bims-moremu Biomed News
on Molecular regulators of muscle mass
Issue of 2024‒04‒28
fifty-two papers selected by
Anna Vainshtein, Craft Science Inc.
  1. Muscle stem cell niche dynamics during muscle homeostasis and regeneration.
  2. Restoring Mitochondrial Function and Muscle Satellite Cell Signaling: Remedies against Age-Related Sarcopenia.
  3. Immunological regulation of skeletal muscle adaptation to exercise.
  4. Pannexin 1 dysregulation in Duchenne muscular dystrophy and its exacerbation of dystrophic features in mdx mice.
  5. Muscle stem cells as immunomodulator during regeneration.
  6. Decoding the forces that shape muscle stem cell function.
  7. Mitochondrial Transplantation's Role in Rodent Skeletal Muscle Bioenergetics: Recharging the Engine of Aging.
  8. Circadian timing of satellite cell function and muscle regeneration.
  9. Skeletal muscle differentiation induces wide-ranging nucleosome repositioning in muscle gene promoters.
  10. Skeletal muscle niche, at the crossroad of cell/cell communications.
  11. The satellite cell in skeletal muscle: A story of heterogeneity.
  12. A novel deep proteomic approach in human skeletal muscle unveils distinct molecular signatures affected by aging and resistance training.
  13. Alterations in skeletal muscle morphology related to impaired mechanical efficiency in immobile older adults.
  14. Accelerated sarcopenia precedes learning and memory impairments in the P301S mouse model of tauopathies and Alzheimer's disease.
  15. Epigenetic integration of signaling from the regenerative environment.
  16. Redox signaling and skeletal muscle adaptation during aerobic exercise.
  17. Muscle stem cell dysfunction in rhabdomyosarcoma and muscular dystrophy.
  18. Network model of skeletal muscle cell signalling predicts differential responses to endurance and resistance exercise training.
  19. Carbon monoxide-loaded cell therapy as an exercise mimetic for sarcopenia treatment.
  20. Muscle weakness and mitochondrial stress occur before metastasis in a novel mouse model of ovarian cancer cachexia.
  21. Sedentary behavior in mice induces metabolic inflexibility by suppressing skeletal muscle pyruvate metabolism.
  22. The effects of resistance training on denervated myofibers, senescent cells, and associated protein markers in middle-aged adults.
  23. Role of microenvironment on muscle stem cell function in health, adaptation, and disease.
  24. Long non-coding RNAs and their role in muscle regeneration.
  25. Lineage tracing reveals a novel PDGFRβ+ satellite cell subset that contributes to myo-regeneration of chronically injured rotator cuff muscle.
  26. Change of voltage-gated sodium channel repertoire in skeletal muscle of a MuSK myasthenia gravis mouse model.
  27. Phosphorylation of AS160-Serine 704 is Not Essential for Exercise-increase in Insulin-stimulated Glucose Uptake by Skeletal Muscles from Female or Male Rats.
  28. Dimorphic effect of TFE3 in determining mitochondrial and lysosomal content in muscle following denervation.
  29. Endocannabinoid remodeling in murine cachexic muscle associates with catabolic and metabolic regulation.
  30. The complex nature of skeletal muscle fatigue: Understanding the interaction of metabolic stress and membrane excitability.
  31. Molecular regulation of myocyte fusion.
  32. Chromatin organization of muscle stem cell.
  33. Navigating translational control of gene expression in satellite cells.
  34. Effect of the Mitochondrial Transaminase (GOT2) on Membrane Potential Sensitive Respiration in Mitochondria of Differentiated C2C12 Muscle Cells.
  35. A tryptophan-derived uremic metabolite-Ahr-Pdk4 axis governs skeletal muscle mitochondrial energetics in chronic kidney disease.
  36. Repeated sprint training in hypoxia induces specific skeletal muscle adaptations through S100A protein signaling.
  37. The extracellular matrix niche of muscle stem cells.
  38. Measurement of Myonuclear Accretion In Vitro and In Vivo.
  39. Postsynaptic BMP signaling regulates myonuclear properties in Drosophila larval muscles.
  40. Multimodal cell atlas of the ageing human skeletal muscle.
  41. Muscle-Specific Pyruvate Kinase Isoforms, Pkm1 and Pkm2, Regulate Mammalian SWI/SNF Proteins and Histone 3 Phosphorylation During Myoblast Differentiation.
  42. LSD1 inhibition circumvents glucocorticoid-induced muscle wasting of male mice.
  43. Aberrant expression of thyroidal hormone receptor α exasperating mitochondrial dysfunction induced sarcopenia in aged mice.
  44. N-Acetylcysteine Attenuates Sepsis-Induced Muscle Atrophy by Downregulating Endoplasmic Reticulum Stress.
  45. MyoD Over-Expression Rescues GST-bFGF Repressed Myogenesis.
  46. Systematic analysis of muscle aging using joint single-cell and single-nucleus sequencing.
  47. Satellite cells in the growth and maintenance of muscle.
  48. Mechanical interaction of myosin and native thin filament in the disused rat soleus muscle.
  49. Resistance training-induced changes in muscle proteolysis and extracellular matrix remodeling biomarkers in the untrained and trained states.
  50. Effects of the immune system on muscle regeneration.
  51. The role of mitochondrial dynamics and mitophagy in skeletal muscle atrophy: from molecular mechanisms to therapeutic insights.
  52. Metabolomics-driven discovery of therapeutic targets for cancer cachexia.
  1. Curr Top Dev Biol. 2024 ;pii: S0070-2153(24)00029-2. [Epub ahead of print]158 151-177
    Muscle stem cell niche dynamics during muscle homeostasis and regeneration.
    Yishu Yin, Gary J He, Shenyuan Hu, Erin H Y Tse, Tom H Cheung.
      The process of skeletal muscle regeneration involves a coordinated interplay of specific cellular and molecular interactions within the injury site. This review provides an overview of the cellular and molecular components in regenerating skeletal muscle, focusing on how these cells or molecules in the niche regulate muscle stem cell functions. Dysfunctions of muscle stem cell-to-niche cell communications during aging and disease will also be discussed. A better understanding of how niche cells coordinate with muscle stem cells for muscle repair will greatly aid the development of therapeutic strategies for treating muscle-related disorders.
    Keywords:  Cell-to-cell communication; Muscle regeneration; Muscle stem cells; Niche
    DOI:  https://doi.org/10.1016/bs.ctdb.2024.02.008
  2. Biomolecules. 2024 Mar 28. pii: 415. [Epub ahead of print]14(4):
    Restoring Mitochondrial Function and Muscle Satellite Cell Signaling: Remedies against Age-Related Sarcopenia.
    Emanuele Marzetti, Biliana Lozanoska-Ochser, Riccardo Calvani, Francesco Landi, Hélio José Coelho-Júnior, Anna Picca.
      Sarcopenia has a complex pathophysiology that encompasses metabolic dysregulation and muscle ultrastructural changes. Among the drivers of intracellular and ultrastructural changes of muscle fibers in sarcopenia, mitochondria and their quality control pathways play relevant roles. Mononucleated muscle stem cells/satellite cells (MSCs) have been attributed a critical role in muscle repair after an injury. The involvement of mitochondria in supporting MSC-directed muscle repair is unclear. There is evidence that a reduction in mitochondrial biogenesis blunts muscle repair, thus indicating that the delivery of functional mitochondria to injured muscles can be harnessed to limit muscle fibrosis and enhance restoration of muscle function. Injection of autologous respiration-competent mitochondria from uninjured sites to damaged tissue has been shown to reduce infarct size and enhance cell survival in preclinical models of ischemia-reperfusion. Furthermore, the incorporation of donor mitochondria into MSCs enhances lung and cardiac tissue repair. This strategy has also been tested for regeneration purposes in traumatic muscle injuries. Indeed, the systemic delivery of mitochondria promotes muscle regeneration and restores muscle mass and function while reducing fibrosis during recovery after an injury. In this review, we discuss the contribution of altered MSC function to sarcopenia and illustrate the prospect of harnessing mitochondrial delivery and restoration of MSCs as a therapeutic strategy against age-related sarcopenia.
    Keywords:  aging; cytokines; inflammation; mitochondrial dysfunction; mitochondrial-derived vesicles; muscle fibrosis; muscle injury; muscle satellite cells; muscle wasting; skeletal muscle fibers
    DOI:  https://doi.org/10.3390/biom14040415
  3. Cell Metab. 2024 Apr 17. pii: S1550-4131(24)00121-9. [Epub ahead of print]
    Immunological regulation of skeletal muscle adaptation to exercise.
    P Kent Langston, Diane Mathis.
      Exercise has long been acknowledged for its powerful disease-preventing, health-promoting effects. However, the cellular and molecular mechanisms responsible for the beneficial effects of exercise are not fully understood. Inflammation is a component of the stress response to exercise. Recent work has revealed that such inflammation is not merely a symptom of exertion; rather, it is a key regulator of exercise adaptations, particularly in skeletal muscle. The purpose of this piece is to provide a conceptual framework that we hope will integrate exercise immunology with exercise physiology, muscle biology, and cellular immunology. We start with an overview of early studies in the field of exercise immunology, followed by an exploration of the importance of stromal cells and immunocytes in the maintenance of muscle homeostasis based on studies of experimental muscle injury. Subsequently, we discuss recent advances in our understanding of the functions and physiological relevance of the immune system in exercised muscle. Finally, we highlight a potential immunological basis for the benefits of exercise in musculoskeletal diseases and aging.
    Keywords:  Tregs; exercise; muscle
    DOI:  https://doi.org/10.1016/j.cmet.2024.04.001
  4. Skelet Muscle. 2024 Apr 26. 14(1): 8
    Pannexin 1 dysregulation in Duchenne muscular dystrophy and its exacerbation of dystrophic features in mdx mice.
    Emily Freeman, Stéphanie Langlois, Marcos F Leyba, Tarek Ammar, Zacharie Léger, Hugh J McMillan, Jean-Marc Renaud, Bernard J Jasmin, Kyle N Cowan.
      BACKGROUND: Duchenne muscular dystrophy (DMD) is associated with impaired muscle regeneration, progressive muscle weakness, damage, and wasting. While the cause of DMD is an X-linked loss of function mutation in the gene encoding dystrophin, the exact mechanisms that perpetuate the disease progression are unknown. Our laboratory has demonstrated that pannexin 1 (Panx1 in rodents; PANX1 in humans) is critical for the development, strength, and regeneration of male skeletal muscle. In normal skeletal muscle, Panx1 is part of a multiprotein complex with dystrophin. We and others have previously shown that Panx1 levels and channel activity are dysregulated in various mouse models of DMD.METHODS: We utilized myoblast cell lines derived from DMD patients to assess PANX1 expression and function. To investigate how Panx1 dysregulation contributes to DMD, we generated a dystrophic (mdx) mouse model that lacks Panx1 (Panx1-/-/mdx). In depth characterization of this model included histological analysis, as well as locomotor, and physiological tests such as muscle force and grip strength assessments.
    RESULTS: Here, we demonstrate that PANX1 levels and channel function are reduced in patient-derived DMD myoblast cell lines. Panx1-/-/mdx mice have a significantly reduced lifespan, and decreased body weight due to lean mass loss. Their tibialis anterior were more affected than their soleus muscles and displayed reduced mass, myofiber loss, increased centrally nucleated myofibers, and a lower number of muscle stem cells compared to that of Panx1+/+/mdx mice. These detrimental effects were associated with muscle and locomotor functional impairments. In vitro, PANX1 overexpression in patient-derived DMD myoblasts improved their differentiation and fusion.
    CONCLUSIONS: Collectively, our findings suggest that PANX1/Panx1 dysregulation in DMD exacerbates several aspects of the disease. Moreover, our results suggest a potential therapeutic benefit to increasing PANX1 levels in dystrophic muscles.
    Keywords:  Duchenne muscular dystrophy; Myoblast; Myofiber; Pannexin 1; Skeletal muscle
    DOI:  https://doi.org/10.1186/s13395-024-00340-8
  5. Curr Top Dev Biol. 2024 ;pii: S0070-2153(24)00010-3. [Epub ahead of print]158 221-238
    Muscle stem cells as immunomodulator during regeneration.
    H Rex Xu, Victor V Le, Stephanie N Oprescu, Shihuan Kuang.
