bims-moremu Biomed News
on Molecular regulators of muscle mass
Issue of 2024‒09‒29
thirty-two papers selected by
Anna Vainshtein, Craft Science Inc.
  1. Epigenome-proteome integration in aged skeletal muscle after exercise training.
  2. Regulation of mitochondria-lysosome interactions in skeletal muscle during exercise, disuse, and aging.
  3. Tubular Aggregates as a Marker of Aging in Skeletal Muscle.
  4. Effects of thyroid hormones in skeletal muscle protein turnover.
  5. Unveiling sex differences in skeletal muscle metabolism: the role of HIF1α in normoxia.
  6. Transcriptomic signatures of human single skeletal muscle fibers in response to high-intensity interval exercise.
  7. Muscle aging and sarcopenia: The pathology, etiology, and most promising therapeutic targets.
  8. Age-induced changes in skeletal muscle mitochondrial DNA synthesis, quantity, and quality in genetically unique rats.
  9. Extracellular vesicle transfer of miR-1 to adipose tissue modifies lipolytic pathways following resistance exercise.
  10. Identification of key genes and signaling pathways based on transcriptomic studies of aerobic and resistance training interventions in sarcopenia in SAMP8 mice.
  11. Extra-osseous Roles of the RANK-RANKL-OPG Axis with a Focus on Skeletal Muscle.
  12. Exercise, autoimmune diseases and T-regulatory cells.
  13. Light-phase time-restricted feeding disrupts the muscle clock and insulin sensitivity yet potentially induces muscle fiber remodeling in mice.
  14. Beyond the bulk: overview and novel insights into the dynamics of muscle satellite cells during muscle regeneration.
  15. Propofol binds and inhibits skeletal muscle ryanodine receptor 1.
  16. Protocol to monitor live-cell, real-time, mitochondrial respiration in mouse muscle cells using the Resipher platform.
  17. LRRK2G2019S Gene Mutation Causes Skeletal Muscle Impairment in Animal Model of Parkinson's Disease.
  18. Profound cellular defects attribute to muscular pathogenesis in the rhesus monkey model of Duchenne muscular dystrophy.
  19. Skeletal muscle-derived exosomes prevent osteoporosis by promoting osteogenesis.
  20. Skeletal Muscle Memory: An Update From the Antidoping Perspective.
  21. Exercise and nutrition benefit skeletal muscle: From influence factor and intervention strategy to molecular mechanism.
  22. Hotspots and trends in satellite cell research in muscle regeneration: A bibliometric visualization and analysis from 2010 to 2023.
  23. Knockout of rbm24a and rbm24b genes in zebrafish impairs skeletal and cardiac muscle integrity and function during development.
  24. Effects of intermittent exposure to hypobaric hypoxia and cold on skeletal muscle regeneration: mitochondrial dynamics, protein oxidation and turnover.
  25. Myotube Guidance: Shaping up the Musculoskeletal System.
  26. Macrophages modulate skeletal muscle wasting and recovery in acute lung injury in mice.
  27. Histone modifications in Duchenne muscular dystrophy: pathogenesis insights and therapeutic implications.
  28. A Voyage on the Role of Nuclear Factor Kappa B (NF-kB) Signaling Pathway in Duchenne Muscular Dystrophy: An Inherited Muscle Disorder.
  29. IGF2BP1-mediated the stability and protein translation of FGFR1 mRNA regulates myogenesis through the ERK signaling pathway.
  30. Loss of SELENOW aggravates muscle loss with regulation of protein synthesis and the ubiquitin-proteasome system.
  31. 6-Gingerol improves lipid metabolism disorders in skeletal muscle by regulating AdipoR1/AMPK signaling pathway.
  32. Amyotrophic lateral sclerosis as a disease model of sarcopenia.
  1. J Physiol. 2024 Sep 19.
    Epigenome-proteome integration in aged skeletal muscle after exercise training.
    Adam P Sharples.
      
    Keywords:  DNA methylation; aged muscle; endurance training; epigenetics; exercise; high‐intensity interval training; methylome; omics; proteome; resistance training; skeletal muscle
    DOI:  https://doi.org/10.1113/JP287235
  2. Free Radic Biol Med. 2024 Sep 25. pii: S0891-5849(24)00675-0. [Epub ahead of print]
    Regulation of mitochondria-lysosome interactions in skeletal muscle during exercise, disuse, and aging.
    N Moradi, V C Sanfrancesco, S Champsi, D A Hood.
      Lysosomes play a critical role as a terminal organelle in autophagy flux and in regulating protein degradation, but their function and adaptability in skeletal muscle is understudied. Lysosome functions include both housekeeping and signaling functions essential for cellular homeostasis. This review focuses on the regulation of lysosomes in skeletal muscle during exercise, disuse, and aging, with a consideration of sex differences as well as the role of lysosomes in mediating the degradation of mitochondria, termed mitophagy. Exercise enhances mitophagy during elevated mitochondrial stress and energy demand. A critical response to this deviation from homeostasis is the activation of transcription factors TFEB and TFE3, which drive the expression of lysosomal and autophagic genes. Conversely, during muscle disuse, the suppression of lysosomal activity contributes to the accumulation of defective mitochondria and other cellular debris, impairing muscle function. Aging further exacerbates these effects by diminishing lysosomal efficacy, leading to the accumulation of damaged cellular components. mTORC1, a key nutrient sensor, modulates lysosomal activity by inhibiting TFEB/TFE3 translocation to the nucleus under nutrient-rich conditions, thereby suppressing autophagy. During nutrient deprivation or exercise, AMPK activation inhibits mTORC1, facilitating TFEB/TFE3 nuclear translocation and promoting lysosomal biogenesis and autophagy. TRPML1 activation by mitochondrial ROS enhances lysosomal calcium release, which is essential for autophagy and maintaining mitochondrial quality. Overall, the intricate regulation of lysosomal functions and signaling pathways in skeletal muscle is crucial for adaptation to physiological demands, and disruptions in these processes during disuse and aging underscore the ubiquitous power of exercise-induced adaptations, and also highlight the potential for targeted therapeutic interventions to preserve muscle health.
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.09.028
  3. Methods Mol Biol. 2024 Sep 25.
    Tubular Aggregates as a Marker of Aging in Skeletal Muscle.
    Felipe Tadeu Galante Rocha de Vasconcelos, Brandow Willy Souza, Lucas Santos Souza, Mariz Vainzof.
      Tubular aggregates (TA) are skeletal muscle structures that arise from the progressive accumulation of sarcoplasmic reticulum proteins, mainly with aging. Muscle regeneration plays a role in TA formation. TA quantification may aid in the evaluation of muscle aging and genetic muscle degeneration. TA form over time, appears in aging in normal murine muscles. TA reduction in injured conditions may be due to the degeneration-regeneration process in muscles, with loss of damaged muscle fibers and formation of new fibers that do not present protein aggregation. These new regenerated fibers do not improve the function capacity of the aged muscle. Here, we present a methodology for labeling and identifying tubular aggregates in muscle fibers and also the standardization of its quantification.
    Keywords:  Aging; Mouse; Muscle regeneration; Muscular dystrophies; Neuromuscular disease; Tubular aggregates
    DOI:  https://doi.org/10.1007/7651_2024_567
  4. J Basic Clin Physiol Pharmacol. 2024 Sep 20.
    Effects of thyroid hormones in skeletal muscle protein turnover.
