bims-moremu 2024-03-31 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2024–03–31
25 papers selected by
Anna Vainshtein, Craft Science Inc.

Apelin regulates skeletal muscle adaptation to exercise in a high intensity interval training (HIIT) model.
Exercise-Regulated Mitochondrial and Nuclear Signalling Networks in Skeletal Muscle.
MST1/2 regulates fibro/adipogenic progenitor fate decisions in skeletal muscle regeneration.
Atrogin-1 promotes muscle homeostasis by regulating levels of endoplasmic reticulum chaperone BiP.
TP53INP2-dependent activation of muscle autophagy ameliorates sarcopenia and promotes healthy aging.
The DUX4-HIF1α Axis in Murine and Human Muscle Cells: A Link More Complex Than Expected.
Metabolomic response to acute resistance exercise in healthy older adults by 1H-NMR.
Characterization of Skeletal Muscle Regeneration Revealed a Novel Growth Network Induced by Molecular Acupuncture-like Transfection.
The Revolution of exosomes: From biological functions to therapeutic applications in skeletal muscle diseases.
Loss of function of phosphatidylserine synthase causes muscle atrophy in Drosophila.
Powerpenia Should be Considered a Biomarker of Healthy Aging.
Review: myogenic and muscle toxicity targets of environmental methylmercury exposure.
Regulation of myo-miR-24-3p on the Myogenesis and Fiber Type Transformation of Skeletal Muscle.
Histone lactylation in macrophages is predictive for gene expression changes during ischemia induced-muscle regeneration.
Myosin-binding protein C regulates the sarcomere lattice and stabilizes the OFF states of myosin heads.
ADAR2 deficiency ameliorates non-alcoholic fatty liver disease and muscle atrophy through modulating serum amyloid A1.
Mitochondrial Transplantation Therapy Ameliorates Muscular Dystrophy in mdx Mouse Model.
Pulsed Electric Fields Induce STING Palmitoylation and Polymerization Independently of Plasmid DNA Electrotransfer.
DELE1 promotes translation-associated homeostasis, growth, and survival in mitochondrial myopathy.
Salubrinal promotes phospho-eIF2α-dependent activation of UPR leading to autophagy-mediated attenuation of iron-induced insulin resistance.
Ruxolitinib: A new hope for ventilator-induced diaphragm dysfunction.
A stagewise response to mitochondrial dysfunction in mitochondrial DNA maintenance disorders.
Aerobic Exercise Modulates Proteomic Profiles in Gastrocnemius Muscle of db/db Mice, Ameliorating Sarcopenia.
Stimulated Single Fiber Electromyography (SFEMG) for Assessing Neuromuscular Junction Transmission in Rodent Models.
Prevention of age-related neuromuscular junction degeneration in sarcopenia by low-magnitude high-frequency vibration.

Am J Physiol Cell Physiol. 2024 Mar 25.

Apelin regulates skeletal muscle adaptation to exercise in a high intensity interval training (HIIT) model.

Teemu Kilpiö, Sini Skarp, Abel Perjes, Julia Swan, Leena Kaikkonen, Samu Saarimaki, Istvan Szokodi, Josef M Penninger, Zoltan Szabo, Johanna Magga, Risto Kerkela.

  Plasma apelin levels are reduced in aging and muscle wasting conditions. We aimed to investigate the significance of apelin signaling in cardiac and skeletal muscle responses to physiological stress. Apelin knockout (KO) and wild type (WT) mice were subjected to high intensity interval training (HIIT) by treadmill running. The effects of apelin on energy metabolism were studied in primary mouse skeletal muscle myotubes and cardiomyocytes. Apelin increased mitochondrial ATP production and mitochondrial coupling efficiency in myotubes and promoted the expression of mitochondrial genes both in primary myotubes and cardiomyocytes. HIIT induced mild concentric cardiac hypertrophy in WT mice, whereas eccentric growth was observed in the left ventricles of apelin KO mice. HIIT did not affect myofiber size in skeletal muscles of WT mice but decreased the myofiber size in apelin KO mice. The decrease in myofiber size resulted from a fiber type switch towards smaller slow-twitch type I fibers. The increased proportion of slow-twitch type I fibers in apelin KO mice was associated with upregulation of myosin heavy chain slow isoform expression, accompanied with upregulated expression of genes related to fatty acid transport and downregulated expression of genes related to glucose metabolism. Mechanistically, skeletal muscles of apelin KO mice showed defective induction of insulin-like growth factor-1 signaling in response to HIIT. In conclusion, apelin is required for proper skeletal and cardiac muscle adaptation to high intensity exercise. Promoting apelinergic signaling may have benefits in aging- or disease-related muscle wasting conditions.