      The skeletal muscle is well known for its remarkable ability to regenerate after injuries. The regeneration is a complex and dynamic process that involves muscle stem cells (also called muscle satellite cells, MuSCs), fibro-adipogenic progenitors (FAPs), immune cells, and other muscle-resident cell populations. The MuSCs are the myogenic cell populaiton that contribute nuclei directly to the regenerated myofibers, while the other cell types collaboratively establish a microenvironment that facilitates myogenesis of MuSCs. The myogenic process includes activation, proliferation and differentiationof MuSCs, and subsequent fusion their descendent mononuclear myocytes into multinuclear myotubes. While the contributions of FAPs and immune cells to this microenvironment have been well studied, the influence of MuSCs on other cell types remains poorly understood. This review explores recent evidence supporting the potential role of MuSCs as immunomodulators during muscle regeneration, either through cytokine production or ligand-receptor interactions.
    Keywords:  Cytokine; Inflammation; Microenvironment; Myoblast; Myogenesis; Satellite Cell; Stem Cell Niche
    DOI:  https://doi.org/10.1016/bs.ctdb.2024.01.010
  6. Curr Top Dev Biol. 2024 ;pii: S0070-2153(24)00030-9. [Epub ahead of print]158 279-306
    Decoding the forces that shape muscle stem cell function.
    Jo Nguyen, Penney M Gilbert.
      Skeletal muscle is a force-producing organ composed of muscle tissues, connective tissues, blood vessels, and nerves, all working in synergy to enable movement and provide support to the body. While robust biomechanical descriptions of skeletal muscle force production at the body or tissue level exist, little is known about force application on microstructures within the muscles, such as cells. Among various cell types, skeletal muscle stem cells reside in the muscle tissue environment and play a crucial role in driving the self-repair process when muscle damage occurs. Early evidence indicates that the fate and function of skeletal muscle stem cells are controlled by both biophysical and biochemical factors in their microenvironments, but much remains to accomplish in quantitatively describing the biophysical muscle stem cell microenvironment. This book chapter aims to review current knowledge on the influence of biophysical stresses and landscape properties on muscle stem cells in heath, aging, and diseases.
    Keywords:  Mechanobiology; Muscle stem cells; Niche; Satellite cells; Skeletal muscle
    DOI:  https://doi.org/10.1016/bs.ctdb.2024.02.009
  7. Biomolecules. 2024 Apr 18. pii: 493. [Epub ahead of print]14(4):
    Mitochondrial Transplantation's Role in Rodent Skeletal Muscle Bioenergetics: Recharging the Engine of Aging.
    Tasnim Arroum, Gerald A Hish, Kyle J Burghardt, James D McCully, Maik Hüttemann, Moh H Malek.
      BACKGROUND: Mitochondria are the 'powerhouses of cells' and progressive mitochondrial dysfunction is a hallmark of aging in skeletal muscle. Although different forms of exercise modality appear to be beneficial to attenuate aging-induced mitochondrial dysfunction, it presupposes that the individual has a requisite level of mobility. Moreover, non-exercise alternatives (i.e., nutraceuticals or pharmacological agents) to improve skeletal muscle bioenergetics require time to be effective in the target tissue and have another limitation in that they act systemically and not locally where needed. Mitochondrial transplantation represents a novel directed therapy designed to enhance energy production of tissues impacted by defective mitochondria. To date, no studies have used mitochondrial transplantation as an intervention to attenuate aging-induced skeletal muscle mitochondrial dysfunction. The purpose of this investigation, therefore, was to determine whether mitochondrial transplantation can enhance skeletal muscle bioenergetics in an aging rodent model. We hypothesized that mitochondrial transplantation would result in sustained skeletal muscle bioenergetics leading to improved functional capacity.METHODS: Fifteen female mice (24 months old) were randomized into two groups (placebo or mitochondrial transplantation). Isolated mitochondria from a donor mouse of the same sex and age were transplanted into the hindlimb muscles of recipient mice (quadriceps femoris, tibialis anterior, and gastrocnemius complex).
    RESULTS: The results indicated significant increases (ranging between ~36% and ~65%) in basal cytochrome c oxidase and citrate synthase activity as well as ATP levels in mice receiving mitochondrial transplantation relative to the placebo. Moreover, there were significant increases (approx. two-fold) in protein expression of mitochondrial markers in both glycolytic and oxidative muscles. These enhancements in the muscle translated to significant improvements in exercise tolerance.
    CONCLUSIONS: This study provides initial evidence showing how mitochondrial transplantation can promote skeletal muscle bioenergetics in an aging rodent model.
    Keywords:  endurance; energy production; exercise physiology
    DOI:  https://doi.org/10.3390/biom14040493
  8. Curr Top Dev Biol. 2024 ;pii: S0070-2153(24)00017-6. [Epub ahead of print]158 307-339
    Circadian timing of satellite cell function and muscle regeneration.
    Pei Zhu, Clara B Peek.
      Recent research has highlighted an important role for the molecular circadian machinery in the regulation of tissue-specific function and stress responses. Indeed, disruption of circadian function, which is pervasive in modern society, is linked to accelerated aging, obesity, and type 2 diabetes. Furthermore, evidence supporting the importance of the circadian clock within both the mature muscle tissue and satellite cells to regulate the maintenance of muscle mass and repair capacity in response injury has recently emerged. Here, we review the discovery of circadian clocks within the satellite cell (a.k.a. adult muscle stem cell) and how they act to regulate metabolism, epigenetics, and myogenesis during both healthy and diseased states.
    Keywords:  Circadian rhythm; Clock; Muscle regeneration; Muscle stem cell; Satellite cell
    DOI:  https://doi.org/10.1016/bs.ctdb.2024.01.017
  9. Sci Rep. 2024 04 24. 14(1): 9396
    Skeletal muscle differentiation induces wide-ranging nucleosome repositioning in muscle gene promoters.
    Sonalí Harris, Iqra Anwar, Syeda S Baksh, Richard E Pratt, Victor J Dzau, Conrad P Hodgkinson.
      In a previous report, we demonstrated that Cbx1, PurB and Sp3 inhibited cardiac muscle differentiation by increasing nucleosome density around cardiac muscle gene promoters. Since cardiac and skeletal muscle express many of the same proteins, we asked if Cbx1, PurB and Sp3 similarly regulated skeletal muscle differentiation. In a C2C12 model of skeletal muscle differentiation, Cbx1 and PurB knockdown increased myotube formation. In contrast, Sp3 knockdown inhibited myotube formation, suggesting that Sp3 played opposing roles in cardiac muscle and skeletal muscle differentiation. Consistent with this finding, Sp3 knockdown also inhibited various muscle-specific genes. The Cbx1, PurB and Sp3 proteins are believed to influence gene-expression in part by altering nucleosome position. Importantly, we developed a statistical approach to determine if changes in nucleosome positioning were significant and applied it to understanding the architecture of muscle-specific genes. Through this novel statistical approach, we found that during myogenic differentiation, skeletal muscle-specific genes undergo a set of unique nucleosome changes which differ significantly from those shown in commonly expressed muscle genes. While Sp3 binding was associated with nucleosome loss, there appeared no correlation with the aforementioned nucleosome changes. In summary, we have identified a novel role for Sp3 in skeletal muscle differentiation and through the application of quantifiable MNase-seq have discovered unique fingerprints of nucleosome changes for various classes of muscle genes during myogenic differentiation.
    Keywords:  Cardiac muscle; ChIP-seq; MNase-seq; Skeletal muscle; Sp3
    DOI:  https://doi.org/10.1038/s41598-024-60236-x
  10. Curr Top Dev Biol. 2024 ;pii: S0070-2153(24)00012-7. [Epub ahead of print]158 203-220
    Skeletal muscle niche, at the crossroad of cell/cell communications.
    Marine Theret, Bénédicte Chazaud.
      Skeletal muscle is composed of a variety of tissue and non-tissue resident cells that participate in homeostasis. In particular, the muscle stem cell niche is a dynamic system, requiring direct and indirect communications between cells, involving local and remote cues. Interactions within the niche must happen in a timely manner for the maintenance or recovery of the homeostatic niche. For instance, after an injury, pro-myogenic cues delivered too early will impact on muscle stem cell proliferation, delaying the repair process. Within the niche, myofibers, endothelial cells, perivascular cells (pericytes, smooth muscle cells), fibro-adipogenic progenitors, fibroblasts, and immune cells are in close proximity with each other. Each cell behavior, membrane profile, and secretome can interfere with muscle stem cell fate and skeletal muscle regeneration. On top of that, the muscle stem cell niche can also be modified by extra-muscle (remote) cues, as other tissues may act on muscle regeneration via the production of circulating factors or the delivery of cells. In this review, we highlight recent publications evidencing both local and remote effectors of the muscle stem cell niche.
    Keywords:  Cell interactions; Crosstalk; Local; Muscle stem cells; Stem cell niche; Systemic
    DOI:  https://doi.org/10.1016/bs.ctdb.2024.01.012
  11. Curr Top Dev Biol. 2024 ;pii: S0070-2153(24)00018-8. [Epub ahead of print]158 15-51
    The satellite cell in skeletal muscle: A story of heterogeneity.
    Corentin Guilhot, Marie Catenacci, Stephanie Lofaro, Michael A Rudnicki.
      Skeletal muscle is a highly represented tissue in mammals and is composed of fibers that are extremely adaptable and capable of regeneration. This characteristic of muscle fibers is made possible by a cell type called satellite cells. Adjacent to the fibers, satellite cells are found in a quiescent state and located between the muscle fibers membrane and the basal lamina. These cells are required for the growth and regeneration of skeletal muscle through myogenesis. This process is known to be tightly sequenced from the activation to the differentiation/fusion of myofibers. However, for the past fifteen years, researchers have been interested in examining satellite cell heterogeneity and have identified different subpopulations displaying distinct characteristics based on localization, quiescence state, stemness capacity, cell-cycle progression or gene expression. A small subset of satellite cells appears to represent multipotent long-term self-renewing muscle stem cells (MuSC). All these distinctions led us to the hypothesis that the characteristics of myogenesis might not be linear and therefore may be more permissive based on the evidence that satellite cells are a heterogeneous population. In this review, we discuss the different subpopulations that exist within the satellite cell pool to highlight the heterogeneity and to gain further understanding of the myogenesis progress. Finally, we discuss the long term self-renewing MuSC subpopulation that is capable of dividing asymmetrically and discuss the molecular mechanisms regulating MuSC polarization during health and disease.
    Keywords:  Duchenne muscular dystrophy; Heterogeneity; Muscle, stem cells; Polarity; Satellite cells; Self-renewal; Skeletal muscle
    DOI:  https://doi.org/10.1016/bs.ctdb.2024.01.018
  12. Aging (Albany NY). 2024 Apr 19. 16
    A novel deep proteomic approach in human skeletal muscle unveils distinct molecular signatures affected by aging and resistance training.
    Michael D Roberts, Bradley A Ruple, Joshua S Godwin, Mason C McIntosh, Shao-Yung Chen, Nicholas J Kontos, Anthony Agyin-Birikorang, Max Michel, Daniel L Plotkin, Madison L Mattingly, Brooks Mobley, Tim N Ziegenfuss, Andrew D Fruge, Andreas N Kavazis.
      The skeletal muscle proteome alterations to aging and resistance training have been reported in prior studies. However, conventional proteomics in skeletal muscle typically yields wide protein abundance ranges that mask the detection of lowly expressed proteins. Thus, we adopted a novel deep proteomics approach whereby myofibril (MyoF) and non-MyoF fractions were separately subjected to protein corona nanoparticle complex formation prior to digestion and Liquid Chromatography Mass Spectrometry (LC-MS). Specifically, we investigated MyoF and non-MyoF proteomic profiles of the vastus lateralis muscle of younger (Y, 22±2 years old; n=5) and middle-aged participants (MA, 56±8 years old; n=6). Additionally, MA muscle was analyzed following eight weeks of resistance training (RT, 2d/week). Across all participants, the number of non-MyoF proteins detected averaged to be 5,645±266 (range: 4,888-5,987) and the number of MyoF proteins detected averaged to be 2,611±326 (range: 1,944-3,101). Differences in the non-MyoF (8.4%) and MyoF (2.5%) proteomes were evident between age cohorts, and most differentially expressed non-MyoF proteins (447/543) were more enriched in MA versus Y. Biological processes in the non-MyoF fraction were predicted to be operative in MA versus Y including increased cellular stress, mRNA splicing, translation elongation, and ubiquitin-mediated proteolysis. RT in MA participants only altered ~0.3% of MyoF and ~1.0% of non-MyoF proteomes. In summary, aging and RT predominantly affect non-contractile proteins in skeletal muscle. Additionally, marginal proteome adaptations with RT suggest more rigorous training may stimulate more robust effects or that RT, regardless of age, subtly alters basal state skeletal muscle protein abundances.