    Annarita Nappi, Caterina Moriello, Maria Morgante, Ferdinando Fusco, Felice Crocetto, Caterina Miro.
      Thyroid hormones (THs) are critical regulators of muscle metabolism in both healthy and unhealthy conditions. Acting concurrently as powerful anabolic and catabolic factors, THs are endowed with a vital role in muscle mass maintenance. As a result, thyroid dysfunctions are the leading cause of a wide range of muscle pathologies, globally identified as myopathies. Whether muscle wasting is a common feature in patients with hyperthyroidism and is mainly caused by THs-dependent stimulation of muscle proteolysis, also muscle growth is often associated with hyperthyroid conditions, linked to THs-dependent stimulation of muscle protein synthesis. Noteworthy, also hypothyroid status negatively impacts on muscle physiology, causing muscle weakness and fatigue. Most of these symptoms are due to altered balance between muscle protein synthesis and breakdown. Thus, a comprehensive understanding of THs-dependent skeletal muscle protein turnover might facilitate the management of physical discomfort or weakness in conditions of thyroid disease. Herein, we describe the molecular mechanisms underlying the THs-dependent alteration of skeletal muscle structure and function associated with muscle atrophy and hypertrophy, thus providing new insights for targeted modulation of skeletal muscle dynamics.
    Keywords:  skeletal muscle; skeletal muscle atrophy; skeletal muscle hypertrophy; thyroid hormones
    DOI:  https://doi.org/10.1515/jbcpp-2024-0139
  5. J Physiol. 2024 Sep 27.
    Unveiling sex differences in skeletal muscle metabolism: the role of HIF1α in normoxia.
    Ashlyn Ro, Dorota Kaminska.
      
    Keywords:  HIF1A; mitochondria; normoxia; sex differences; skeletal muscle
    DOI:  https://doi.org/10.1113/JP287250
  6. Am J Physiol Cell Physiol. 2024 Sep 24.
    Transcriptomic signatures of human single skeletal muscle fibers in response to high-intensity interval exercise.
    Thibaux Van der Stede, Alexia Van de Loock, Eline Lievens, Nurten Yigit, Jasper Anckaert, Ruud Van Thienen, Anneleen Weyns, Pieter Mestdagh, Jo Vandesompele, Wim Derave.
      The heterogeneous fiber type composition of skeletal muscle makes it challenging to decipher the molecular signaling events driving the health- and performance benefits of exercise. We developed an optimized workflow for transcriptional profiling of individual human muscle fibers before, immediately after, and after three hours of recovery from high-intensity interval cycling exercise. From a transcriptional point-of-view, we observe that there is no dichotomy in fiber activation, that could refer to a fiber being recruited or non-recruited. Rather, the activation pattern displays a continuum with a more uniform response within fast versus slow fibers during the recovery from exercise. The transcriptome-wide response immediately after exercise is characterized by some distinct signatures for slow versus fast fibers, although the most exercise-responsive genes are common between the two fiber types. The temporal transcriptional waves further converge the gene signatures of both fiber types towards a more similar profile during the recovery from exercise. Furthermore, a large heterogeneity among all resting and exercised fibers was observed, with the principal drivers being independent of a slow/fast typology. This profound heterogeneity extends to distinct exercise responses of fibers beyond a classification based on myosin heavy chains. Collectively, our single-fiber methodological approach points to a substantial between-fiber diversity in muscle fiber responses to high-intensity interval exercise.
    Keywords:  Exercise; Muscle fibers; Skeletal muscle; Transcriptomics; high-intensity interval exercise
    DOI:  https://doi.org/10.1152/ajpcell.00299.2024
  7. Mol Aspects Med. 2024 Sep 22. pii: S0098-2997(24)00078-5. [Epub ahead of print]100 101319
    Muscle aging and sarcopenia: The pathology, etiology, and most promising therapeutic targets.
    Mercedes Grima-Terrén, Silvia Campanario, Ignacio Ramírez-Pardo, Andrés Cisneros, Xiaotong Hong, Eusebio Perdiguero, Antonio L Serrano, Joan Isern, Pura Muñoz-Cánoves.
      Sarcopenia is a progressive muscle wasting disorder that severely impacts the quality of life of elderly individuals. Although the natural aging process primarily causes sarcopenia, it can develop in response to other conditions. Because muscle function is influenced by numerous changes that occur with age, the etiology of sarcopenia remains unclear. However, recent characterizations of the aging muscle transcriptional landscape, signaling pathway disruptions, fiber and extracellular matrix compositions, systemic metabolomic and inflammatory responses, mitochondrial function, and neurological inputs offer insights and hope for future treatments. This review will discuss age-related changes in healthy muscle and our current understanding of how this can deteriorate into sarcopenia. As our elderly population continues to grow, we must understand sarcopenia and find treatments that allow individuals to maintain independence and dignity throughout an extended lifespan.
    Keywords:  Aging; Atrophy; Proteostasis; Sarcopenia; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.mam.2024.101319
  8. Geroscience. 2024 Sep 23.
    Age-induced changes in skeletal muscle mitochondrial DNA synthesis, quantity, and quality in genetically unique rats.
    Robert V Musci, Jordan D Fuqua, Frederick F Peelor, Hoang Van Michelle Nguyen, Arlan Richardson, Solbie Choi, Benjamin F Miller, Jonathan Wanagat.
      Mitochondrial genomic integrity is a key element of physiological processes and health. Changes in the half-life of the mitochondrial genome are implicated in the generation and accumulation of age-induced mitochondrial DNA (mtDNA) mutations, which are implicated in skeletal muscle aging and sarcopenia. There are conflicting data on the half-life of mtDNA, and there is limited information on how aging affects half-life in skeletal muscle. We hypothesized that skeletal muscle mtDNA synthesis rates would decrease with age in both female and male rats concomitant with changes in mtDNA integrity reflected in mtDNA copy number and mutation frequency. We measured mitochondrial genome half-life using stable isotope labeling over a period of 14 days and assessed mtDNA copy number and deletion mutation frequency using digital PCR in the quadriceps muscle of 9-month-old and 26-month-old male and female OKC-HET rats. We found a significant age-related increase in mtDNA half-life, from 132 days at 9 months to 216 days at 26 months of age in OKC-HET quadriceps. Concomitant with the increase in mtDNA half-life, we found an age-related increase in mtDNA deletion mutation frequency in both male and female rats. Notably, 26-month-old female rats had a lower mutation frequency than male rats, and there were no changes in mtDNA copy number with sex, age, or mitochondrial genotype. These data reveal several key findings: (1) mtDNA turnover in rat skeletal muscle decreases with age, (2) mtDNA half-lives in skeletal muscle are approximately an order of magnitude longer than what is reported for other tissues, and (3) muscle mtDNA turnover differs significantly from the turnover of other mitochondrial macromolecules including components of the mitochondrial nucleoid. These findings provide insight into the factors driving age-induced mtDNA mutation accumulation, which contribute to losses of mitochondrial genomic integrity and may play a role in skeletal muscle dysfunction.