Keywords:  Apelin; Cardiac muscle; Exercise; Metabolism; Muscle physiology

DOI:  https://doi.org/10.1152/ajpcell.00427.2023
Sports Med. 2024 Mar 25.

Exercise-Regulated Mitochondrial and Nuclear Signalling Networks in Skeletal Muscle.

Elizabeth G Reisman, John A Hawley, Nolan J Hoffman.

Exercise perturbs energy homeostasis in skeletal muscle and engages integrated cellular signalling networks to help meet the contraction-induced increases in skeletal muscle energy and oxygen demand. Investigating exercise-associated perturbations in skeletal muscle signalling networks has uncovered novel mechanisms by which exercise stimulates skeletal muscle mitochondrial biogenesis and promotes whole-body health and fitness. While acute exercise regulates a complex network of protein post-translational modifications (e.g. phosphorylation) in skeletal muscle, previous investigations of exercise signalling in human and rodent skeletal muscle have primarily focused on a select group of exercise-regulated protein kinases [i.e. 5' adenosine monophosphate-activated protein kinase (AMPK), protein kinase A (PKA), Ca2+/calmodulin-dependent protein kinase (CaMK) and mitogen-activated protein kinase (MAPK)] and only a small subset of their respective protein substrates. Recently, global mass spectrometry-based phosphoproteomic approaches have helped unravel the extensive complexity and interconnection of exercise signalling pathways and kinases beyond this select group and phosphorylation and/or translocation of exercise-regulated mitochondrial and nuclear protein substrates. This review provides an overview of recent advances in our understanding of the molecular events associated with acute endurance exercise-regulated signalling pathways and kinases in skeletal muscle with a focus on phosphorylation. We critically appraise recent evidence highlighting the involvement of mitochondrial and nuclear protein phosphorylation and/or translocation in skeletal muscle adaptive responses to an acute bout of endurance exercise that ultimately stimulate mitochondrial biogenesis and contribute to exercise's wider health and fitness benefits.

DOI: https://doi.org/10.1007/s40279-024-02007-2
Stem Cell Reports. 2024 Mar 21. pii: S2213-6711(24)00050-X. [Epub ahead of print]

MST1/2 regulates fibro/adipogenic progenitor fate decisions in skeletal muscle regeneration.

Kezhi Wang, Jingjing Yang, Yina An, Jing Wang, Shuyu Tan, Hui Xu, Yanjun Dong.

  Defective skeletal muscle regeneration is often accompanied by fibrosis. Fibroblast/adipose progenitors (FAPs) are important in these processes, however, the regulation of FAP fate decisions is unclear. Here, using inducible conditional knockout mice, we show that blocking mammalian Ste20-like kinases 1/2 (MST1/2) of FAPs prevented apoptosis and reduced interleukin-6 secretion in vivo and in vitro, which impaired myoblast proliferation and differentiation, as well as impaired muscle regeneration. Deletion of Mst1/2 increased co-localization of Yes-associated protein (YAP) with Smad2/3 in nuclei and promoted differentiation of FAPs toward myofibroblasts, resulting in excessive collagen deposition and skeletal muscle fibrosis. Meanwhile, inhibition of MST1/2 increased YAP/Transcriptional co-activator with PDZ-binding motif activation, which promoted activation of the WNT/β-catenin pathway and impaired the differentiation of FAPs toward adipocytes. These results reveal a new mechanism for MST1/2 action in disrupted skeletal muscle regeneration and fibrosis via regulation of FAP apoptosis and differentiation. MST1/2 is a potential therapeutic target for the treatment of some myopathies.