    Keywords:  aging; deep proteomics; resistance training; skeletal muscle
    DOI:  https://doi.org/10.18632/aging.205751
  13. J Physiol. 2024 Apr 22.
    Alterations in skeletal muscle morphology related to impaired mechanical efficiency in immobile older adults.
    Ever Espino-Gonzalez, Caio Yogi Yonamine.
      
    Keywords:  mechanical efficiency; physical inactivity; skeletal muscle
    DOI:  https://doi.org/10.1113/JP286525
  14. J Cachexia Sarcopenia Muscle. 2024 Apr 22.
    Accelerated sarcopenia precedes learning and memory impairments in the P301S mouse model of tauopathies and Alzheimer's disease.
    Savannah Longo, María Laura Messi, Zhong-Min Wang, William Meeker, Osvaldo Delbono.
      BACKGROUND: Alzheimer's disease (AD) impairs cognitive functions and peripheral systems, including skeletal muscles. The PS19 mouse, expressing the human tau P301S mutation, shows cognitive and muscular pathologies, reflecting the central and peripheral atrophy seen in AD.METHODS: We analysed skeletal muscle morphology and neuromuscular junction (NMJ) through immunohistochemistry and advanced image quantification. A factorial Analysis of Variance assessed muscle weight, NCAM expression, NMJ, myofibre type distribution, cross-sectional areas, expression of single or multiple myosin heavy-chain isoforms, and myofibre grouping in PS19 and wild type (WT) mice over their lifespan (1-12 months).
    RESULTS: Significant weight differences in extensor digitorum longus (EDL) and soleus muscles between WT and PS19 mice were noted by 7-8 months. For EDL muscle in females, WT weighed 0.0113 ± 0.0005 compared with PS19's 0.0071 ± 0.0008 (P < 0.05), and in males, WT was 0.0137 ± 0.0001 versus PS19's 0.0069 ± 0.0006 (P < 0.005). Similarly, soleus muscle showed significant differences; females (WT: 0.0084 ± 0.0004; PS19: 0.0057 ± 0.0005, P < 0.005) and males (WT: 0.0088 ± 0.0003; PS19: 0.0047 ± 0.0004, P < 0.0001). Analysis of the NMJ in PS19 mice revealed a marked reduction in myofibre innervation at 5 months, with further decline by 10 months. NMJ pre-terminals in PS19 mice became shorter and simpler by 5 months, showing a steep decline by 10 months. Genotype and age strongly influenced muscle NCAM immunoreactivity, denoting denervation as early as 5-6 months in EDL muscle Type II fibres, with earlier effects in soleus muscle Type I and II fibres at 3-4 months. Muscle denervation and subsequent myofibre atrophy were linked to a reduction in Type IIB fibres in the EDL muscle and Type IIA fibres in the soleus muscle, accompanied by an increase in hybrid fibres. The EDL muscle showed Type IIB fibre atrophy with WT females at 1505 ± 110 μm2 versus PS19's 1208 ± 94 μm2, and WT males at 1731 ± 185 μm2 versus PS19's 1227 ± 116 μm2. Similarly, the soleus muscle demonstrated Type IIA fibre atrophy from 5 to 6 months, with WT females at 1194 ± 52 μm2 versus PS19's 858 ± 62 μm2, and WT males at 1257 ± 43 μm2 versus PS19's 1030 ± 55 μm2. Atrophy also affected Type IIX, I + IIA, and IIA + IIX fibres in both muscles. The timeline for both myofibre and overall muscle atrophy in PS19 mice was consistent, indicating a simultaneous decline.
    CONCLUSIONS: Progressive and accelerated neurogenic sarcopenia may precede and potentially predict cognitive deficits observed in AD.
    Keywords:  Alzheimer's disease; Denervation; P301S tau mutation; PS19 mouse line; Sarcopenia; Skeletal muscle; Tauopathies
    DOI:  https://doi.org/10.1002/jcsm.13482
  15. Curr Top Dev Biol. 2024 ;pii: S0070-2153(24)00024-3. [Epub ahead of print]158 341-374
    Epigenetic integration of signaling from the regenerative environment.
    Perla Geara, F Jeffrey Dilworth.
      Skeletal muscle has an extraordinary capacity to regenerate itself after injury due to the presence of tissue-resident muscle stem cells. While these muscle stem cells are the primary contributor to the regenerated myofibers, the process occurs in a regenerative microenvironment where multiple different cell types act in a coordinated manner to clear the damaged myofibers and restore tissue homeostasis. In this regenerative environment, immune cells play a well-characterized role in initiating repair by establishing an inflammatory state that permits the removal of dead cells and necrotic muscle tissue at the injury site. More recently, it has come to be appreciated that the immune cells also play a crucial role in communicating with the stem cells within the regenerative environment to help coordinate the timing of repair events through the secretion of cytokines, chemokines, and growth factors. Evidence also suggests that stem cells can help modulate the extent of the inflammatory response by signaling to the immune cells, demonstrating a cross-talk between the different cells in the regenerative environment. Here, we review the current knowledge on the innate immune response to sterile muscle injury and provide insight into the epigenetic mechanisms used by the cells in the regenerative niche to integrate the cellular cross-talk required for efficient muscle repair.
    Keywords:  Cytokines; Epigenetics; Inflammation; Macrophages; Muscle stem cells; Neutrophils; Regeneration
    DOI:  https://doi.org/10.1016/bs.ctdb.2024.02.003
  16. iScience. 2024 May 17. 27(5): 109643
    Redox signaling and skeletal muscle adaptation during aerobic exercise.
    Yingsong Zhou, Xuan Zhang, Julien S Baker, Gareth W Davison, Xiaojun Yan.
      Redox regulation is a fundamental physiological phenomenon related to oxygen-dependent metabolism, and skeletal muscle is mainly regarded as a primary site for oxidative phosphorylation. Several studies have revealed the importance of reactive oxygen and nitrogen species (RONS) in the signaling process relating to muscle adaptation during exercise. To date, improving knowledge of redox signaling in modulating exercise adaptation has been the subject of comprehensive work and scientific inquiry. The primary aim of this review is to elucidate the molecular and biochemical pathways aligned to RONS as activators of skeletal muscle adaptation and to further identify the interconnecting mechanisms controlling redox balance. We also discuss the RONS-mediated pathways during the muscle adaptive process, including mitochondrial biogenesis, muscle remodeling, vascular angiogenesis, neuron regeneration, and the role of exogenous antioxidants.
    Keywords:  Biological sciences; Cell biology; Cellular physiology; Molecular physiology
    DOI:  https://doi.org/10.1016/j.isci.2024.109643
  17. Curr Top Dev Biol. 2024 ;pii: S0070-2153(24)00019-X. [Epub ahead of print]158 83-121
    Muscle stem cell dysfunction in rhabdomyosarcoma and muscular dystrophy.
    Rebecca Robertson, Shulei Li, Romina L Filippelli, Natasha C Chang.
      Muscle stem cells (MuSCs) are crucial to the repair and homeostasis of mature skeletal muscle. MuSC dysfunction and dysregulation of the myogenic program can contribute to the development of pathology ranging from cancers like rhabdomyosarcoma (RMS) or muscle degenerative diseases such as Duchenne muscular dystrophy (DMD). Both diseases exhibit dysregulation at nearly all steps of myogenesis. For instance, MuSC self-renewal processes are altered. In RMS, this leads to the creation of tumor propagating cells. In DMD, impaired asymmetric stem cell division creates a bias towards producing self-renewing stem cells instead of committing to differentiation. Hyperproliferation of these cells contribute to tumorigenesis in RMS and symmetric expansion of the self-renewing MuSC population in DMD. Both diseases also exhibit a repression of factors involved in terminal differentiation, halting RMS cells in the proliferative stage and thus driving tumor growth. Conversely, the MuSCs in DMD exhibit impaired differentiation and fuse prematurely, affecting myonuclei maturation and the integrity of the dystrophic muscle fiber. Finally, both disease states cause alterations to the MuSC niche. Various elements of the niche such as inflammatory and migratory signaling that impact MuSC behavior are dysregulated. Here we show how these seemingly distantly related diseases indeed have similarities in MuSC dysfunction, underlying the importance of considering MuSCs when studying the pathophysiology of muscle diseases.
    Keywords:  Duchenne muscular dystrophy; Muscle regeneration; Muscle stem cells; Myogenesis; Myogenic differentiation; Myopathy; Rhabdomyosarcoma; Satellite cells
    DOI:  https://doi.org/10.1016/bs.ctdb.2024.01.019
  18. Exp Physiol. 2024 Apr 21.
    Network model of skeletal muscle cell signalling predicts differential responses to endurance and resistance exercise training.
    Annabelle Fowler, Katherine R Knaus, Stephanie Khuu, Ali Khalilimeybodi, Simon Schenk, Samuel R Ward, Andrew C Fry, Padmini Rangamani, Andrew D McCulloch.
      Exercise-induced muscle adaptations vary based on exercise modality and intensity. We constructed a signalling network model from 87 published studies of human or rodent skeletal muscle cell responses to endurance or resistance exercise in vivo or simulated exercise in vitro. The network comprises 259 signalling interactions between 120 nodes, representing eight membrane receptors and eight canonical signalling pathways regulating 14 transcriptional regulators, 28 target genes and 12 exercise-induced phenotypes. Using this network, we formulated a logic-based ordinary differential equation model predicting time-dependent molecular and phenotypic alterations following acute endurance and resistance exercises. Compared with nine independent studies, the model accurately predicted 18/21 (85%) acute responses to resistance exercise and 12/16 (75%) acute responses to endurance exercise. Detailed sensitivity analysis of differential phenotypic responses to resistance and endurance training showed that, in the model, exercise regulates cell growth and protein synthesis primarily by signalling via mechanistic target of rapamycin, which is activated by Akt and inhibited in endurance exercise by AMP-activated protein kinase. Endurance exercise preferentially activates inflammation via reactive oxygen species and nuclear factor κB signalling. Furthermore, the expected preferential activation of mitochondrial biogenesis by endurance exercise was counterbalanced in the model by protein kinase C in response to resistance training. This model provides a new tool for investigating cross-talk between skeletal muscle signalling pathways activated by endurance and resistance exercise, and the mechanisms of interactions such as the interference effects of endurance training on resistance exercise outcomes.
    Keywords:  computational model; endurance exercise; exercise; resistance exercise; signalling network; skeletal muscle
    DOI:  https://doi.org/10.1113/EP091712
  19. Free Radic Biol Med. 2024 Apr 22. pii: S0891-5849(24)00410-6. [Epub ahead of print]
    Carbon monoxide-loaded cell therapy as an exercise mimetic for sarcopenia treatment.
    Isamu Noguchi, Maeda Hitoshi, Kazuki Kobayashi, Taisei Nagasaki, Hiromasa Kato, Hiroki Yanagisawa, Naoki Wada, Gai Kanazawa, Tsubasa Kaji, Hiromi Sakai, Shin Fujimaki, Yusuke Ono, Kazuaki Taguchi, Victor Tuan Giam Chuang, Junji Saruwatari, Masaki Otagiri, Hiroshi Watanabe, Toru Maruyama.