    Keywords:  Aging; Deuterium oxide; Mitochondrial DNA; Mutation; Rats; Skeletal muscle
    DOI:  https://doi.org/10.1007/s11357-024-01344-4
  9. JCI Insight. 2024 Sep 24. pii: e182589. [Epub ahead of print]
    Extracellular vesicle transfer of miR-1 to adipose tissue modifies lipolytic pathways following resistance exercise.
    Benjamin I Burke, Ahmed Ismaeel, Douglas E Long, Lauren A Depa, Peyton T Coburn, Jensen Goh, Tolulope P Saliu, Bonnie J Walton, Ivan J Vechetti, Bailey D Peck, Taylor R Valentino, C Brooks Mobley, Hasiyet Memetimin, Dandan Wang, Brian S Finlin, Philip A Kern, Charlotte A Peterson, John J McCarthy, Yuan Wen.
      Extracellular vesicles (EVs) have emerged as important mediators of inter-tissue signaling and exercise adaptations. In this human study (n = 32), we provide evidence that muscle-specific microRNA-1 (miR-1) was transferred to adipose tissue via EVs following an acute bout of resistance exercise. Using a multi-model machine learning automation tool, we discovered muscle primary miR-1 transcript and CD63+ EV count in circulation as top explanatory features for changes in adipose miR-1 levels in response to resistance exercise. RNA-sequencing (RNA-seq) and in-silico prediction of miR-1 target genes identified caveolin 2 (CAV2) and tripartite motif containing 6 (TRIM6) as miR-1 target genes downregulated in the adipose tissue of a subset of participants with the highest increases in miR-1 levels following resistance exercise (n = 6). Overexpression of miR-1 in differentiated human adipocyte-derived stem cells downregulated these miR-1 targets and enhanced catecholamine-induced lipolysis. These data identify a potential EV-mediated mechanism by which skeletal muscle communicates to adipose tissue and modulates lipolysis via miR-1.
    Keywords:  Adipose tissue; Metabolism; Muscle biology; Skeletal muscle; Transport
    DOI:  https://doi.org/10.1172/jci.insight.182589
  10. Sports Med Health Sci. 2024 Dec;6(4): 358-369
    Identification of key genes and signaling pathways based on transcriptomic studies of aerobic and resistance training interventions in sarcopenia in SAMP8 mice.
    Lunyu Li, Xiaotian Guan, Ying Huang, Bo Qu, Binyu Yao, Haili Ding.
      We examined the effects of resistance and aerobic exercise on the gene expression and biometabolic processes of aging skeletal muscle in senescence-accelerated mouse/prone 8 mice, a model of sarcopenia, and compared them with senescence-accelerated mouse/resistant 1 mice acting as controls. We found that exercise improved muscle strength, endurance, fiber size, also modulated genes and pathways related to synaptic transmission, potassium transport, JAK-STAT signaling, and PI3K-Akt signaling. Our results suggested that BDNF, JAK2, RhoC, Myh6, Stat5a, Tnnc1, and other genes may mediate the beneficial effects of exercise on sarcopenia through these pathways.
    Keywords:  Aerobic training; Resistance training; Sarcopenia; Transcriptome
    DOI:  https://doi.org/10.1016/j.smhs.2024.01.005
  11. Curr Osteoporos Rep. 2024 Sep 26.
    Extra-osseous Roles of the RANK-RANKL-OPG Axis with a Focus on Skeletal Muscle.
    John Gostage, Paul Kostenuik, Katarzyna Goljanek-Whysall, Ilaria Bellantuono, Eugene McCloskey, Nicolas Bonnet.
      PURPOSE OF REVIEW: This review aims to consolidate recent observations regarding extra-osseous roles of the RANK-RANKL-OPG axis, primarily within skeletal muscle.RECENT FINDINGS: Preclinical efforts to decipher a common signalling pathway that links the synchronous decline in bone and muscle health in ageing and disease disclosed a potential role of the RANK-RANKL-OPG axis in skeletal muscle. Evidence suggests RANKL inhibition benefits skeletal muscle function, mass, fibre-type switching, calcium homeostasis and reduces fall incidence. However, there still exists ambiguity regarding the exact mechanistic actions and subsequent functional improvements. Other potential RANK-RANKL-OPG extra-osseous roles include regulation of neural-inflammation and glucose metabolism. Growing evidence suggests the RANK-RANKL-OPG axis may play a regulatory role in extra-osseous tissues, especially in skeletal muscle. Targeting RANKL may be a novel therapy in ameliorating loss of muscle mass and function. More research is warranted to determine the causality of the RANK-RANKL-OPG axis in extra-osseous tissues, especially those affected by aging.
    Keywords:  Denosumab; Extra-osseous; NF-κB signalling; Osteoprotegerin; RANK-RANKL-OPG axis; Skeletal muscle
    DOI:  https://doi.org/10.1007/s11914-024-00890-2
  12. J Autoimmun. 2024 Sep 19. pii: S0896-8411(24)00151-3. [Epub ahead of print]149 103317
    Exercise, autoimmune diseases and T-regulatory cells.
    Miri Blank, Daphna Israeli, Yehuda Shoenfeld.
      Diverse forms of physical activities contribute to improvement of autoimmune diseases and may prevent disease burst. T regulatory cells (Tregs) maintain tolerance in autoimmune condition. Physical activity is one of the key factors causing enhancement of Tregs number and functions, keeping homeostatic state by its secrotome. Muscles secrete myokines like IL-6, PGC1α (PPARγ coactivator-1 α), myostatin, transforming growth factor β (TGF-β) superfamily), IL-15, brain derived neurotrophic factor (BDNF) and others. The current concept points to the role of exercise in induction of highly functional and stable muscle Treg phenotype. The residing-Tregs require IL6Rα signaling to control muscle function and regeneration. Skeletal muscle Tregs IL-6Rα is a key target for muscle-Tregs cross-talk. Thus, interplay between the Tregs-skeletal muscle, following exercise, contribute to the balance of immune tolerance and autoimmunity. The cargo delivery, in the local environment and periphery, is performed by extracellular vesicles (EVs) secreted by muscle and Tregs, which deliver proteins, lipids and miRNA during persistent exercise protocols. It has been suggested that this ensemble induce protection against autoimmune diseases.
    Keywords:  Autoimmunity; Extracellular vesicles; Muscles; Physical exercise; T regulatory cells
    DOI:  https://doi.org/10.1016/j.jaut.2024.103317
  13. Heliyon. 2024 Sep 30. 10(18): e37475
    Light-phase time-restricted feeding disrupts the muscle clock and insulin sensitivity yet potentially induces muscle fiber remodeling in mice.
    Zhou Ye, Kai Huang, Xueqin Dai, Dandan Gao, Yue Gu, Jun Qian, Feng Zhang, Qiaocheng Zhai.