Keywords:  FAPs; IL-6; MST1/2; YAP; apoptosis; differentiation

DOI:  https://doi.org/10.1016/j.stemcr.2024.02.010
JCI Insight. 2024 Mar 26. pii: e167578. [Epub ahead of print]

Atrogin-1 promotes muscle homeostasis by regulating levels of endoplasmic reticulum chaperone BiP.

Avnika A Ruparelia, Margo Montandon, Jo Merriner, Cheng Huang, Siew Fen Lisa Wong, Carmen Sonntag, Justin P Hardee, Gordon S Lynch, Lee B Miles, Ashley Siegel, Thomas E Hall, Ralf B Schittenhelm, Peter D Currie.

  Skeletal muscle wasting results from numerous pathological conditions impacting both the musculoskeletal and nervous systems. A unifying feature of these pathologies is the upregulation of members of the E3 ubiquitin ligase family, resulting in increased proteolytic degradation of target proteins. Despite the critical role E3 ubiquitin ligases in regulating muscle mass, the specific proteins they target for degradation and the mechanisms by which they regulate skeletal muscle homeostasis remain ill-defined. Here, using zebrafish loss of function models combined with in vivo cell biology and proteomic approaches, we reveal a role of atrogin-1 in regulating the levels of the endoplasmic reticulum chaperone BiP. Loss of atrogin-1 results in an accumulation of BiP, leading to impaired mitochondrial dynamics and a subsequent loss in muscle fibre integrity. We further implicate a disruption in atrogin-1 mediated BiP regulation in the pathogenesis of Duchenne muscular dystrophy. We reveal that BiP is not only upregulated in Duchenne muscular dystrophy, but its inhibition using pharmacological strategies, or by upregulating atrogin-1, significantly ameliorates pathology in a zebrafish model of Duchenne muscular dystrophy. Collectively, our data implicates atrogin-1 and BiP in the pathogenesis of Duchenne muscular dystrophy, and highlights atrogin-1's essential role in maintaining muscle homeostasis.

Keywords:  Genetic diseases; Muscle; Muscle biology; Ubiquitin-proteosome system

DOI:  https://doi.org/10.1172/jci.insight.167578
Autophagy. 2024 Mar 28. 1-10

TP53INP2-dependent activation of muscle autophagy ameliorates sarcopenia and promotes healthy aging.

David Sebastián, Marc Beltrà, Andrea Irazoki, David Sala, Pilar Aparicio, Cecilia Aris, Esmaeil Alibakhshi, Maria Rubio-Valera, Manuel Palacín, Juan Castellanos, Luis Lores, Antonio Zorzano.

  Sarcopenia is a major contributor to disability in older adults, and thus, it is key to elucidate the mechanisms underlying its development. Increasing evidence suggests that impaired macroautophagy/autophagy contributes to the development of sarcopenia. However, the mechanisms leading to reduced autophagy during aging remain largely unexplored, and whether autophagy activation protects from sarcopenia has not been fully addressed. Here we show that the autophagy regulator TP53INP2/TRP53INP2 is decreased during aging in mouse and human skeletal muscle. Importantly, chronic activation of autophagy by muscle-specific overexpression of TRP53INP2 prevents sarcopenia and the decline of muscle function in mice. Acute re-expression of TRP53INP2 in aged mice also improves muscle atrophy, enhances mitophagy, and reduces ROS production. In humans, high levels of TP53INP2 in muscle are associated with increased muscle strength and healthy aging. Our findings highlight the relevance of an active muscle autophagy in the maintenance of muscle mass and prevention of sarcopenia.Abbreviation: ATG7: autophagy related 7; BMI: body mass index; EIF4EBP1: eukaryotic translation initiation factor 4E binding protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; ROS: reactive oxygen species; TP53INP2: tumor protein p53 inducible nuclear protein 2; WT: wild type.

Keywords:  Sarcopenia; aging; autophagy; mitophagy; muscle atrophy

DOI:  https://doi.org/10.1080/15548627.2024.2333717
Int J Mol Sci. 2024 Mar 15. pii: 3327. [Epub ahead of print]25(6):

The DUX4-HIF1α Axis in Murine and Human Muscle Cells: A Link More Complex Than Expected.