      Sarcopenia is characterized by loss of muscle strength and muscle mass with aging. The growing number of sarcopenia patients as a result of the aging population has no viable treatment. Exercise maintains muscle strength and mass by increasing peroxisome growth factor activating receptor γ-conjugating factor-1α (PGC-1α) and Akt signaling in skeletal muscle. The present study focused on the carbon monoxide (CO), endogenous activator of PGC-1α and Akt, and investigated the therapeutic potential of CO-loaded red blood cells (CO-RBCs), which is bioinspired from in vivo CO delivery system, as an exercise mimetic for the treatment of sarcopenia. Treatment of C2C12 myoblasts with the CO-donor increased the protein levels of PGC-1α which enhanced mitochondrial biogenesis and energy production. The CO-donor treatment also activated Akt, indicating that CO promotes muscle synthesis. CO levels were significantly elevated in the skeletal muscle of normal mice after intravenous administration of CO-RBCs. Furthermore, CO-RBCs restored the mRNA expression levels of PGC-1α in the skeletal muscle of two experimental sarcopenia mouse models, denervated (Den) and hindlimb unloading (HU) models. CO-RBCs also restored muscle mass in Den mice by activating Akt signaling and suppressing the muscle atrophy factors myostatin and atrogin-1, and oxidative stress. Treadmill tests further showed that the reduced running distance in HU mice was significantly restored by CO-RBC administration. These findings suggest that CO-RBCs have potential as an exercise mimetic for sarcopenia treatment.
    Keywords:  Akt; Carbon monoxide; Exercise mimetic; Mitochondrial biogenesis; PGC-1α; Sarcopenia
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.04.231
  20. bioRxiv. 2024 Apr 08. pii: 2024.04.08.588639. [Epub ahead of print]
    Muscle weakness and mitochondrial stress occur before metastasis in a novel mouse model of ovarian cancer cachexia.
    Luca J Delfinis, Leslie M Ogilvie, Shahrzad Khajehzadehshoushtar, Shivam Gandhi, Madison C Garibotti, Arshdeep K Thuhan, Kathy Matuszewska, Madison Pereira, Ronald G Jones, Arthur J Cheng, Thomas J Hawke, Nicholas P Greene, Kevin A Murach, Jeremy A Simpson, Jim Petrik, Christopher G R Perry.
      Objectives: A high proportion of women with advanced epithelial ovarian cancer (EOC) experience weakness and cachexia. This relationship is associated with increased morbidity and mortality. EOC is the most lethal gynecological cancer, yet no preclinical cachexia model has demonstrated the combined hallmark features of metastasis, ascites development, muscle loss and weakness in adult immunocompetent mice.Methods: Here, we evaluated a new model of ovarian cancer-induced cachexia with the advantages of inducing cancer in adult immunocompetent C57BL/6J mice through orthotopic injections of EOC cells in the ovarian bursa. We characterized the development of metastasis, ascites, muscle atrophy, muscle weakness, markers of inflammation, and mitochondrial stress in the tibialis anterior (TA) and diaphragm ~45, ~75 and ~90 days after EOC injection.
    Results: Primary ovarian tumour sizes were progressively larger at each time point while robust metastasis, ascites development, and reductions in body, fat and muscle weights occurred by 90 Days. There were no changes in certain inflammatory (TNFα), atrogene (MURF1 and Atrogin) or GDF15 markers within both muscles whereas IL-6 was increased at 45 and 90 Day groups in the diaphragm. TA weakness in 45 Day preceded atrophy and metastasis that were observed later (75 and 90 Day, respectively). The diaphragm demonstrated both weakness and atrophy in 45 Day. In both muscles, this pre-metastatic muscle weakness corresponded with considerable reprogramming of gene pathways related to mitochondrial bioenergetics as well as reduced functional measures of mitochondrial pyruvate oxidation and creatine-dependent ADP/ATP cycling as well as increased reactive oxygen species emission (hydrogen peroxide). Remarkably, muscle force per unit mass at 90 days was partially restored in the TA despite the presence of atrophy and metastasis. In contrast, the diaphragm demonstrated progressive weakness. At this advanced stage, mitochondrial pyruvate oxidation in both muscles exceeded control mice suggesting an apparent metabolic super-compensation corresponding with restored indices of creatine-dependent adenylate cycling.
    Conclusion: This mouse model demonstrates the concurrent development of cachexia and metastasis that occurs in women with EOC. The model provides physiologically relevant advantages of inducing tumour development within the ovarian bursa in immunocompetent adult mice. Moreover, the model reveals that muscle weakness in both TA and diaphragm precedes metastasis while weakness also precedes atrophy in the TA. An underlying mitochondrial bioenergetic stress corresponded with this early weakness. Collectively, these discoveries can direct new research towards the development of therapies that target pre-atrophy and pre-metastatic weakness during EOC in addition to therapies targeting cachexia.
    Keywords:  Ovarian cancer cachexia; metastasis; mitochondria; skeletal muscle
    DOI:  https://doi.org/10.1101/2024.04.08.588639
  21. J Clin Invest. 2024 Apr 23. pii: e167371. [Epub ahead of print]
    Sedentary behavior in mice induces metabolic inflexibility by suppressing skeletal muscle pyruvate metabolism.
    Piyarat Siripoksup, Guoshen Cao, Ahmad A Cluntun, J Alan Maschek, Quentinn Pearce, Marisa J Lang, Mi-Young Jeong, Hiroaki Eshima, Patrick J Ferrara, Precious C Opurum, Ziad S Mahmassani, Alek D Peterlin, Shinya Watanabe, Maureen A Walsh, Eric B Taylor, James E Cox, Micah J Drummond, Jared Rutter, Katsuhiko Funai.
      Carbohydrates and lipids provide the majority of substrates to fuel mitochondrial oxidative phosphorylation (OXPHOS). Metabolic inflexibility, defined as an impaired ability to switch between these fuels, is implicated in a number of metabolic diseases. Here we explore the mechanism by which physical inactivity promotes metabolic inflexibility in skeletal muscle. We developed a mouse model of sedentariness, small mouse cage (SMC) that, unlike other classic models of disuse in mice, faithfully recapitulated metabolic responses that occur in humans. Bioenergetic phenotyping of skeletal muscle mitochondria displayed metabolic inflexibility induced by physical inactivity, demonstrated by a reduction in pyruvate-stimulated respiration (JO2) in absence of a change in palmitate-stimulated JO2. Pyruvate resistance in these mitochondria was likely driven by a decrease in phosphatidylethanolamine (PE) abundance in the mitochondrial membrane. Reduction in mitochondrial PE by heterozygous deletion of phosphatidylserine decarboxylase (PSD) was sufficient to induce metabolic inflexibility measured at the whole-body level, as well as at the level of skeletal muscle mitochondria. Low mitochondrial PE in C2C12 myotubes was sufficient to increase glucose flux towards lactate. We further implicate that resistance to pyruvate metabolism is due to attenuated mitochondrial entry via mitochondrial pyruvate carrier (MPC). These findings suggest a mechanism by which mitochondrial PE directly regulates MPC activity to modulate metabolic flexibility in mice.
    Keywords:  Metabolism; Mitochondria; Skeletal muscle
    DOI:  https://doi.org/10.1172/JCI167371
  22. FASEB J. 2024 Apr 30. 38(8): e23621
    The effects of resistance training on denervated myofibers, senescent cells, and associated protein markers in middle-aged adults.
    Bradley A Ruple, Madison L Mattingly, Joshua S Godwin, Mason C McIntosh, Nicholas J Kontos, Anthony Agyin-Birikorang, J Max Michel, Daniel L Plotkin, Shao-Yung Chen, Tim N Ziegenfuss, Andrew D Fruge, L Bruce Gladden, Austin T Robinson, C Brooks Mobley, Abigail L Mackey, Michael D Roberts.
      Denervated myofibers and senescent cells are hallmarks of skeletal muscle aging. However, sparse research has examined how resistance training affects these outcomes. We investigated the effects of unilateral leg extensor resistance training (2 days/week for 8 weeks) on denervated myofibers, senescent cells, and associated protein markers in apparently healthy middle-aged participants (MA, 55 ± 8 years old, 17 females, 9 males). We obtained dual-leg vastus lateralis (VL) muscle cross-sectional area (mCSA), VL biopsies, and strength assessments before and after training. Fiber cross-sectional area (fCSA), satellite cells (Pax7+), denervated myofibers (NCAM+), senescent cells (p16+ or p21+), proteins associated with denervation and senescence, and senescence-associated secretory phenotype (SASP) proteins were analyzed from biopsy specimens. Leg extensor peak torque increased after training (p < .001), while VL mCSA trended upward (interaction p = .082). No significant changes were observed for Type I/II fCSAs, NCAM+ myofibers, or senescent (p16+ or p21+) cells, albeit satellite cells increased after training (p = .037). While >90% satellite cells were not p16+ or p21+, most p16+ and p21+ cells were Pax7+ (>90% on average). Training altered 13 out of 46 proteins related to muscle-nerve communication (all upregulated, p < .05) and 10 out of 19 proteins related to cellular senescence (9 upregulated, p < .05). Only 1 out of 17 SASP protein increased with training (IGFBP-3, p = .031). In conclusion, resistance training upregulates proteins associated with muscle-nerve communication in MA participants but does not alter NCAM+ myofibers. Moreover, while training increased senescence-related proteins, this coincided with an increase in satellite cells but not alterations in senescent cell content or SASP proteins. These latter findings suggest shorter term resistance training is an unlikely inducer of cellular senescence in apparently healthy middle-aged participants. However, similar study designs are needed in older and diseased populations before definitive conclusions can be drawn.
    Keywords:  aging; denervation; muscle; resistance training; senescence
    DOI:  https://doi.org/10.1096/fj.202302103RRR
  23. Curr Top Dev Biol. 2024 ;pii: S0070-2153(24)00023-1. [Epub ahead of print]158 179-201
    Role of microenvironment on muscle stem cell function in health, adaptation, and disease.
    Daniel Helzer, Pranav Kannan, Joseph C Reynolds, Devin E Gibbs, Rachelle H Crosbie.
      The role of the cellular microenvironment has recently gained attention in the context of muscle health, adaption, and disease. Emerging evidence supports major roles for the extracellular matrix (ECM) in regeneration and the dynamic regulation of the satellite cell niche. Satellite cells normally reside in a quiescent state in healthy muscle, but upon muscle injury, they activate, proliferate, and fuse to the damaged fibers to restore muscle function and architecture. This chapter reviews the composition and mechanical properties of skeletal muscle ECM and the role of these factors in contributing to the satellite cell niche that impact muscle regeneration. In addition, the chapter details the effects of satellite cell-matrix interactions and provides evidence that there is bidirectional regulation affecting both the cellular and extracellular microenvironment within skeletal muscle. Lastly, emerging methods to investigate satellite cell-matrix interactions will be presented.
    Keywords:  Extracellular matrix; Myoscaffolds; Satellite cell; Stem cell
    DOI:  https://doi.org/10.1016/bs.ctdb.2024.02.002
  24. Curr Top Dev Biol. 2024 ;pii: S0070-2153(24)00031-0. [Epub ahead of print]158 433-465
    Long non-coding RNAs and their role in muscle regeneration.
    Beatrice Biferali, Emanuele Mocciaro, Valeria Runfola, Davide Gabellini.
      In mammals, most of the genome is transcribed to generate a large and heterogeneous variety of non-protein coding RNAs, that are broadly grouped according to their size. Long noncoding RNAs include a very large and versatile group of molecules. Despite only a minority of them has been functionally characterized, there is emerging evidence indicating long noncoding RNAs as important regulators of expression at multiple levels. Several of them have been shown to be modulated during myogenic differentiation, playing important roles in the regulation of skeletal muscle development, differentiation and homeostasis, and contributing to neuromuscular diseases. In this chapter, we have summarized the current knowledge about long noncoding RNAs in skeletal muscle and discussed specific examples of long noncoding RNAs (lncRNAs and circRNAs) regulating muscle stem cell biology. We have also discussed selected long noncoding RNAs involved in the most common neuromuscular diseases.
    Keywords:  Chromatin; CircRNA; DMD; FSHD, muscular dystrophy; LncRNA; Muscle stem cells (MuSCs); NcRNA; Satellite cells (SCs); Transcription; Translation
    DOI:  https://doi.org/10.1016/bs.ctdb.2024.02.010
  25. Sci Rep. 2024 Apr 26. 14(1): 9668
    Lineage tracing reveals a novel PDGFRβ+ satellite cell subset that contributes to myo-regeneration of chronically injured rotator cuff muscle.
    Ayelet Dar, Angela Li, Frank A Petrigliano.