      Skeletal muscle plays a critical role in regulating systemic metabolic homeostasis. It has been demonstrated that time-restricted feeding (TRF) during the rest phase can desynchronize the suprachiasmatic nucleus (SCN) and peripheral clocks, thereby increasing the risk of metabolic diseases. However, the impact of dietary timing on the muscle clock and health remains poorly understood. Here, through the analysis of cycling genes and differentially expressed genes in the skeletal muscle transcriptome, we identified disruptions in muscle diurnal rhythms by 2 weeks of light-phase TRF. Furthermore, compared with ad libitum (AL) feeding mice, 2 weeks of light-phase TRF was found to induce insulin resistance, muscle fiber type remodeling, and changes in the expression of muscle growth-related genes, while both light-phase and dark-phase TRF having a limited impact on bone quality relative to AL mice. In summary, our research reveals that the disruption of the skeletal muscle clock may contribute to the abnormal metabolic phenotype resulting from feeding restricted to the inactive period. Additionally, our study provides a comprehensive omics atlas of the diurnal rhythms in skeletal muscle regulated by dietary timing.
    Keywords:  Bone mass; Circadian clock; Muscle fiber remodeling; Skeletal muscle; Time-restricted feeding
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e37475
  14. Inflamm Regen. 2024 Sep 26. 44(1): 39
    Beyond the bulk: overview and novel insights into the dynamics of muscle satellite cells during muscle regeneration.
    Woo Seok Byun, Jinu Lee, Jea-Hyun Baek.
      Skeletal muscle possesses remarkable regenerative capabilities, fully recovering within a month following severe acute damage. Central to this process are muscle satellite cells (MuSCs), a resident population of somatic stem cells capable of self-renewal and differentiation. Despite the highly predictable course of muscle regeneration, evaluating this process has been challenging due to the heterogeneous nature of myogenic precursors and the limited insight provided by traditional markers with overlapping expression patterns. Notably, recent advancements in single-cell technologies, such as single-cell (scRNA-seq) and single-nucleus RNA sequencing (snRNA-seq), have revolutionized muscle research. These approaches allow for comprehensive profiling of individual cells, unveiling dynamic heterogeneity among myogenic precursors and their contributions to regeneration. Through single-cell transcriptome analyses, researchers gain valuable insights into cellular diversity and functional dynamics of MuSCs post-injury. This review aims to consolidate classical and new insights into the heterogeneity of myogenic precursors, including the latest discoveries from novel single-cell technologies.
    Keywords:  Cellular dynamics; Macrophage; Single-cell technology; Skeletal muscle satellite cell; Tissue regeneration
    DOI:  https://doi.org/10.1186/s41232-024-00354-1
  15. Br J Anaesth. 2024 Sep 19. pii: S0007-0912(24)00469-0. [Epub ahead of print]
    Propofol binds and inhibits skeletal muscle ryanodine receptor 1.
    Thomas T Joseph, Weiming Bu, Omid Haji-Ghassemi, Yu S Chen, Kellie Woll, Paul D Allen, Grace Brannigan, Filip van Petegem, Roderic G Eckenhoff.
      BACKGROUND: As the primary Ca2+ release channel in skeletal muscle sarcoplasmic reticulum (SR), mutations in type 1 ryanodine receptor (RyR1) or its binding partners underlie a constellation of muscle disorders, including malignant hyperthermia (MH). In patients with MH mutations, triggering agents including halogenated volatile anaesthetics bias RyR1 to an open state resulting in uncontrolled Ca2+ release, increased sarcomere tension, and heat production. Propofol does not trigger MH and is commonly used for patients at risk of MH. The atomic-level interactions of any anaesthetic with RyR1 are unknown.METHODS: RyR1 opening was measured by [3H]ryanodine binding in heavy SR vesicles (wild type) and single-channel recordings of MH mutant R615C RyR1 in planar lipid bilayers, each exposed to propofol or the photoaffinity ligand analogue m-azipropofol (AziPm). Activator-mediated wild-type RyR1 opening as a function of propofol concentration was measured by Fura-2 Ca2+ imaging of human skeletal myotubes. AziPm binding sites, reflecting propofol binding, were identified on RyR1 using photoaffinity labelling. Propofol binding affinity to a photoadducted site was predicted using molecular dynamics (MD) simulation.
    RESULTS: Both propofol and AziPm decreased RyR1 opening in planar lipid bilayers (P<0.01) and heavy SR vesicles, and inhibited activator-induced Ca2+ release from human skeletal myotube SR. Several putative propofol binding sites on RyR1 were photoadducted by AziPm. MD simulation predicted propofol KD values of 55.8 μM and 1.4 μM in the V4828 pocket in open and closed RyR1, respectively.
    CONCLUSIONS: Propofol demonstrated direct binding and inhibition of RyR1 at clinically plausible concentrations, consistent with the hypothesis that propofol partially mitigates MH by inhibition of induced Ca2+ flux through RyR1.
    Keywords:  free energy perturbation; malignant hyperthermia; photoaffinity labelling; propofol; ryanodine receptor 1; skeletal muscle
    DOI:  https://doi.org/10.1016/j.bja.2024.06.048
  16. STAR Protoc. 2024 Sep 20. pii: S2666-1667(24)00495-7. [Epub ahead of print]5(4): 103330
    Protocol to monitor live-cell, real-time, mitochondrial respiration in mouse muscle cells using the Resipher platform.
    Matthew Triolo, Mireille Khacho.
      Mitochondrial function is typically assessed by measuring oxygen consumption at a given time point. However, this approach cannot monitor respiratory changes that occur over time. Here, we present a protocol to measure mitochondrial respiration in freshly isolated muscle stem cells, primary skeletal muscle, and immortalized C2C12 myoblasts in real time using the Resipher platform. We describe steps for preparing and plating cells, performing media changes, setting up the software and device, and analyzing data. This method can be adapted to other cell types. For complete details on the use and execution of this protocol, please refer to Triolo et al.1.
    Keywords:  Cell Biology; Metabolism; Stem Cells
    DOI:  https://doi.org/10.1016/j.xpro.2024.103330
  17. J Cachexia Sarcopenia Muscle. 2024 Sep 23.
    LRRK2G2019S Gene Mutation Causes Skeletal Muscle Impairment in Animal Model of Parkinson's Disease.
    Yiying Hu, Huijia Yang, Chunli Song, Lulu Tian, Panpan Wang, Tianbai Li, Cheng Cheng, Murad AlNusaif, Song Li, Zhanhua Liang, Weidong Le.
      BACKGROUND: While the gradually aggravated motor and non-motor disorders of Parkinson's disease (PD) lead to progressive disability and frequent falling, skeletal muscle impairment may contribute to this condition. The leucine-rich repeat kinase2 (LRRK2) is a common disease-causing gene in PD. Little is known about its role in skeletal muscle impairment and its underlying mechanisms.METHODS: To investigate whether the mutation in LRRK2 causes skeletal muscle impairment, we used 3-month-old (3mo) and 14-month-old (14mo) LRRK2G2019S transgenic (TG) mice as a model of PD, compared with the age-matched littermate wild-type (WT) controls. We measured the muscle mass and strength, ultrastructure, inflammatory infiltration, mitochondrial morphology and dynamics dysfunction through behavioural analysis, electromyography (EMG), immunostaining, transmission electron microscopy (TEM) and other molecular biology techniques.