Thuy-Hang Nguyen, Maelle Limpens, Sihame Bouhmidi, Lise Paprzycki, Alexandre Legrand, Anne-Emilie Declèves, Philipp Heher, Alexandra Belayew, Christopher R S Banerji, Peter S Zammit, Alexandra Tassin.

  FacioScapuloHumeral muscular Dystrophy (FSHD) is one of the most prevalent inherited muscle disorders and is linked to the inappropriate expression of the DUX4 transcription factor in skeletal muscles. The deregulated molecular network causing FSHD muscle dysfunction and pathology is not well understood. It has been shown that the hypoxia response factor HIF1α is critically disturbed in FSHD and has a major role in DUX4-induced cell death. In this study, we further explored the relationship between DUX4 and HIF1α. We found that the DUX4 and HIF1α link differed according to the stage of myogenic differentiation and was conserved between human and mouse muscle. Furthermore, we found that HIF1α knockdown in a mouse model of DUX4 local expression exacerbated DUX4-mediated muscle fibrosis. Our data indicate that the suggested role of HIF1α in DUX4 toxicity is complex and that targeting HIF1α might be challenging in the context of FSHD therapeutic approaches.

Keywords:  DUX4; FSHD; HIF1α; myogenesis; skeletal muscle

DOI:  https://doi.org/10.3390/ijms25063327
PLoS One. 2024 ;19(3): e0301037

Metabolomic response to acute resistance exercise in healthy older adults by 1H-NMR.

Darya Moosavi, Ivan Vuckovic, Hawley E Kunz, Ian R Lanza.

BACKGROUND: The favorable health-promoting adaptations to exercise result from cumulative responses to individual bouts of physical activity. Older adults often exhibit anabolic resistance; a phenomenon whereby the anabolic responses to exercise and nutrition are attenuated in skeletal muscle. The mechanisms contributing to age-related anabolic resistance are emerging, but our understanding of how chronological age influences responsiveness to exercise is incomplete. The objective was to determine the effects of healthy aging on peripheral blood metabolomic response to a single bout of resistance exercise and whether any metabolites in circulation are predictive of anabolic response in skeletal muscle.
METHODS: Thirty young (20-35 years) and 49 older (65-85 years) men and women were studied in a cross-sectional manner. Participants completed a single bout of resistance exercise consisting of eight sets of 10 repetitions of unilateral knee extension at 70% of one-repetition maximum. Blood samples were collected before exercise, immediately post exercise, and 30-, 90-, and 180-minutes into recovery. Proton nuclear magnetic resonance spectroscopy was used to profile circulating metabolites at all timepoints. Serial muscle biopsies were collected for measuring muscle protein synthesis rates.
RESULTS: Our analysis revealed that one bout of resistance exercise elicits significant changes in 26 of 33 measured plasma metabolites, reflecting alterations in several biological processes. Furthermore, 12 metabolites demonstrated significant interactions between exercise and age, including organic acids, amino acids, ketones, and keto-acids, which exhibited distinct responses to exercise in young and older adults. Pre-exercise histidine and sarcosine were negatively associated with muscle protein synthesis, as was the pre/post-exercise fold change in plasma histidine.
CONCLUSIONS: This study demonstrates that while many exercise-responsive metabolites change similarly in young and older adults, several demonstrate age-dependent changes even in the absence of evidence of sarcopenia or frailty.
TRIAL REGISTRATION: Clinical trial registry: ClinicalTrials.gov NCT03350906.

DOI: https://doi.org/10.1371/journal.pone.0301037
Biomolecules. 2024 Mar 19. pii: 363. [Epub ahead of print]14(3):

Characterization of Skeletal Muscle Regeneration Revealed a Novel Growth Network Induced by Molecular Acupuncture-like Transfection.

Ernő Zádor.