      Massive rotator cuff (RC) tendon tears are associated with progressive fibro-adipogenesis and muscle atrophy that altogether cause shoulder muscle wasting. Platelet derived growth factor β (PDGFRβ) lineage cells, that co-express PDGFRα have previously been shown to directly contribute to scar formation and fat accumulation in a mouse model of irreversible tendon and nerve transection (TTDN). Conversely, PDGFRβ+ lineage cells have also been  shown to be myogenic in cultures and in other models of skeletal muscle injury. We therefore hypothesized that PDGFRβ demarcates two distinct RC residing subpopulations, fibro-adipogenic and myogenic, and aimed to elucidate the identity of the PDGFRβ myogenic precursors and evaluate their contribution, if any, to RC myo-regeneration. Lineage tracing revealed increasing contribution of PDGFRβ+ myo-progenitors to the formation of GFP+ myofibers, which were the most abundant myofiber type in regenerated muscle at 2 weeks post-TTDN. Muscle regeneration preceded muscle atrophy and both advanced from the lateral site of tendon transection to the farthest medial region. GFP+/PDGFRβ+Sca-1-lin-CXCR4+Integrin-β1+ marked a novel subset of satellite cells with confirmed myogenic properties. Further studies are warranted to identify the existence of PDGFRβ+ satellite cells in human and other mouse muscles and to define their myo-regenerative potential following acute and chronic muscle injury.
    DOI:  https://doi.org/10.1038/s41598-024-58926-7
  26. Eur J Neurosci. 2024 Apr 22.
    Change of voltage-gated sodium channel repertoire in skeletal muscle of a MuSK myasthenia gravis mouse model.
    Olena Butenko, Stine Marie Jensen, Yvonne E Fillié-Grijpma, Robyn Verpalen, Jan J Verschuuren, Silvère M van der Maarel, Maartje G Huijbers, Jaap J Plomp.
      Muscle-specific kinase myasthenia gravis (MuSK MG) is caused by autoantibodies against MuSK in the neuromuscular junction (NMJ). MuSK MG patients have fluctuating, fatigable skeletal muscle weakness, in particular of bulbar muscles. Severity differs greatly between patients, in spite of comparable autoantibody levels. One explanation for inter-patient and inter-muscle variability in sensitivity might be variations in compensatory muscle responses. Previously, we developed a passive transfer mouse model for MuSK MG. In preliminary ex vivo experiments, we observed that muscle contraction of some mice, in particular those with milder myasthenia, had become partially insensitive to inhibition by μ-Conotoxin-GIIIB, a blocker of skeletal muscle NaV1.4 voltage-gated sodium channels. We hypothesised that changes in NaV channel expression profile, possibly co-expression of (μ-Conotoxin-GIIIB insensitive) NaV1.5 type channels, might lower the muscle fibre's firing threshold and facilitate neuromuscular synaptic transmission. To test this hypothesis, we here performed passive transfer in immuno-compromised mice, using 'high', 'intermediate' and 'low' dosing regimens of purified MuSK MG patient IgG4. We compared myasthenia levels, μ-Conotoxin-GIIIB resistance and muscle fibre action potential characteristics and firing thresholds. High- and intermediate-dosed mice showed clear, progressive myasthenia, not seen in low-dosed animals. However, diaphragm NMJ electrophysiology demonstrated almost equal myasthenic severities amongst all regimens. Nonetheless, low-dosed mouse diaphragms showed a much higher degree of μ-Conotoxin-GIIIB resistance. This was not explained by upregulation of Scn5a (the NaV1.5 gene), lowered muscle fibre firing thresholds or histologically detectable upregulated NaV1.5 channels. It remains to be established which factors are responsible for the observed μ-Conotoxin-GIIIB insensitivity and whether the NaV repertoire change is compensatory beneficial or a bystander effect.
    Keywords:  MuSK; NaV channels; homeostasis; myasthenia gravis; neuromuscular junction; passive transfer
    DOI:  https://doi.org/10.1111/ejn.16347
  27. Am J Physiol Endocrinol Metab. 2024 Apr 24.
    Phosphorylation of AS160-Serine 704 is Not Essential for Exercise-increase in Insulin-stimulated Glucose Uptake by Skeletal Muscles from Female or Male Rats.
    Haiyan Wang, Seong Eun Kwak, Amy Zheng, Edward B Arias, Xiufang Pan, Dongsheng Duan, Gregory D Cartee.
      One exercise session can increase subsequent insulin-stimulated glucose uptake (ISGU) by skeletal muscle from rodents and humans of both sexes. We recently found that concurrent mutation of three key sites to prevent their phosphorylation (Ser588, Thr642, and Ser704) on Akt substrate of 160 kDa (AS160; also known as TBC1D4) reduced the magnitude of the enhancement of postexercise ISGU (PEX-ISGU) by muscle from male, but not female rats. However, we did not test the role of individual phosphorylation sites on PEX-ISGU. Accordingly, our current aim was to test if AS160 Ser704 phosphorylation (pSer704) is required for elevated PEX-ISGU by muscle. AS160-knockout (AS160-KO) rats (female and male) were studied when either sedentary or 3 hours after acute exercise. Adeno-associated virus (AAV) vectors were used to enable muscle expression of wildtype-AS160 (AAV-WT-AS160) or AS160 mutated Ser704 to alanine to prevent phosphorylation (AAV-1P-AS160). Paired epitrochlearis muscles from each rat were injected with AAV-WT-AS160 or AAV-1P-AS160. We discovered that regardless of sex: 1) AS160 abundance in AS160-KO rats was similar in paired muscles expressing WT-AS160 versus 1P-AS160; 2) muscles from exercised versus sedentary rats had greater ISGU, and PEX-ISGU was slightly greater for muscles expressing 1P-AS160 versus contralateral muscles expressing WT-AS160; 3) pAS160 Thr642 was lower in muscles expressing 1P-AS160 versus paired muscles expressing WT-AS160. These results indicate that pAS160 Ser704 was not essential for elevated PEX-ISGU by skeletal muscle from rats of either sex. Furthermore, elimination of the postexercise increase in pAS160 Thr642 did not lessen the postexercise effect on ISGU.
    Keywords:  GLUT4 glucose transporter; acute exercise; glucose transport; insulin resistance; insulin signaling
    DOI:  https://doi.org/10.1152/ajpendo.00010.2024
  28. Skelet Muscle. 2024 Apr 20. 14(1): 7
    Dimorphic effect of TFE3 in determining mitochondrial and lysosomal content in muscle following denervation.
    Ashley N Oliveira, Jonathan M Memme, Jenna Wong, David A Hood.
      BACKGROUND: Muscle atrophy is a common consequence of the loss of innervation and is accompanied by mitochondrial dysfunction. Mitophagy is the adaptive process through which damaged mitochondria are removed via the lysosomes, which are regulated in part by the transcription factor TFE3. The role of lysosomes and TFE3 are poorly understood in muscle atrophy, and the effect of biological sex is widely underreported.METHODS: Wild-type (WT) mice, along with mice lacking TFE3 (KO), a transcriptional regulator of lysosomal and autophagy-related genes, were subjected to unilateral sciatic nerve denervation for up to 7 days, while the contralateral limb was sham-operated and served as an internal control. A subset of animals was treated with colchicine to capture mitophagy flux.
    RESULTS: WT females exhibited elevated oxygen consumption rates during active respiratory states compared to males, however this was blunted in the absence of TFE3. Females exhibited higher mitophagy flux rates and greater lysosomal content basally compared to males that was independent of TFE3 expression. Following denervation, female mice exhibited less muscle atrophy compared to male counterparts. Intriguingly, this sex-dependent muscle sparing was lost in the absence of TFE3. Denervation resulted in 45% and 27% losses of mitochondrial content in WT and KO males respectively, however females were completely protected against this decline. Decreases in mitochondrial function were more severe in WT females compared to males following denervation, as ROS emission was 2.4-fold higher. In response to denervation, LC3-II mitophagy flux was reduced by 44% in females, likely contributing to the maintenance of mitochondrial content and elevated ROS emission, however this response was dysregulated in the absence of TFE3. While both males and females exhibited increased lysosomal content following denervation, this response was augmented in females in a TFE3-dependent manner.
    CONCLUSIONS: Females have higher lysosomal content and mitophagy flux basally compared to males, likely contributing to the improved mitochondrial phenotype. Denervation-induced mitochondrial adaptations were sexually dimorphic, as females preferentially preserve content at the expense of function, while males display a tendency to maintain mitochondrial function. Our data illustrate that TFE3 is vital for the sex-dependent differences in mitochondrial function, and in determining the denervation-induced atrophy phenotype.
    Keywords:  Autophagy; Lysosomal biogenesis; Mitochondrial respiration; Mitophagy; ROS emission; Sex differences
    DOI:  https://doi.org/10.1186/s13395-024-00339-1
  29. Biochim Biophys Acta Mol Basis Dis. 2024 Apr 21. pii: S0925-4439(24)00168-6. [Epub ahead of print]1870(5): 167179
    Endocannabinoid remodeling in murine cachexic muscle associates with catabolic and metabolic regulation.
    Sebastiaan Dalle, Charlotte Hiroux, Katrien Koppo.
      Muscle degeneration is a common feature in cancer cachexia that cannot be reversed. Recent advances show that the endocannabinoid system, and more particularly cannabinoid receptor 1 (CB1), regulates muscle processes, including metabolism, anabolism and regenerative capacity. However, it is unclear whether muscle endocannabinoids, their receptors and enzymes are responsive to cachexia and exercise. Therefore, this study investigated whether cachexia and exercise affected muscle endocannabinoid signaling, and whether CB1 expression correlated with markers of muscle anabolism, catabolism and metabolism. Male BALB/c mice were injected with PBS (CON) or C26 colon carcinoma cells (C26) and had access to wheel running (VWR) or remained sedentary (n = 5-6/group). Mice were sacrificed 18 days upon PBS/tumor cell injection. Cachexic mice exhibited a lower muscle CB1 expression (-43 %; p < 0.001) and lower levels of the endocannabinoid anandamide (AEA; -22 %; p = 0.044), as well as a lower expression of the AEA-synthesizing enzyme NAPE-PLD (-37 %; p < 0.001), whereas the expression of the AEA degrading enzyme FAAH was higher (+160 %; p < 0.001). The 2-AG-degrading enzyme MAGL, was lower in cachexic muscle (-34 %; p = 0.007), but 2-AG and its synthetizing enzyme DAGLβ were not different between CON and C26. VWR increased muscle CB1 (+25 %; p = 0.005) and increased MAGL expression (+30 %; p = 0.035). CB1 expression correlated with muscle mass, markers of metabolism (e.g. p-AMPK, PGC1α) and of catabolism (e.g. p-FOXO, LC3b, Atg5). Our findings depict an emerging role of the endocannabinoid system in muscle physiology. Future studies should elaborate how this translates into potential therapies to combat cancer cachexia, and other degenerative conditions.
    Keywords:  Anabolism; Atrophy; Cachexia; Endocannabinoid system; Exercise
    DOI:  https://doi.org/10.1016/j.bbadis.2024.167179
  30. J Physiol. 2024 Apr 23.
    The complex nature of skeletal muscle fatigue: Understanding the interaction of metabolic stress and membrane excitability.
    Jeppe Blichfeldt Winther, Jesper Emil Jakobsgaard.
      
    Keywords:  glycogen depletion; journal club; metabolic stress; muscle excitability; muscle fatigue; protein signalling
    DOI:  https://doi.org/10.1113/JP286454
  31. Curr Top Dev Biol. 2024 ;pii: S0070-2153(24)00016-4. [Epub ahead of print]158 53-82
    Molecular regulation of myocyte fusion.
    Tanner J Wherley, Serena Thomas, Douglas P Millay, Timothy Saunders, Sudipto Roy.
      Myocyte fusion is a pivotal process in the development and regeneration of skeletal muscle. Failure during fusion can lead to a range of developmental as well as pathological consequences. This review aims to comprehensively explore the intricate processes underlying myocyte fusion, from the molecular to tissue scale. We shed light on key players, such as the muscle-specific fusogens - Myomaker and Myomixer, in addition to some lesser studied molecules contributing to myocyte fusion. Conserved across vertebrates, Myomaker and Myomixer play a crucial role in driving the merger of plasma membranes of fusing myocytes, ensuring the formation of functional muscle syncytia. Our multiscale approach also delves into broader cell and tissue dynamics that orchestrate the timing and positioning of fusion events. In addition, we explore the relevance of muscle fusogens to human health and disease. Mutations in fusogen genes have been linked to congenital myopathies, providing unique insights into the molecular basis of muscle diseases. We conclude with a discussion on potential therapeutic avenues that may emerge from manipulating the myocyte fusion process to remediate skeletal muscle disorders.