    RESULTS: The 3mo-TG mice display mild skeletal muscle impairment with spontaneous potentials in EMG (increased by 130%, p < 0.05), myofibre necrosis (p < 0.05) and myosin heavy chain-II changes (reduced by 19%, p < 0.01). The inflammatory cells and macrophage infiltration are significantly increased (CD8a+ and CD68+ cells up 1060% and 579%, respectively, both p < 0.0001) compared with the WT mice. All of the above pathogenic processes are aggravated by aging. The 14mo-TG mice EMG examinations show a reduced duration (by 31%, p < 0.01) and increased polyphasic waves of motor unit action potentials (by 28%, p < 0.05). The 14mo-TG mice present motor behavioural deficits (p < 0.05), muscle strength and mass reduction by 37% and 8% (p < 0.05 and p < 0.01, respectively). A remarkable increase in inflammatory infiltration is accompanied by pro-inflammatory cytokines in the skeletal muscles. TEM analysis shows muscle fibre regeneration with the reduced length of sarcomeres (by 6%;p < 0.05). The muscle regeneration is activated as Pax7+ cells increased by 106% (p < 0.0001), andmyoblast determination protein elevated by 71% (p < 0.01). We also document the morphological changes and dynamics dysfunction of mitochondria with the increase of mitofusin1 by 43% (p < 0.05) and voltage-dependent anion channel 1 by 115% (p < 0.001) in the skeletal muscles of 14mo-TG mice.
    CONCLUSIONS: Taken together, these findings may provide new insights into the clinical and pathogenic involvement of LRRK2G2019 mutation in muscles, suggesting that the diseases may affect not only midbrain dopaminergic neurons, but also other tissues, and it may help overall clinical management of this devastating disease.
    Keywords:  LRRK2G2019S mutation; Parkinson's disease; electromyography; mitochondrial impairment; skeletal muscle impairment
    DOI:  https://doi.org/10.1002/jcsm.13604
  18. Cell. 2024 Sep 13. pii: S0092-8674(24)00970-X. [Epub ahead of print]
    Profound cellular defects attribute to muscular pathogenesis in the rhesus monkey model of Duchenne muscular dystrophy.
    Shuaiwei Ren, Xin Fu, Wenting Guo, Raoxian Bai, Sheng Li, Ting Zhang, Jie Liu, Zhengbo Wang, Hui Zhao, Shengbao Suo, Weikang Zhang, Minzhi Jia, Weizhi Ji, Ping Hu, Yongchang Chen.
      Duchenne muscular dystrophy (DMD) is a progressive muscle-wasting disease caused by mutations in the DMD gene. Muscle fibers rely on the coordination of multiple cell types for repair and regenerative capacity. To elucidate the cellular and molecular changes in these cell types under pathologic conditions, we generated a rhesus monkey model for DMD that displays progressive muscle deterioration and impaired motor function, mirroring human conditions. By leveraging these DMD monkeys, we analyzed freshly isolated muscle tissues using single-cell RNA sequencing (scRNA-seq). Our analysis revealed changes in immune cell landscape, a reversion of lineage progressing directions in fibrotic fibro-adipogenic progenitors (FAPs), and TGF-β resistance in FAPs and muscle stem cells (MuSCs). Furthermore, MuSCs displayed cell-intrinsic defects, leading to differentiation deficiencies. Our study provides important insights into the pathogenesis of DMD, offering a valuable model and dataset for further exploration of the underlying mechanisms, and serves as a suitable platform for developing and evaluating therapeutic interventions.
    Keywords:  DMD; Duchenne muscular dystrophy; FAPs; MuSCs; NHP model; fibro-adipogenic progenitors; fibrosis; immune cells; inflammation; muscle regeneration; muscle stem cells; muscle weakness; nonhuman primate model; scRNA-seq; single cell sequencing
    DOI:  https://doi.org/10.1016/j.cell.2024.08.041
  19. Life Sci. 2024 Sep 24. pii: S0024-3205(24)00669-6. [Epub ahead of print] 123079
    Skeletal muscle-derived exosomes prevent osteoporosis by promoting osteogenesis.
    Zheng Xing, Lanlan Guo, Shitian Li, Wenhua Huang, Jie Su, Xuefei Chen, Yanjun Li, Jing Zhang.
      Skeletal muscle and bone are the major organs for physical activity, in which there is a parallel correlation between muscle mass and bone density throughout a lifetime. Osteoporosis is a systemic bone metabolic disorder caused by reduced bone formation and increased bone resorption. Based on the metabolic symbiosis relationship between skeletal muscle and bone, we hypothesis that skeletal muscle secretory factors could play constructive roles in osteoporosis. Exosomes have been verified to transfer bioactive factors among cells. However, the role of skeletal muscle derived-exosomes (SM-Exos) in osteoporosis is still unclear. In this study, we isolated the exosomes derived from denervated skeletal muscles intervened by neuromuscular electrical stimulation (DN + ES-Exo), and then injected these DN + ES-Exo into sarco-osteoporotic rats through tail vein. In vitro studies, we cocultured SM-Exos from different states with differentiated MC3T3-E1 osteoblasts. In brief, our research results demonstrate that SM-Exos could partially promote osteogenesis both in vivo and in vitro. Further, our findings indicate that skeletal muscle contraction induced by neuromuscular electrical stimulation (NMES) can reverse the incidence of sarco-osteoporosis to a certain degree, and DN + ES-Exo contributes to the improvement in osteoporosis by facilitating osteoblast differentiation. Then, we revealed that NMES might regulate several miRNAs in skeletal muscle, the miRNAs that are encapsulated by SM-Exos might be involved in osteogenic differentiation in a network manner. All in all, this study confirmed the effect of NMES on sarco-osteoporosis and explored the role of SM-Exos in the improvement osteoporosis, which provide an effective theoretical support for the physical therapy of clinical sarco-osteoporosis.
    Keywords:  Exosomes; Osteoporosis; Skeletal muscle; miRNA
    DOI:  https://doi.org/10.1016/j.lfs.2024.123079
  20. Drug Test Anal. 2024 Sep 24.
    Skeletal Muscle Memory: An Update From the Antidoping Perspective.
    Claire Traversa.
      This narrative review explores the concept of muscle memory, focusing on the physiological and biochemical mechanisms underlying information retention in skeletal muscle tissue as it relates to antidoping. The discussion encompasses the role of satellite cells (SCs) in myonuclei recruitment, resulting in increased myonuclear density and heightened muscle protein turnover. The myonuclear domain theory suggests that myonuclei acquired during hypertrophy may persist, contributing to enhanced muscle protein synthesis (MPS) and potential benefits of muscle memory. The impact of sustained training, protein intake, and resistance exercise on muscle memory, especially in elite athletes, is considered. The review also delves into the influence of anabolic androgenic steroids (AAS) on muscle tissue, highlighting their role in elevating the performance threshold and supporting recovery during intense training through increased muscle protein turnover rates. Additionally, genetic and epigenetic modifications, such as DNA methylation, are explored as potential contributors to muscle memory. The complex interplay of continuous training, AAS use, and genetic factors offers avenues for further research, especially in the context of antidoping efforts. The understanding of muscle memory has implications for maintaining performance gains and addressing ethical challenges in sports.
    Keywords:  anabolic androgenic steroids; antidoping; doping; muscle anabolism; muscle hypertrophy; muscle memory; myonculei density; myonuclear domain theory; myonuclei
    DOI:  https://doi.org/10.1002/dta.3804
  21. Sports Med Health Sci. 2024 Dec;6(4): 302-314
    Exercise and nutrition benefit skeletal muscle: From influence factor and intervention strategy to molecular mechanism.