  The low efficiency of in vivo transfection of a few fibres revealed a novel tissue network that temporally amplified growth stimulation in the entire regenerating rat soleus muscle. This acupuncture-like effect was demonstrated when the fibres began to grow after complete fibre degradation, synchronous inflammation, myoblast and myotube formation. Neonatal sarcoplasmic/endoplasmic reticulum ATPase (SERCA1b) was first detected in this system. The neonatal, fast and slow SERCA isoforms displayed consequent changes with innervation and differentiation, recapitulating events in muscle development. In vivo transfection of myotubes with plasmids expressing dominant negative Ras or a calcineurin inhibitor peptide (Cain/cabin) proved that expression of the slow myosin heavy chain and the slow muscle type SERCA2a are differentially regulated. In vivo transfection of a few nuclei of myotubes with dnRas or SERCA1b shRNA stimulated fibre size growth in the whole regenerating muscle but only until the full size had been reached. Growth stimulation by Ras and SERCA1b antisense was abolished by co-transfection of Cain or with perimuscular injection of IL4 antibody. This revealed a novel signalling network resembling scale-free networks which, starting from transfected fibre myonuclei as "hubs", can amplify growth stimulation uniformly in the entire regenerating muscle.

Keywords:  Ras; SERCA; in vivo transfection; molecular acupuncture; regeneration; skeletal muscle

DOI:  https://doi.org/10.3390/biom14030363
J Orthop Translat. 2024 Mar;45 132-139

The Revolution of exosomes: From biological functions to therapeutic applications in skeletal muscle diseases.

Renwen Wan, Shan Liu, Xinting Feng, Wei Luo, Hanli Zhang, Yang Wu, Shiyi Chen, Xiliang Shang.

  Skeletal muscle diseases, a broad category encompassing a myriad of afflictions such as acute muscle injury and muscular dystrophies, pose a significant health burden globally. These conditions often lead to muscle weakness, compromised mobility, and a diminished quality of life. In light of this, innovative and effective therapeutic strategies are fervently sought after. Exosomes, naturally extracellular vesicles with a diameter of 30-150 nm, pervade biological fluids. These microscopic entities harbor a host of biological molecules, including proteins, nucleic acids, and lipids, bearing a significant resemblance to their parent cells. The roles they play in the biological theater are manifold, influencing crucial physiological and pathological processes within the organism. In the context of skeletal muscle diseases, their potential extends beyond these roles, as they present a promising therapeutic target and a vehicle for targeted drug delivery. This potentially paves the way for significant clinical applications. This review aims to elucidate the mechanisms underpinning exosome action, their myriad biological functions, and the strides made in exosome research and application. A comprehensive exploration of the part played by exosomes in skeletal muscle repair and regeneration is undertaken. In addition, we delve into the use of exosomes in the therapeutic landscape of skeletal muscle diseases, providing a valuable reference for a deeper understanding of exosome applications in this realm. The concluding section encapsulates the prospective avenues for exosome research and the promising future they hold, underscoring the tremendous potential these diminutive vesicles possess in the field of skeletal muscle diseases. The Translational Potential of this Article. The comprehensive exploration of exosome's diverse biological functions and translational potential in the context of skeletal muscle diseases presented in this review underscores their promising future as a therapeutic target with significant clinical applications, thus paving the way for innovative and effective therapeutic strategies in this realm.

Keywords:  Exosomes; Extracellular vesicle; Mechanism; Skeletal muscle diseases; Stem cell; Treatment

DOI:  https://doi.org/10.1016/j.jot.2024.01.001
Dev Biol. 2024 Mar 26. pii: S0012-1606(24)00088-5. [Epub ahead of print]

Loss of function of phosphatidylserine synthase causes muscle atrophy in Drosophila.

Sangseob Kim, Hyun Heo, Seung-Hae Kwon, Jae H Park, Gyunghee Lee, Sang-Hak Jeon.

  Maintenance of appropriate muscle mass is crucial for physical activity and metabolism. Aging and various pathological conditions can cause sarcopenia, a condition characterized by muscle mass decline. Although sarcopenia has been actively studied, the mechanisms underlying muscle atrophy are not well understood. Thus, we aimed to investigate the role of Phosphatidylserine synthase (Pss) in muscle development and homeostasis in Drosophila. The results showed that muscle-specific Pss knockdown decreased exercise capacity and produced sarcopenic phenotypes. In addition, it increased the apoptosis rate because of the elevated reactive oxygen species production resulting from mitochondrial dysfunction. Moreover, the autophagy rate increased due to increased FoxO activity caused by reduced Akt activity. Collectively, these findings demonstrate that enhanced apoptosis and autophagy rates resulting from muscle-specific Pss knockdown jointly contribute to sarcopenia development, highlighting the key role of the PSS pathway in muscle health.