    Keywords:  Carey-Fineman-Ziter syndrome; Fusogen; Myocyte fusion; Myogenesis; Myomaker; Myomixer; Myopathies
    DOI:  https://doi.org/10.1016/bs.ctdb.2024.01.016
  32. Curr Top Dev Biol. 2024 ;pii: S0070-2153(24)00014-0. [Epub ahead of print]158 375-406
    Chromatin organization of muscle stem cell.
    Philina Santarelli, Valentina Rosti, Maria Vivo, Chiara Lanzuolo.
      The proper functioning of skeletal muscles is essential throughout life. A crucial crosstalk between the environment and several cellular mechanisms allows striated muscles to perform successfully. Notably, the skeletal muscle tissue reacts to an injury producing a completely functioning tissue. The muscle's robust regenerative capacity relies on the fine coordination between muscle stem cells (MuSCs or "satellite cells") and their specific microenvironment that dictates stem cells' activation, differentiation, and self-renewal. Critical for the muscle stem cell pool is a fine regulation of chromatin organization and gene expression. Acquiring a lineage-specific 3D genome architecture constitutes a crucial modulator of muscle stem cell function during development, in the adult stage, in physiological and pathological conditions. The context-dependent relationship between genome structure, such as accessibility and chromatin compartmentalization, and their functional effects will be analysed considering the improved 3D epigenome knowledge, underlining the intimate liaison between environmental encounters and epigenetics.
    DOI:  https://doi.org/10.1016/bs.ctdb.2024.01.014
  33. Curr Top Dev Biol. 2024 ;pii: S0070-2153(24)00034-6. [Epub ahead of print]158 253-277
    Navigating translational control of gene expression in satellite cells.
    Holly Jiogo, Colin Crist.
      Satellite cells, named for their satellite position around the sarcolemma of the myofibre, are responsible for skeletal muscle regeneration. Satellite cells normally reside in a quiescent state, but rapidly activate the myogenic program and the cell cycle in response to injury. Translational control of gene expression has emerged as an important regulator of satellite cell activity. Quiescent satellite cells maintain low levels of protein synthesis and selectively translate specific mRNAs to conserve limited energy. Activated satellite cells rapidly restore global protein synthesis to meet the demands of proliferating myogenic progenitors that participate in muscle repair. We propose a model by which translational control enables rapid protein level changes in response to injury-induced environmental shifts, serving as both a brake mechanism during quiescence and an accelerator for injury response. In this Chapter, we navigate the processing, translation and metabolism of newly transcribed mRNAs. We review the modifications of mRNA that occur during mRNA processing in the nucleus of satellite cells, and illustrate how these modifications impact the translation and stability of mRNAs. In the cytoplasm, we review how pathways work in concert to regulate protein synthesis globally, while trans acting microRNAs and RNA binding proteins modify specific mRNA translation within a context of tightly regulated protein synthesis. While navigating translational control of gene expression in satellite cells, this chapter reveals that despite significant progress, the field remains nascent in the broader scope of translational control in cell biology. We propose that future investigations will benefit from incorporating emerging global analyses to study translational control of gene expression in rare satellite cells, and we pose unanswered questions that warrant future exploration.
    Keywords:  RNA binding proteins; Satellite cell; Stress granules and P bodies; Translation; eIF2α phosphorylation; mRNA processing; mTOR signaling; microRNA
    DOI:  https://doi.org/10.1016/bs.ctdb.2024.02.013
  34. Am J Physiol Cell Physiol. 2024 Apr 22.
    Effect of the Mitochondrial Transaminase (GOT2) on Membrane Potential Sensitive Respiration in Mitochondria of Differentiated C2C12 Muscle Cells.
    Ritu Som, Brian D Fink, Liping Yu, William I Sivitz.
      We previously showed that the transaminase inhibitor, aminooxyacetic acid, reduced respiration energized at complex II (succinate dehydrogenase, SDH) in mitochondria isolated from mouse hindlimb muscle. The effect required a reduction in membrane potential with resultant accumulation of oxaloacetate (OAA), a potent inhibitor of SDH. To specifically assess the effect of the mitochondrial transaminase, glutamic oxaloacetic transaminase (GOT2) on complex II respiration and to determine the effect in intact cells as well as isolated mitochondria, we performed respiratory and metabolic studies in wildtype (WT) and CRISPR-generated GOT2 knockdown (KD) C2C12 myocytes. Intact cell respiration by GOT2KD cells versus WT was reduced by adding carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP) to lower potential. In mitochondria of C2C12 KD cells, respiration at low potential generated by 1µM FCCP and energized at complex II by 10mM succinate + 0.5mM glutamate, (but not by complex I substrates) was reduced versus WT mitochondria. Although we could not detect OAA, metabolite data suggested that OAA inhibition of SDH may have contributed to the FCCP effect. C2C12 mitochondria differed from skeletal muscle mitochondria in that the effect of FCCP on complex II respiration was not evident with ADP addition. We also observed that C2C12 cells, unlike skeletal muscle, expressed glutamate dehydrogenase, which competes with GOT2 for glutamate metabolism. In summary, GOT2 KD reduced C2C12 respiration in intact cells at low potential. From differential substrate effects, this occurred largely at complex II. Moreover, C2C12 versus muscle mitochondria differ in complex II sensitivity to ADP and differ markedly in expression of glutamate dehydrogenase.
    Keywords:  aspartate aminotransferase; mitochondria; myocytes; oxaloacetate; succinate dehydrogenase
    DOI:  https://doi.org/10.1152/ajpcell.00576.2023
  35. JCI Insight. 2024 Apr 23. pii: e178372. [Epub ahead of print]
    A tryptophan-derived uremic metabolite-Ahr-Pdk4 axis governs skeletal muscle mitochondrial energetics in chronic kidney disease.
    Trace Thome, Nicholas A Vugman, Lauren E Stone, Keon Wimberly, Salvatore T Scali, Terence E Ryan.
      Chronic kidney disease (CKD) causes an accumulation of uremic metabolites that negatively impact skeletal muscle function. Tryptophan-derived uremic metabolites are agonists of the aryl hydrocarbon receptor (AHR) which has been shown to be activated in the blood of CKD patients. This study investigated the role of the AHR in skeletal muscle pathology of CKD. Compared to control participants with normal kidney function, AHR-dependent gene expression (CYP1A1 and CYP1B1) was significantly upregulated in skeletal muscle of patients with CKD (P=0.032) and the magnitude of AHR activation was inversely correlated with mitochondrial respiration (P<0.001). In mice with CKD, muscle mitochondrial oxidative phosphorylation (OXPHOS) was significantly impaired and strongly correlated with both the serum level of tryptophan-derived uremic metabolites and AHR activation. Muscle-specific deletion of the AHR significantly improved mitochondrial OXPHOS in male mice with the greatest uremic toxicity (CKD+probenecid) and abolished the relationship between uremic metabolites and OXPHOS. The uremic metabolite-AHR-mitochondrial axis in skeletal muscle was further confirmed using muscle-specific AHR knockdown in C57BL6J that harbour a high-affinity AHR allele, as well as ectopic viral expression of constitutively active mutant AHR in mice with normal renal function. Notably, OXPHOS changes in AHRmKO mice were only present when mitochondria were fueled by carbohydrates. Further analyses revealed that AHR activation in mice led to significant increases in Pdk4 expression (P<0.05) and phosphorylation of pyruvate dehydrogenase enzyme (P<0.05). These findings establish a uremic metabolite-AHR-Pdk4 axis in skeletal muscle that governs mitochondrial deficits in carbohydrate oxidation during CKD.
    Keywords:  Chronic kidney disease; Mitochondria; Muscle biology; Nephrology; Skeletal muscle
    DOI:  https://doi.org/10.1172/jci.insight.178372
  36. FASEB J. 2024 Apr 30. 38(8): e23615
    Repeated sprint training in hypoxia induces specific skeletal muscle adaptations through S100A protein signaling.
    Clément Lanfranchi, Sarah J Willis, Louis Laramée, Sonia Conde Alonso, Vincent Pialoux, Bengt Kayser, Nicolas Place, Grégoire P Millet, Nadège Zanou.
      Athletes increasingly engage in repeated sprint training consisting in repeated short all-out efforts interspersed by short recoveries. When performed in hypoxia (RSH), it may lead to greater training effects than in normoxia (RSN); however, the underlying molecular mechanisms remain unclear. This study aimed at elucidating the effects of RSH on skeletal muscle metabolic adaptations as compared to RSN. Sixteen healthy young men performed nine repeated sprint training sessions in either normoxia (FIO2 = 0.209, RSN, n = 7) or normobaric hypoxia (FIO2 = 0.136, RSH, n = 9). Before and after the training period, exercise performance was assessed by using repeated sprint ability (RSA) and Wingate tests. Vastus lateralis muscle biopsies were performed to investigate muscle metabolic adaptations using proteomics combined with western blot analysis. Similar improvements were observed in RSA and Wingate tests in both RSN and RSH groups. At the muscle level, RSN and RSH reduced oxidative phosphorylation protein content but triggered an increase in mitochondrial biogenesis proteins. Proteomics showed an increase in several S100A family proteins in the RSH group, among which S100A13 most strongly. We confirmed a significant increase in S100A13 protein by western blot in RSH, which was associated with increased Akt phosphorylation and its downstream targets regulating protein synthesis. Altogether our data indicate that RSH may activate an S100A/Akt pathway to trigger specific adaptations as compared to RSN.
    Keywords:  HIF‐1α; OXPHOS; RSH; S100A13; exercise; glycolysis
    DOI:  https://doi.org/10.1096/fj.202302084RR
  37. Curr Top Dev Biol. 2024 ;pii: S0070-2153(24)00021-8. [Epub ahead of print]158 123-150
    The extracellular matrix niche of muscle stem cells.
    Eleni Chrysostomou, Philippos Mourikis.
      Preserving the potency of stem cells in adult tissues is very demanding and relies on the concerted action of various cellular and non-cellular elements in a precise stoichiometry. This balanced microenvironment is found in specific anatomical "pockets" within the tissue, known as the stem cell niche. In this review, we explore the interplay between stem cells and their niches, with a primary focus on skeletal muscle stem cells and the extracellular matrix (ECM). Quiescent muscle stem cells, known as satellite cells are active producers of a diverse array of ECM molecules, encompassing major constituents like collagens, laminins, and integrins, some of which are explored in this review. The conventional perception of ECM as merely a structural scaffold is evolving. Collagens can directly interact as ligands with receptors on satellite cells, while other ECM proteins have the capacity to sequester growth factors and regulate their release, especially relevant during satellite cell turnover in homeostasis or activation upon injury. Additionally, we explore an evolutionary perspective on the ECM across a range of multicellular organisms and discuss a model wherein satellite cells are self-sustained by generating their own niche. Considering the prevalence of ECM proteins in the connective tissue of various organs it is not surprising that mutations in ECM genes have pathological implications, including in muscle, where they can lead to myopathies. However, the particular role of certain disease-related ECM proteins in stem cell maintenance highlights the potential contribution of stem cell deregulation to the progression of these disorders.
    Keywords:  Collagen; Extracellular matrix; Integrin; Laminin; Niche; Quiescence; Satellite cells; Skeletal muscle
    DOI:  https://doi.org/10.1016/bs.ctdb.2024.01.021
  38. Methods Mol Biol. 2024 Apr 23.
    Measurement of Myonuclear Accretion In Vitro and In Vivo.
    Lola Lessard, Audrey Saugues, Julien Gondin, Rémi Mounier, Anita Kneppers.
      Adult skeletal muscle stem cells (MuSC) are the regenerative precursors of myofibers and also have an important role in myofiber growth, adaptation, and maintenance by fusing to the myofibers-a process referred to as "myonuclear accretion." Due to a focus on MuSC function during regeneration, myofibers remain a largely overlooked component of the MuSC niche influencing MuSC fate. Here, we describe a method to directly measure the rate of myonuclear accretion in vitro and in vivo using ethynyl-2'-deoxyuridine (EdU)-based tracing of MuSC progeny. This method supports the dissection of MuSC intrinsic and myofiber-derived factors influencing myonuclear accretion as an alternative fate of MuSCs supporting myofiber homeostasis and plasticity.