    Lili Feng, Bowen Li, Su Sean Yong, Xiaonan Wu, Zhenjun Tian.
      Sarcopenia is a progressive systemic skeletal muscle disease induced by various physiological and pathological factors, including aging, malnutrition, denervation, and cardiovascular diseases, manifesting as the decline of skeletal muscle mass and function. Both exercise and nutrition produce beneficial effects on skeletal muscle growth and are viewed as feasible strategies to prevent sarcopenia. Mechanisms involve regulating blood flow, oxidative stress, inflammation, apoptosis, protein synthesis and degradation, and satellite cell activation through exerkines and gut microbiomes. In this review, we summarized and discussed the latest progress and future development of the above mechanisms for providing a theoretical basis and ideas for the prevention and treatment of sarcopenia.
    Keywords:  Diet; Exercise; Exerkines; Sarcopenia; Satellite cells; Signaling pathway; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.smhs.2024.02.004
  22. Heliyon. 2024 Sep 30. 10(18): e37529
    Hotspots and trends in satellite cell research in muscle regeneration: A bibliometric visualization and analysis from 2010 to 2023.
    Nan Huang, Kang Zou, Yanbiao Zhong, Yun Luo, Maoyuan Wang, Li Xiao.
      Background: The incidence of muscle atrophy or sports injuries is increasing with time and population aging, thereby attracting considerable attention to muscle generation research. Muscle satellite cells, which play an important role in this process, lack comprehensive literature regarding their use for muscle regeneration. Hence, this study aimed to analyze the hotspots and trends in satellite cell research from 2010 to 2023, providing a reference for muscle regeneration research.Methods: Studies on satellite cells' role in muscle regeneration from 2010 to 2023 were retrieved from the Web of Science Core Collection. Using CiteSpace and VOSviewer, we analyzed annual publications, authors and co-citing authors, countries and institutions, journals and co-citing journals, co-citing references, and keywords.
    Results: From 2010 to 2023, 1468 papers were retrieved, indicating an overall increasing trend in the number of annual publications related to satellite cells in muscle regeneration. The United States had the highest number of publications, while the Institut National de la Santé et de la Recherche Médicale was the institution with the most publications. Among journals, " PloS One" had the highest number of published papers, and "Cell" emerged as the most co-cited journal. A total of 7425 authors were involved, with Michael A. Rudnicki being the author with the highest number of publications and the most co-cited author. The most cited reference was "Satellite cells and the muscle stem cell niche." Among keywords, "satellite cells" was the most common, with "heterogeneity" having the highest centrality. Frontier themes included "Duchenne muscular dystrophy," "skeletal muscle," "in-vivo," "muscle regeneration," "mice," "muscle atrophy," "muscle fibers," "inflammation," " mesenchymal stem cells," and "satellite cell."
    Conclusion: This study presents the current status and trends in satellite cell research on muscle regeneration from 2010 to 2023 using bibliometric analyses, providing valuable insights into numerous future research directions.
    Keywords:  Bibliometrics; Muscle atrophy; Muscle injury; Muscle regeneration; Satellite cells
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e37529
  23. Dev Dyn. 2024 Sep 26.
    Knockout of rbm24a and rbm24b genes in zebrafish impairs skeletal and cardiac muscle integrity and function during development.
    Audrey Saquet, Ziwei Ying, De-Li Shi, Raphaëlle Grifone.
      BACKGOUND: Skeletal and cardiac muscles are contractile tissues whose development and function are dependent on genetic programs that must be precisely orchestrated in time and space. In addition to transcription factors, RNA-binding proteins tightly regulate gene expression by controlling the fate of RNA transcripts, thus specific proteins levels within the cell. Rbm24 has been identified as a key player of myogenesis and cardiomyogenesis in several vertebrates, by controlling various aspects of post-transcriptional regulation, including pre-mRNA alternative splicing and mRNA stabilization. In zebrafish, knockdown of rbm24a or rbm24b also causes skeletal and cardiac muscle phenotypes, but how their combined loss affects muscle integrity and function remains elusive.RESULTS: By genome editing, we have generated rbm24a and rbm24b single mutants as well as double mutants. Structural analyses indicate that homozygous rbm24a and rbm24b double mutants exhibit severe somitic muscle and cardiac phenotypes, although rbm24b single mutants are obviously normal. We further show that the loss of rbm24a and rbm24b disrupts sarcomere organization, impairing functional contractility and motility of skeletal and cardiac muscles.
    CONCLUSION: The rbm24 mutant zebrafish represents a new genetic tool for in-depth studies of Rbm24-mediated post-transcriptional regulation of skeletal and cardiac muscle development, disease and regeneration.
    Keywords:  RNA‐binding protein; Rbm24; heart; post‐transcriptional regulation; sarcomere; skeletal muscle; zebrafish
    DOI:  https://doi.org/10.1002/dvdy.743
  24. Free Radic Biol Med. 2024 Sep 21. pii: S0891-5849(24)00679-8. [Epub ahead of print]
    Effects of intermittent exposure to hypobaric hypoxia and cold on skeletal muscle regeneration: mitochondrial dynamics, protein oxidation and turnover.
    Sergio Sánchez-Nuño, Garoa Santocildes, Josep Rebull, Raquel G Bardallo, Montserrat Girabent, Ginés Viscor, Teresa Carbonell, Joan Ramon Torrella.
      Muscle injuries and the subsequent regeneration events compromise muscle homeostasis at morphological, functional and molecular levels. Among the molecular alterations, those derived from the mitochondrial function are especially relevant. We analysed the mitochondrial dynamics, the redox balance, the protein oxidation and the main protein repairing mechanisms after 9 days of injury in the rat gastrocnemius muscle. During the recovery rats were exposed to intermittent cold exposure (ICE), intermittent hypobaric hypoxia (IHH), and both simultaneous combined stimuli. Non-injured contralateral legs were also analysed to evaluate the specific effects of the three environmental exposures. Our results showed that ICE enhanced mitochondrial adaptation by improving the electron transport chain efficiency during muscle recovery, decreased the expression of regulatory subunit of proteasome and accumulated oxidised proteins. Exposure to IHH did not show mitochondrial compensation or increased protein turnover mechanisms; however, no accumulation of oxidized proteins was observed. Both ICE and IHH, when applied separately, elicited an increased expression of eNOS, which could have played an important role in accelerating muscle recovery. The combined effect of ICE and IHH led to a complex response that could potentially impede optimal mitochondrial function and enhanced the accumulation of protein oxidation. These findings underscore the nuanced role of environmental stressors in the muscle healing process and their implications for optimizing recovery strategies.
    Keywords:  Electron transport chain; Intermittent cold exposure; Intermittent hypobaric hypoxia; protein oxidation; redox
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.09.032
  25. J Dev Biol. 2024 Sep 17. pii: 25. [Epub ahead of print]12(3):
    Myotube Guidance: Shaping up the Musculoskeletal System.
    Aaron N Johnson.
