophy type 1 (DM1). We identified cyclin D3 (CCND3) mRNA, which is partially located in the nucleolus, as a target for SNORA40 and SNORA70, which are required for its pseudouridylated status. Expression of the CCND3 protein is required for muscle progenitors to exit the cell-cycle when they are induced to differentiate. We revealed that this switch requires SNORA40/70. Finally, we observed that DM1 cells show reduced levels of SNORA40/70 and undetectable CCND3 protein. However, restoring normal levels of SNORA40/70 partially restored CCND3 protein expression, coinciding with improved cell fusion capacity in DM1 muscle progenitors. Collectively, these data suggest that this effect may stem from SNORA40/70-dependent pseudouridylation of CCND3 mRNA, emphasizing snoRNAs as key players in normal and pathological muscle differentiation.

DOI: https://doi.org/10.1093/nar/gkaf232
FASEB J. 2025 Apr 15. 39(7): e70514

The role of inner nuclear membrane protein emerin in myogenesis.

Nicholas Marano, James M Holaska.

  Emerin, a ubiquitously expressed inner nuclear membrane protein, plays a central role in maintaining nuclear structure and genomic organization, and in regulating gene expression and cellular signaling pathways. These functions are critical for proper myogenic differentiation and are closely linked to the pathology of Emery-Dreifuss muscular dystrophy 1 (EDMD1), a laminopathy caused by mutations in the EMD gene. Emerin, along with other nuclear lamina proteins, modulates chromatin organization, cell signaling, gene expression, and cellular mechanotransduction, processes essential for muscle development and homeostasis. Loss of emerin function disrupts chromatin localization, causes dysregulated gene expression, and alters nucleoskeletal organization, resulting in impaired myogenic differentiation. Recent findings suggest that emerin tethers repressive chromatin at the nuclear envelope, a process essential for robust myogenesis. This review provides an in-depth discussion of emerin's multifaceted roles in nuclear organization, gene regulation, and cellular signaling, highlighting its importance in myogenic differentiation and disease progression.

Keywords:  Emery‐Dreifuss muscular dystrophy; emerin; laminopathy; myogenic differentiation

DOI:  https://doi.org/10.1096/fj.202500323
Mol Ther. 2025 Apr 02. pii: S1525-0016(25)00274-6. [Epub ahead of print]

The road towards AAV-mediated gene therapy of Duchenne muscular dystrophy.

Niclas E Bengtsson, Hichem Tasfaout, Jeffrey S Chamberlain.

Forty years after the dystrophin gene was cloned, significant progress has been made in developing gene therapy approaches for Duchenne muscular dystrophy (DMD). The disorder has presented numerous challenges, including the enormous size of the gene (2.2 MB), the need to target muscles body wide, and immunogenic issues against both vectors and dystrophin. Among human genetic disorders, DMD is relatively common and the genetics are complicated since one-third of all cases arise from a spontaneous new mutation, resulting in thousands of independent lesions throughout the locus. Many approaches have been pursued in the goal of finding an effective therapy, including exon skipping, nonsense codon suppression, upregulation of surrogate genes, gene replacement and gene editing. Here we focus specifically on methods using AAV vectors, as these approaches have been tested in numerous clinical trials and are able to target muscles systemically. We discuss early advances to understand the structure of dystrophin, which are crucial for design of effective DMD gene therapies. Included is a summary of efforts to deliver micro-, mini- and full-length dystrophins to muscles. Finally, we also review current approaches to adapt gene editing to the enormous DMD gene with prospects for improved therapies using all these methods.

DOI: https://doi.org/10.1016/j.ymthe.2025.03.065