    Keywords:  EdU-based lineage tracing; Heterologous cell-cell fusion; Skeletal muscle hypertrophy; Skeletal muscle regeneration; Skeletal muscle stem cells
    DOI:  https://doi.org/10.1007/7651_2024_540
  39. bioRxiv. 2024 Apr 11. pii: 2024.04.10.588944. [Epub ahead of print]
    Postsynaptic BMP signaling regulates myonuclear properties in Drosophila larval muscles.
    Victoria E von Saucken, Stefanie E Windner, Mary K Baylies.
      The syncytial mammalian muscle fiber contains a heterogeneous population of (myo)nuclei. At the neuromuscular junction (NMJ), myonuclei have specialized positioning and gene expression. However, it remains unclear how myonuclei are recruited and what regulates myonuclear output at the NMJ. Here, we identify specific properties of myonuclei located near the Drosophila larval NMJ. These synaptic myonuclei have increased size in relation to their surrounding cytoplasmic domain (scaling), increased DNA content (ploidy), and increased levels of transcription factor pMad, a readout for BMP signaling activity. Our genetic manipulations show local BMP signaling affects muscle size, nuclear size, ploidy, and NMJ size and function. In support, RNA sequencing analysis reveals that pMad regulates genes involved in muscle growth, ploidy (i.e., E2f1 ), and neurotransmission. Our data suggest that muscle BMP signaling instructs synaptic myonuclear output that then positively shapes the NMJ synapse. This study deepens our understanding of how myonuclear heterogeneity supports local signaling demands to fine tune cellular function and NMJ activity.Summary: The neuromuscular junction (NMJ) is a well characterized synapse, yet the postsynaptic contributions that allow for synapse function are not well understood. This study by von Saucken et al . uses the Drosophila larval NMJ to define synaptic muscle (myo)nuclei and their properties and determine how BMP signaling regulates these myonuclear properties.
    DOI:  https://doi.org/10.1101/2024.04.10.588944
  40. Nature. 2024 Apr 22.
    Multimodal cell atlas of the ageing human skeletal muscle.
    Yiwei Lai, Ignacio Ramírez-Pardo, Joan Isern, Juan An, Eusebio Perdiguero, Antonio L Serrano, Jinxiu Li, Esther García-Domínguez, Jessica Segalés, Pengcheng Guo, Vera Lukesova, Eva Andrés, Jing Zuo, Yue Yuan, Chuanyu Liu, José Viña, Julio Doménech-Fernández, Mari Carmen Gómez-Cabrera, Yancheng Song, Longqi Liu, Xun Xu, Pura Muñoz-Cánoves, Miguel A Esteban.
      Muscle atrophy and functional decline (sarcopenia) are common manifestations of frailty and are critical contributors to morbidity and mortality in older people1. Deciphering the molecular mechanisms underlying sarcopenia has major implications for understanding human ageing2. Yet, progress has been slow, partly due to the difficulties of characterizing skeletal muscle niche heterogeneity (whereby myofibres are the most abundant) and obtaining well-characterized human samples3,4. Here we generate a single-cell/single-nucleus transcriptomic and chromatin accessibility map of human limb skeletal muscles encompassing over 387,000 cells/nuclei from individuals aged 15 to 99 years with distinct fitness and frailty levels. We describe how cell populations change during ageing, including the emergence of new populations in older people, and the cell-specific and multicellular network features (at the transcriptomic and epigenetic levels) associated with these changes. On the basis of cross-comparison with genetic data, we also identify key elements of chromatin architecture that mark susceptibility to sarcopenia. Our study provides a basis for identifying targets in the skeletal muscle that are amenable to medical, pharmacological and lifestyle interventions in late life.
    DOI:  https://doi.org/10.1038/s41586-024-07348-6
  41. bioRxiv. 2024 Apr 11. pii: 2024.04.10.588959. [Epub ahead of print]
    Muscle-Specific Pyruvate Kinase Isoforms, Pkm1 and Pkm2, Regulate Mammalian SWI/SNF Proteins and Histone 3 Phosphorylation During Myoblast Differentiation.
    Monserrat Olea-Flores, Tapan Sharma, Odette Verdejo-Torres, Imaru DiBartolomeo, Paul R Thompson, Teresita Padilla-Benavides, Anthony N Imbalzano.
      Pyruvate kinase is a glycolytic enzyme that converts phosphoenolpyruvate and ADP into pyruvate and ATP. There are two genes that encode pyruvate kinase in vertebrates; Pkm and Pkl encode muscle- and liver/erythrocyte-specific forms, respectively. Each gene encodes two isoenzymes due to alternative splicing. Both muscle-specific enzymes, Pkm1 and Pkm2, function in glycolysis, but Pkm2 also has been implicated in gene regulation due to its ability to phosphorylate histone 3 threonine 11 (H3T11) in cancer cells. Here, we examined the roles of Pkm1 and Pkm2 during myoblast differentiation. RNA-seq analysis revealed that Pkm2 promotes the expression of Dpf2/Baf45d and Baf250a/Arid1A . Dpf2 and Baf250a are subunits that identify a specific sub-family of the mammalian SWI/SNF (mSWI/SNF) of chromatin remodeling enzymes that is required for activation of myogenic gene expression during differentiation. Pkm2 also mediated the incorporation of Dpf2 and Baf250a into the regulatory sequences controlling myogenic gene expression. Pkm1 did not affect expression but was required for nuclear localization of Dpf2. Additionally, Pkm2 was required not only for the incorporation of phosphorylated H3T11 in myogenic promoters, but also for the incorporation of phosphorylated H3T6 and H3T45 at myogenic promoters via regulation of AKT and protein kinase C isoforms that phosphorylate those amino acids. Our results identify multiple unique roles for Pkm2 and a novel function for Pkm1 in gene expression and chromatin regulation during myoblast differentiation.
    DOI:  https://doi.org/10.1101/2024.04.10.588959
  42. Nat Commun. 2024 Apr 26. 15(1): 3563
    LSD1 inhibition circumvents glucocorticoid-induced muscle wasting of male mice.
    Qingshuang Cai, Rajesh Sahu, Vanessa Ueberschlag-Pitiot, Sirine Souali-Crespo, Céline Charvet, Ilyes Silem, Félicie Cottard, Tao Ye, Fatima Taleb, Eric Metzger, Roland Schuele, Isabelle M L Billas, Gilles Laverny, Daniel Metzger, Delphine Duteil.
      Synthetic glucocorticoids (GC), such as dexamethasone, are extensively used to treat chronic inflammation and autoimmune disorders. However, long-term treatments are limited by various side effects, including muscle atrophy. GC activities are mediated by the glucocorticoid receptor (GR), that regulates target gene expression in various tissues in association with cell-specific co-regulators. Here we show that GR and the lysine-specific demethylase 1 (LSD1) interact in myofibers of male mice, and that LSD1 connects GR-bound enhancers with NRF1-associated promoters to stimulate target gene expression. In addition, we unravel that LSD1 demethylase activity is required for triggering starvation- and dexamethasone-induced skeletal muscle proteolysis in collaboration with GR. Importantly, inhibition of LSD1 circumvents muscle wasting induced by pharmacological levels of dexamethasone, without affecting their anti-inflammatory activities. Thus, our findings provide mechanistic insights into the muscle-specific GC activities, and highlight the therapeutic potential of targeting GR co-regulators to limit corticotherapy-induced side effects.
    DOI:  https://doi.org/10.1038/s41467-024-47846-9
  43. Aging (Albany NY). 2024 Apr 18. 16
    Aberrant expression of thyroidal hormone receptor α exasperating mitochondrial dysfunction induced sarcopenia in aged mice.
    Yunlu Sheng, Xiaoxia Zhu, Lijun Wei, Yuxin Zou, Xinyu Qi, Runqing Shi, Wenli Xu, Xiaodong Wang, Guoxian Ding, Yu Duan.
      Disrupted mitochondrial dynamics and mitophagy contribute to functional deterioration of skeletal muscle (SM) during aging, but the regulatory mechanisms are poorly understood. Our previous study demonstrated that the expression of thyroid hormone receptor α (TRα) decreased significantly in aged mice, suggesting that the alteration of thyroidal elements, especially the decreased TRα, might attenuate local THs action thus to cause the degeneration of SM with aging, while the underlying mechanism remains to be further explored. In this study, decreased expression of myogenic regulators Myf5, MyoD1, mitophagy markers Pink1, LC3II/I, p62, as well as mitochondrial dynamic factors Mfn1 and Opa1, accompanied by increased reactive oxygen species (ROS), showed concomitant changes with reduced TRα expression in aged mice. Further TRα loss- and gain-of-function studies in C2C12 revealed that silencing of TRα not only down-regulated the expression of above-mentioned myogenic regulators, mitophagy markers and mitochondrial dynamic factors, but also led to a significant decrease in mitochondrial activity and maximum respiratory capacity, as well as more mitochondrial ROS and damaged mitochondria. Notedly, overexpression of TRα could up-regulate the expression of those myogenic regulators, mitophagy markers and mitochondrial dynamic factors, meanwhile also led to an increase in mitochondrial activity and number. These results confirmed that TRα could concertedly regulate mitochondrial dynamics, autophagy, and activity, and myogenic regulators rhythmically altered with TRα expression. Summarily, these results suggested that the decline of TRα might cause the degeneration of SM with aging by regulating mitochondrial dynamics, mitophagy and myogenesis.
    Keywords:  aging mice; mitochondrial dysfunction; mitophagy; skeletal muscles; thyroid hormone receptor α
    DOI:  https://doi.org/10.18632/aging.205748
  44. Biomedicines. 2024 Apr 18. pii: 902. [Epub ahead of print]12(4):
    N-Acetylcysteine Attenuates Sepsis-Induced Muscle Atrophy by Downregulating Endoplasmic Reticulum Stress.
    Renyu Chen, Yingfang Zheng, Chenchen Zhou, Hongkai Dai, Yurou Wang, Yun Chu, Jinlong Luo.
      (1) Background: Sepsis-induced muscle atrophy is characterized by a loss of muscle mass and function which leads to decreased quality of life and worsens the long-term prognosis of patients. N-acetylcysteine (NAC) has powerful antioxidant and anti-inflammatory properties, and it relieves muscle wasting caused by several diseases, whereas its effect on sepsis-induced muscle atrophy has not been reported. The present study investigated the effect of NAC on sepsis-induced muscle atrophy and its possible mechanisms. (2) Methods: The effect of NAC on sepsis-induced muscle atrophy was assessed in vivo and in vitro using cecal ligation and puncture-operated (CLP) C57BL/6 mice and LPS-treated C2C12 myotubes. We used immunofluorescence staining to analyze changes in the cross-sectional area (CSA) of myofibers in mice and the myotube diameter of C2C12. Protein expressions were analyzed by Western blotting. (3) Results: In the septic mice, the atrophic response manifested as a reduction in skeletal muscle weight and myofiber cross-sectional area, which is mediated by muscle-specific ubiquitin ligases-muscle atrophy F-box (MAFbx)/Atrogin-1 and muscle ring finger 1 (MuRF1). NAC alleviated sepsis-induced skeletal muscle wasting and LPS-induced C2C12 myotube atrophy. Meanwhile, NAC inhibited the sepsis-induced activation of the endoplasmic reticulum (ER) stress signaling pathway. Furthermore, using 4-Phenylbutyric acid (4-PBA) to inhibit ER stress in LPS-treated C2C12 myotubes could partly abrogate the anti-muscle-atrophy effect of NAC. Finally, NAC alleviated myotube atrophy induced by the ER stress agonist Thapsigargin (Thap). (4) Conclusions: NAC can attenuate sepsis-induced muscle atrophy, which may be related to downregulating ER stress.
    Keywords:  N-acetylcysteine; endoplasmic reticulum stress; muscle atrophy; sepsis
    DOI:  https://doi.org/10.3390/biomedicines12040902
  45. Int J Mol Sci. 2024 Apr 13. pii: 4308. [Epub ahead of print]25(8):
    MyoD Over-Expression Rescues GST-bFGF Repressed Myogenesis.