      Myofibers are highly specialized contractile cells of skeletal muscles, and dysregulation of myofiber morphogenesis is emerging as a contributing cause of myopathies and structural birth defects. Myotubes are the myofiber precursors and undergo a dramatic morphological transition into long bipolar myofibers that are attached to tendons on two ends. Similar to axon growth cones, myotube leading edges navigate toward target cells and form cell-cell connections. The process of myotube guidance connects myotubes with the correct tendons, orients myofiber morphology with the overall body plan, and generates a functional musculoskeletal system. Navigational signaling, addition of mass and volume, and identification of target cells are common events in myotube guidance and axon guidance, but surprisingly, the mechanisms regulating these events are not completely overlapping in myotubes and axons. This review summarizes the strategies that have evolved to direct myotube leading edges to predetermined tendon cells and highlights key differences between myotube guidance and axon guidance. The association of myotube guidance pathways with developmental disorders is also discussed.
    Keywords:  Drosophila; morphogenetic gene regulatory network; muscle shape; myogenesis; myotube guidance; skeletal muscle
    DOI:  https://doi.org/10.3390/jdb12030025
  26. Physiol Rep. 2024 Sep;12(18): e70052
    Macrophages modulate skeletal muscle wasting and recovery in acute lung injury in mice.
    Jennifer T W Krall, Lanazha Belfield, Claire Strysick, Chun Liu, Lina Purcell, Renee Stapleton, Michael Toth, Matthew Poynter, Xuewei Zhu, Kevin Gibbs, D Clark Files.
      Skeletal muscle dysfunction in critical illnesses leaves survivors weak and functionally impaired. Macrophages infiltrate muscles; however, their functional role is unclear. We aim to examine muscle leukocyte composition and the effect of macrophages on muscle mass and function in the murine acute lung injury (ALI)-associated skeletal muscle wasting model. We performed flow cytometry of hindlimb muscle to identify myeloid cells pre-injury and time points up to 29 days after intratracheal lipopolysaccharide ALI. We evaluated muscle force and morphometrics after systemic and intramuscular clodronate-induced macrophage depletions between peak lung injury and recovery (day 5-6) versus vehicle control. Our results show muscle leukocytes changed over ALI course with day 3 neutrophil infiltration (130.5 ± 95.6cells/mg control to 236.3 ± 70.6cells/mg day 3) and increased day 10 monocyte abundance (5.0 ± 3.4%CD45+CD11b+ day 3 to 14.0 ± 2.6%CD45+CD11b+ day 10, p = 0.005). Although macrophage count did not significantly change, pro-inflammatory (27.0 ± 7.2% day 3 to 7.2 ± 3.8% day 10, p = 0.02) and anti-inflammatory (30.5 ± 11.1% day 3 to 52.7 ± 9.7% day 10, p = 0.09) surface marker expression changed over the course of ALI. Macrophage depletion following peak lung injury increased muscle mass and force generation. These data suggest muscle macrophages beyond peak lung injury limit or delay muscle recovery. Targeting macrophages could augment muscle recovery following lung injury.
    Keywords:  acute lung injury; acute respiratory distress syndrome; intensive care unit acquired weakness; macrophage; skeletal muscle wasting
    DOI:  https://doi.org/10.14814/phy2.70052
  27. J Med Genet. 2024 Sep 26. pii: jmg-2024-110045. [Epub ahead of print]
    Histone modifications in Duchenne muscular dystrophy: pathogenesis insights and therapeutic implications.
    Yanning Wei, Yuanyuan Jiang, Yufei Lu, Qiping Hu.
      Duchenne muscular dystrophy (DMD) is a commonly encountered genetic ailment marked by loss-of-function mutations in the Dystrophin gene, ultimately resulting in progressive debilitation of skeletal muscle. The investigation into the pathogenesis of DMD has increasingly converged on the role of histone modifications within the broader context of epigenetic regulation. These modifications, including histone acetylation, methylation and phosphorylation, are catalysed by specific enzymes and play a critical role in gene expression. This article provides an overview of the histone modifications occurring in DMD and analyses the research progress and potential of different types of histone modifications in DMD due to changes in cellular signalling for muscle regeneration, to provide new insights into diagnostic and therapeutic options for DMD.
    Keywords:  Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Drug Discovery; Gene Expression Regulation; Genetic Diseases, X-Linked; Phenomics
    DOI:  https://doi.org/10.1136/jmg-2024-110045
  28. Cureus. 2024 Aug;16(8): e67901
    A Voyage on the Role of Nuclear Factor Kappa B (NF-kB) Signaling Pathway in Duchenne Muscular Dystrophy: An Inherited Muscle Disorder.
    Akshaya R, Sumithra Mohan, Chitra Vellapandian.
      A recessive X-linked illness called Duchenne muscular dystrophy (DMD) is characterized by increasing muscle weakening and degradation. It primarily affects boys and is one of the most prevalent and severe forms of muscular dystrophy. Mutations in the DMD gene, which codes for the essential protein dystrophin, which aids in maintaining the stability of muscle cell membranes during contraction, are the cause of the illness. Dystrophin deficiency or malfunction damages muscle cells, resulting in persistent inflammation and progressive loss of muscular mass. The pathophysiology and genetic foundation of DMD are thoroughly examined in this review paper, focusing on the function of the NF-κB signaling system in the disease's progression. An important immune response regulator, NF-κB, is aberrantly activated in DMD, which exacerbates the inflammatory milieu in dystrophic muscles. Muscle injury and fibrosis are exacerbated and muscle regeneration is hampered by the pro-inflammatory cytokines and chemokines that are produced when NF-κB is persistently activated in muscle cells. The paper also examines our existing knowledge of treatment approaches meant to inhibit the progression of disease by modifying NF-κB signaling. These include new molecular techniques, gene treatments, and pharmacological inhibitors that are intended to lessen inflammation and improve muscle healing. Furthermore covered in the analysis is the significance of supportive care for DMD patients, including physical therapy and corticosteroid treatment, in symptom management and quality of life enhancement. The article seeks to provide a thorough understanding of the mechanisms causing DMD, possible therapeutic targets, and developing treatment options by combining recent research findings. This will provide clinicians and researchers involved in DMD care and research with invaluable insights.
    Keywords:  duchenne muscular dystrophy (dmd); dystrophin; fibrosis; glucocorticoids; inflammation; muscle degeneration; nf-κb signaling pathway
    DOI:  https://doi.org/10.7759/cureus.67901
  29. Int J Biol Macromol. 2024 Sep 24. pii: S0141-8130(24)06798-9. [Epub ahead of print] 135989
    IGF2BP1-mediated the stability and protein translation of FGFR1 mRNA regulates myogenesis through the ERK signaling pathway.
    Zhipeng Liu, Kaiping Deng, Yalong Su, Zhen Zhang, Congyu Shi, Jingang Wang, Yixuan Fan, Guoming Zhang, Feng Wang.