Keywords:  Akt/FoxO; Autophagy; Mitochondria; Muscle atrophy; Phosphatidylserine synthase; Sarcopenia

DOI:  https://doi.org/10.1016/j.ydbio.2024.03.006
Sports Med Open. 2024 Mar 25. 10(1): 27

Powerpenia Should be Considered a Biomarker of Healthy Aging.

Sandro R Freitas, Carlos Cruz-Montecinos, Sébastien Ratel, Ronei S Pinto.

  To identify biomarkers that precede the decline of human function and independence during the lifespan, two important concepts have been introduced in recent decades: sarcopenia and dynapenia. While the former is originally focused on skeletal muscle loss, the latter is on maximal strength loss. Although the dynapenia concept implies the inclusion of skeletal muscle power, in practical terms, this has not been specifically addressed. For instance, only 2 out of 220 studies published between 2008 and 2023 have directly measured muscle power to classify individuals with dynapenia. As previous studies have shown a greater relevance of skeletal muscle power in healthy aging, we hereby propose the introduction of the term "powerpenia" to specifically reflect the loss of skeletal muscle power along lifespan, but also with disease and/or physical inactivity. Together with sarcopenia and dynapenia, we contend that powerpenia should be considered a biomarker of healthy aging.

Keywords:  Dynapenia; Health; Neuromuscular function; Quality of life; Sarcopenia; Sedentarism

DOI:  https://doi.org/10.1186/s40798-024-00689-6
Arch Toxicol. 2024 Mar 28.

Review: myogenic and muscle toxicity targets of environmental methylmercury exposure.

Lok Ming Tam, Matthew D Rand.

  A number of environmental toxicants are noted for their activity that leads to declined motor function. However, the role of muscle as a proximal toxicity target organ for environmental agents has received considerably less attention than the toxicity targets in the nervous system. Nonetheless, the effects of conventional neurotoxicants on processes of myogenesis and muscle maintenance are beginning to resolve a concerted role of muscle as a susceptible toxicity target. A large body of evidence from epidemiological, animal, and in vitro studies has established that methylmercury (MeHg) is a potent developmental toxicant, with the nervous system being a preferred target. Despite its well-recognized status as a neurotoxicant, there is accumulating evidence that MeHg also targets muscle and neuromuscular development as well as contributes to the etiology of motor defects with prenatal MeHg exposure. Here, we summarize evidence for targets of MeHg in the morphogenesis and maintenance of skeletal muscle that reveal effects on MeHg distribution, myogenesis, myotube formation, myotendinous junction formation, neuromuscular junction formation, and satellite cell-mediated muscle repair. We briefly recapitulate the molecular and cellular mechanisms of skeletal muscle development and highlight the pragmatic role of alternative model organisms, Drosophila and zebrafish, in delineating the molecular underpinnings of muscle development and MeHg-mediated myotoxicity. Finally, we discuss how toxicity targets in muscle development may inform the developmental origins of health and disease theory to explain the etiology of environmentally induced adult motor deficits and accelerated decline in muscle fitness with aging.

Keywords:  Developmental origins of health and disease; Methylmercury; Myogenesis; Myotoxicity; Skeletal muscle

DOI:  https://doi.org/10.1007/s00204-024-03724-3
Genes (Basel). 2024 Feb 21. pii: 269. [Epub ahead of print]15(3):

Regulation of myo-miR-24-3p on the Myogenesis and Fiber Type Transformation of Skeletal Muscle.

Danyang Fan, Yilong Yao, Yanwen Liu, Chao Yan, Fanqinyu Li, Shilong Wang, Mei Yu, Bingkun Xie, Zhonglin Tang.