    Shu-Hsin Fan, Ning Li, Kai-Fan Huang, Yun-Ting Chang, Chuan-Che Wu, Shen-Liang Chen.
      During embryogenesis, basic fibroblast growth factor (bFGF) is released from neural tube and myotome to promote myogenic fate in the somite, and is routinely used for the culture of adult skeletal muscle (SKM) stem cells (MuSC, called satellite cells). However, the mechanism employed by bFGF to promote SKM lineage and MuSC proliferation has not been analyzed in detail. Furthermore, the question of if the post-translational modification (PTM) of bFGF is important to its stemness-promoting effect has not been answered. In this study, GST-bFGF was expressed and purified from E.coli, which lacks the PTM system in eukaryotes. We found that both GST-bFGF and commercially available bFGF activated the Akt-Erk pathway and had strong cell proliferation effect on C2C12 myoblasts and MuSC. GST-bFGF reversibly compromised the myogenesis of C2C12 myoblasts and MuSC, and it increased the expression of Myf5, Pax3/7, and Cyclin D1 but strongly repressed that of MyoD, suggesting the maintenance of myogenic stemness amid repressed MyoD expression. The proliferation effect of GST-bFGF was conserved in C2C12 over-expressed with MyoD (C2C12-tTA-MyoD), implying its independence of the down-regulation of MyoD. In addition, the repressive effect of GST-bFGF on myogenic differentiation was almost totally rescued by the over-expression of MyoD. Together, these evidences suggest that (1) GST-bFGF and bFGF have similar effects on myogenic cell proliferation and differentiation, and (2) GST-bFGF can promote MuSC stemness and proliferation by differentially regulating MRFs and Pax3/7, (3) MyoD repression by GST-bFGF is reversible and independent of the proliferation effect, and (4) GST-bFGF can be a good substitute for bFGF in sustaining MuSC stemness and proliferation.
    Keywords:  MyoD; bFGF; cell cycle; differentiation; muscle; myogenesis
    DOI:  https://doi.org/10.3390/ijms25084308
  46. Nat Aging. 2024 Apr 24.
    Systematic analysis of muscle aging using joint single-cell and single-nucleus sequencing.
      
    DOI:  https://doi.org/10.1038/s43587-024-00629-9
  47. Curr Top Dev Biol. 2024 ;pii: S0070-2153(24)00020-6. [Epub ahead of print]158 1-14
    Satellite cells in the growth and maintenance of muscle.
    John F Bachman, Joe V Chakkalakal.
      Embryonic skeletal muscle growth is contingent upon a population of somite derived satellite cells, however, the contribution of these cells to early postnatal skeletal muscle growth remains relatively high. As prepubertal postnatal development proceeds, the activity and contribution of satellite cells to skeletal muscle growth diminishes. Eventually, at around puberty, a population of satellite cells escapes terminal commitment, continues to express the paired box transcription factor Pax7, and reside in a quiescent state orbiting the myofiber periphery adjacent to the basal lamina. After adolescence, some satellite cell contributions to muscle maintenance and adaptation occur, however, their necessity is reduced relative to embryonic, early postnatal, and prepubertal growth.
    Keywords:  Aging; Development; Hypertrophy; Musculoskeletal; Neuromuscular; Regeneration; Stem cell
    DOI:  https://doi.org/10.1016/bs.ctdb.2024.01.020
  48. Life Sci Space Res (Amst). 2024 May;pii: S2214-5524(24)00019-1. [Epub ahead of print]41 80-85
    Mechanical interaction of myosin and native thin filament in the disused rat soleus muscle.
    Oksana Gerzen, Iulia Potoskueva, Veronika Votinova, Ksenia Sergeeva, Sergey Tyganov, Alena Tzybina, Boris S Shenkman, Larisa Nikitina.
      The disuse of skeletal limb muscles occurs in a variety of conditions, yet our comprehension of the molecular mechanisms involved in adaptation to disuse remains incomplete. We studied the mechanical characteristics of actin-myosin interaction using an in vitro motility assay and isoform composition of myosin heavy and light chains by dint of SDS-PAGE in soleus muscle of both control and hindlimb-unloaded rats. 14 days of hindlimb unloading led to the increased maximum sliding velocity of actin, reconstituted, and native thin filaments over rat soleus muscle myosin by 24 %, 19 %, and 20 %, respectively. The calcium sensitivity of the "pCa-velocity" relationship decreased. There was a 26 % increase in fast myosin heavy chain IIa (MHC IIa), a 22 % increase in fast myosin light chain 2 (MLC 2f), and a 13 % increase in fast MLC 1f content. The content of MLC 1s/v, typical for slow skeletal muscles and cardiac ventricles did not change. At the same time, MLC 1s, typical only for slow skeletal muscles, disappeared. The maximum velocity of soleus muscle native thin filaments was 24 % higher compared to control ones sliding over the same rabbit myosin. Therefore, both myosin and native thin filament kinetics could influence the mechanical characteristics of the soleus muscle. Additionally, the MLC 1s and MLC 1s/v ratio may contribute to the mechanical characteristics of slow skeletal muscle, along with MHC, MLC 2, and MLC 1 slow/fast isoforms ratio.
    Keywords:  Hindlimb unloading; Myosin heavy chains; Myosin light chains; Native thin filament; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.lssr.2024.01.009
  49. Eur J Appl Physiol. 2024 Apr 23.
    Resistance training-induced changes in muscle proteolysis and extracellular matrix remodeling biomarkers in the untrained and trained states.
    Maíra C Scarpelli, João G A Bergamasco, Joshua S Godwin, Paulo H C Mesquita, Talisson S Chaves, Deivid G Silva, Diego Bittencourt, Nathalia F Dias, Ricardo A Medalha Junior, Paulo C Carello Filho, Vitor Angleri, Luiz A R Costa, Andreas N Kavazis, Carlos Ugrinowitsch, Michael D Roberts, Cleiton A Libardi.
      PURPOSE: Resistance training (RT) induces muscle growth at varying rates across RT phases, and evidence suggests that the muscle-molecular responses to training bouts become refined or attenuated in the trained state. This study examined how proteolysis-related biomarkers and extracellular matrix (ECM) remodeling factors respond to a bout of RT in the untrained (UT) and trained (T) state.METHODS: Participants (19 women and 19 men) underwent 10 weeks of RT. Biopsies of vastus lateralis were collected before and after (24 h) the first (UT) and last (T) sessions. Vastus lateralis cross-sectional area (CSA) was assessed before and after the experimental period.
    RESULTS: There were increases in muscle and type II fiber CSAs. In both the UT and T states, calpain activity was upregulated and calpain-1/-2 protein expression was downregulated from Pre to 24 h. Calpain-2 was higher in the T state. Proteasome activity and 20S proteasome protein expression were upregulated from Pre to 24 h in both the UT and T. However, proteasome activity levels were lower in the T state. The expression of poly-ubiquitinated proteins was unchanged. MMP activity was downregulated, and MMP-9 protein expression was elevated from Pre to 24 h in UT and T. Although MMP-14 protein expression was acutely unchanged, this marker was lower in T state. TIMP-1 protein levels were reduced Pre to 24 h in UT and T, while TIMP-2 protein levels were unchanged.
    CONCLUSION: Our results are the first to show that RT does not attenuate the acute-induced response of proteolysis and ECM remodeling-related biomarkers.
    Keywords:  Calpain; Exercise training; Metalloproteinase; Muscle hypertrophy; Ubiquitin‒proteasome
    DOI:  https://doi.org/10.1007/s00421-024-05484-5
  50. Curr Top Dev Biol. 2024 ;pii: S0070-2153(24)00013-9. [Epub ahead of print]158 239-251
    Effects of the immune system on muscle regeneration.
    Ping Hu.
      Muscle regeneration is a complex process orchestrated by multiple steps. Recent findings indicate that inflammatory responses could play central roles in bridging initial muscle injury responses and timely muscle injury reparation. The various types of immune cells and cytokines have crucial roles in muscle regeneration process. In this review, we provide an overview of the functions of acute inflammation in muscle regeneration.
    Keywords:  Immune system, Acute inflammation; Muscle injury; Muscle regeneration
    DOI:  https://doi.org/10.1016/bs.ctdb.2024.01.013
  51. Cell Mol Biol Lett. 2024 Apr 23. 29(1): 59
    The role of mitochondrial dynamics and mitophagy in skeletal muscle atrophy: from molecular mechanisms to therapeutic insights.
    Yuhang Lei, Mailin Gan, Yanhao Qiu, Qiuyang Chen, Xingyu Wang, Tianci Liao, Mengying Zhao, Lei Chen, Shunhua Zhang, Ye Zhao, Lili Niu, Yan Wang, Li Zhu, Linyuan Shen.
      Skeletal muscle is the largest metabolic organ of the human body. Maintaining the best quality control and functional integrity of mitochondria is essential for the health of skeletal muscle. However, mitochondrial dysfunction characterized by mitochondrial dynamic imbalance and mitophagy disruption can lead to varying degrees of muscle atrophy, but the underlying mechanism of action is still unclear. Although mitochondrial dynamics and mitophagy are two different mitochondrial quality control mechanisms, a large amount of evidence has indicated that they are interrelated and mutually regulated. The former maintains the balance of the mitochondrial network, eliminates damaged or aged mitochondria, and enables cells to survive normally. The latter degrades damaged or aged mitochondria through the lysosomal pathway, ensuring cellular functional health and metabolic homeostasis. Skeletal muscle atrophy is considered an urgent global health issue. Understanding and gaining knowledge about muscle atrophy caused by mitochondrial dysfunction, particularly focusing on mitochondrial dynamics and mitochondrial autophagy, can greatly contribute to the prevention and treatment of muscle atrophy. In this review, we critically summarize the recent research progress on mitochondrial dynamics and mitophagy in skeletal muscle atrophy, and expound on the intrinsic molecular mechanism of skeletal muscle atrophy caused by mitochondrial dynamics and mitophagy. Importantly, we emphasize the potential of targeting mitochondrial dynamics and mitophagy as therapeutic strategies for the prevention and treatment of muscle atrophy, including pharmacological treatment and exercise therapy, and summarize effective methods for the treatment of skeletal muscle atrophy.
    Keywords:  Intermodulation; Mitochondrial dynamics; Mitophagy; Molecular mechanism; Prevention and treatment; Skeletal muscle atrophy
    DOI:  https://doi.org/10.1186/s11658-024-00572-y
  52. J Cachexia Sarcopenia Muscle. 2024 Apr 21.
    Metabolomics-driven discovery of therapeutic targets for cancer cachexia.
    Pengfei Cui, Xiaoyi Li, Caihua Huang, Donghai Lin.
      Cancer cachexia (CC) is a devastating metabolic syndrome characterized by skeletal muscle wasting and body weight loss, posing a significant burden on the health and survival of cancer patients. Despite ongoing efforts, effective treatments for CC are still lacking. Metabolomics, an advanced omics technique, offers a comprehensive analysis of small-molecule metabolites involved in cellular metabolism. In CC research, metabolomics has emerged as a valuable tool for identifying diagnostic biomarkers, unravelling molecular mechanisms and discovering potential therapeutic targets. A comprehensive search strategy was implemented to retrieve relevant articles from primary databases, including Web of Science, Google Scholar, Scopus and PubMed, for CC and metabolomics. Recent advancements in metabolomics have deepened our understanding of CC by uncovering key metabolic signatures and elucidating underlying mechanisms. By targeting crucial metabolic pathways including glucose metabolism, amino acid metabolism, fatty acid metabolism, bile acid metabolism, ketone body metabolism, steroid metabolism and mitochondrial energy metabolism, it becomes possible to restore metabolic balance and alleviate CC symptoms. This review provides a comprehensive summary of metabolomics studies in CC, focusing on the discovery of potential therapeutic targets and the evaluation of modulating specific metabolic pathways for CC treatment. By harnessing the insights derived from metabolomics, novel interventions for CC can be developed, leading to improved patient outcomes and enhanced quality of life.
    Keywords:  Cancer cachexia; Metabolic pathway; Metabolomics; Therapeutic target
    DOI:  https://doi.org/10.1002/jcsm.13465
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