      N6-methyladenosine (m6A) is the most prevalent post-transcriptional modification of RNAs and plays a key regulatory role in various biological processes. As a member of the insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs) family, IGF2BP1 has recently demonstrated its ability to specifically bind m6A-modified sites within mRNAs and effectively regulate their mRNA stability. However, the precise roles of IGF2BP1 in mammalian skeletal muscle development, along with its downstream mRNA targets during myogenesis, have yet to be fully elucidated. Here, we observed that IGF2BP1 expression significantly decreased during myogenic differentiation. Knockdown of IGF2BP1 significantly inhibited myoblast proliferation while promoted myogenic differentiation. In contrast, IGF2BP1 overexpression robustly stimulated myoblast proliferation but suppressed their differentiation. Combined analysis of high-throughput sequencing and RNA stability assays revealed that IGF2BP1 can enhance fibroblast growth factor receptor 1 (FGFR1) mRNA stability and promote its translation in an m6A-dependent manner, thereby regulating its expression level and the Extracellular Signal-Regulated Kinase (ERK) pathway. Additionally, knockdown of FGFR1 rescued the phenotypic changes (namely increased cell proliferation and suppressed differentiation) induced by IGF2BP1 overexpression via attenuating ERK signaling. Taken together, our findings suggest that IGF2BP1 maintains the stability and translation of FGFR1 mRNA in an m6A-dependent manner, thereby inhibiting skeletal myogenesis through activation of the ERK signaling pathway. This study further enriches the understanding of the molecular mechanisms by which RNA methylation regulates myogenesis, providing valuable insights into the role of IGF2BP1-mediated post-transcriptional regulation in muscle development.
    Keywords:  Competitive binding; IGF2BP1; Myogenic differentiation; Post-transcriptional regulation; Protein translation; mRNA stability
    DOI:  https://doi.org/10.1016/j.ijbiomac.2024.135989
  30. Sci Adv. 2024 Sep 20. 10(38): eadj4122
    Loss of SELENOW aggravates muscle loss with regulation of protein synthesis and the ubiquitin-proteasome system.
    Jia-Cheng Yang, Meng Liu, Rong-Hui Huang, Ling Zhao, Qin-Jian Niu, Ze-Jing Xu, Jin-Tao Wei, Xin Gen Lei, Lv-Hui Sun.
      Sarcopenia is characterized by accelerated muscle mass and function loss, which burdens and challenges public health worldwide. Several studies indicated that selenium deficiency is associated with sarcopenia; however, the specific mechanism remains unclear. Here, we demonstrated that selenoprotein W (SELENOW) containing selenium in the form of selenocysteine functioned in sarcopenia. SELENOW expression is up-regulated in dexamethasone (DEX)-induced muscle atrophy and age-related sarcopenia mouse models. Knockout (KO) of SELENOW profoundly aggravated the process of muscle mass loss in the two mouse models. Mechanistically, SELENOW KO suppressed the RAC1-mTOR cascade by the interaction between SELENOW and RAC1 and induced the imbalance of protein synthesis and degradation. Consistently, overexpression of SELENOW in vivo and in vitro alleviated the muscle and myotube atrophy induced by DEX. SELENOW played a role in age-related sarcopenia and regulated the genes associated with aging. Together, our study uncovered the function of SELENOW in age-related sarcopenia and provides promising evidence for the prevention and treatment of sarcopenia.
    DOI:  https://doi.org/10.1126/sciadv.adj4122
  31. Biomed Pharmacother. 2024 Sep 23. pii: S0753-3322(24)01348-9. [Epub ahead of print]180 117462
    6-Gingerol improves lipid metabolism disorders in skeletal muscle by regulating AdipoR1/AMPK signaling pathway.
    Ze Peng, Yan Zeng, Xin Zeng, Qi Tan, Qifeng He, Shang Wang, Jianwei Wang.
      BACKGROUND: To delve into the precise mechanisms by which 6-gingerol ameliorates lipid metabolism disorders in skeletal muscle.METHODS: The level of triglycerides (TG) was used to evaluate lipid deposition. In skeletal muscle, transmission electron microscopy (TEM) was employed to observe mitochondrial morphology. Additionally, PCR was applied to detect mitochondrial biogenesis, and levels of malondialdehyde (MDA), catalase (CAT), glutathione, r-glutamyl cysteingl+glycine (GSH) and nicotinamide adenine dinucleotide (NADH) were measured to assess mitochondrial oxidative stress levels. In vivo, flow cytometry and immunofluorescence assays were conducted to quantify reactive oxygen species (ROS) and mitochondrial membrane potential (MMP). Furthermore, the Seahorse XF assays was utilized to assess mitochondrial respiratory capacity. Fluorescence confocal microscopy and molecular docking were applied to analyze the binding of 6-gingerol and adiponectin receptor 1 (AdipoR1). The expression of AdipoR1, AMPK, PGC-1α and SIRT1 were detected by Western Blot.
    RESULTS: In vivo, 6-gingerol could reduce body weight in mice induced by a high-fat diet, enhance metabolic profiles in plasma, decrease lipid accumulation in skeletal muscle and liver, and elevate adiponectin levels. In skeletal muscle, it could restore mitochondrial morphology, boost mitochondrial copy number and biogenesis, and mitigate oxidative stress. In vitro, 6-gingerol may directly interact with AdipoR1 to upregulate the expression of downstream proteins p-AMPK, SIRT1, and PGC-1α, leading to a reduction in lipid deposition, a decrease in ROS production, an increase in mitochondrial membrane potential, and an enhancement of mitochondrial respiratory capacity in C2C12 myotubes.
    CONCLUSION: 6-Gingerol ameliorated lipid metabolism in skeletal muscle by regulating the AdipoR1/AMPK signaling pathway.
    Keywords:  6-gingerol; Ginger; Lipid metabolism disorders; Mitochondria; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.biopha.2024.117462
  32. Age Ageing. 2024 Sep 01. pii: afae209. [Epub ahead of print]53(9):
    Amyotrophic lateral sclerosis as a disease model of sarcopenia.
    Domenico Azzolino, Rachele Piras, Aida Zulueta, Tiziano Lucchi, Christian Lunetta.
      Sarcopenia, the progressive decline of muscle mass and function, has traditionally been viewed as an age-related process leading to a broad range of adverse outcomes. However, it has been widely reported that sarcopenia can occur earlier in life in association with various conditions (i.e. disease-related sarcopenia), including neuromuscular disorders. As early as 2010, the European Working Group on Sarcopenia in Older People included neurodegenerative diseases characterised by motor neuron loss among the mechanisms underlying sarcopenia. Despite some differences in pathogenetic mechanisms, both amyotrophic lateral sclerosis (ALS) and age-related sarcopenia share common characteristics, such as the loss of motor units and muscle fibre atrophy, oxidative stress, mitochondrial dysfunction and inflammation. The histology of older muscle shows fibre size heterogeneity, fibre grouping and a loss of satellite cells, similar to what is observed in ALS patients. Regrettably, the sarcopenic process in ALS patients has been largely overlooked, and literature on the condition in this patient group is very scarce. Some instruments used for the assessment of sarcopenia in older people could also be applied to ALS patients. At this time, there is no approved specific pharmacological treatment to reverse damage to motor neurons or cure ALS, just as there is none for sarcopenia. However, some agents targeting the muscle, like myostatin and mammalian target of rapamycin inhibitors, are under investigation both in the sarcopenia and ALS context. The development of new therapeutic agents targeting the skeletal muscle may indeed be beneficial to both ALS patients and older people with sarcopenia.
    Keywords:  frailty; motor neuron; muscle; neurodegeneration; nutrition; older people
    DOI:  https://doi.org/10.1093/ageing/afae209
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