  Skeletal muscle plays critical roles in providing a protein source and contributing to meat production. It is well known that microRNAs (miRNAs) exert important effects on various biological processes in muscle, including cell fate determination, muscle fiber morphology, and structure development. However, the role of miRNA in skeletal muscle development remains incompletely understood. In this study, we observed a critical miRNA, miR-24-3p, which exhibited higher expression levels in Tongcheng (obese-type) pigs compared to Landrace (lean-type) pigs. Furthermore, we found that miR-24-3p was highly expressed in the dorsal muscle of pigs and the quadriceps muscle of mice. Functionally, miR-24-3p was found to inhibit proliferation and promote differentiation in muscle cells. Additionally, miR-24-3p was shown to facilitate the conversion of slow muscle fibers to fast muscle fibers and influence the expression of GLUT4, a glucose transporter. Moreover, in a mouse model of skeletal muscle injury, we demonstrated that overexpression of miR-24-3p promoted rapid myogenesis and contributed to skeletal muscle regeneration. Furthermore, miR-24-3p was found to regulate the expression of target genes, including Nek4, Pim1, Nlk, Pskh1, and Mapk14. Collectively, our findings provide evidence that miR-24-3p plays a regulatory role in myogenesis and fiber type conversion. These findings contribute to our understanding of human muscle health and have implications for improving meat production traits in livestock.

Keywords:  miR-24-3p; porcine; regeneration; skeletal muscle fiber transformation

DOI:  https://doi.org/10.3390/genes15030269
Mol Metab. 2024 Mar 22. pii: S2212-8778(24)00054-1. [Epub ahead of print] 101923

Histone lactylation in macrophages is predictive for gene expression changes during ischemia induced-muscle regeneration.

T Desgeorges, E Galle, J Zhang, F von Meyenn, K De Bock.

   OBJECTIVES: We have previously shown that lactate is an essential metabolite for macrophage polarisation during ischemia-induced muscle regeneration. Recent in vitro work has implicated histone lactylation, a direct derivative of lactate, in macrophage polarisation. Here, we explore the in vivo relevance of histone lactylation for macrophage polarisation after muscle injury.
METHODS: To evaluate macrophage dynamics during muscle regeneration, we subjected mice to ischemia-induced muscle damage by ligating the femoral artery. Muscle samples were harvested at 1, 2, 4, and 7 days post injury (dpi). CD45+CD11b+F4/80+CD64+ macrophages were isolated and processed for RNA sequencing, Western Blotting, and CUT&Tag-sequencing to investigate gene expression, histone lactylation levels, and histone lactylation genomic localisation and enrichment, respectively.
RESULTS: We show that, over time, macrophages in the injured muscle undergo extensive gene expression changes, which are similar in nature and in timing to those seen after other types of muscle-injuries. We find that the macrophage histone lactylome is modified between 2 and 4 dpi, which is a crucial window for macrophage polarisation. Absolute histone lactylation levels increase, and, although subtly, the genomic enrichment of H3K18la changes. Overall, we find that histone lactylation is important at both promoter and enhancer elements. Lastly, H3K18la genomic profile changes from 2 to 4 dpi were predictive for gene expression changes later in time, rather than being a reflection of prior gene expression changes.
CONCLUSIONS: Our results suggest that histone lactylation dynamics are functionally important for the function of macrophages during muscle regeneration.

Keywords:  Inflammation; Lactylation; Macrophage; Muscle regeneration

DOI:  https://doi.org/10.1016/j.molmet.2024.101923
Nat Commun. 2024 Mar 23. 15(1): 2628

Myosin-binding protein C regulates the sarcomere lattice and stabilizes the OFF states of myosin heads.

Anthony L Hessel, Nichlas M Engels, Michel N Kuehn, Devin Nissen, Rachel L Sadler, Weikang Ma, Thomas C Irving, Wolfgang A Linke, Samantha P Harris.

Muscle contraction is produced via the interaction of myofilaments and is regulated so that muscle performance matches demand. Myosin-binding protein C (MyBP-C) is a long and flexible protein that is tightly bound to the thick filament at its C-terminal end (MyBP-CC8C10), but may be loosely bound at its middle- and N-terminal end (MyBP-CC1C7) to myosin heads and/or the thin filament. MyBP-C is thought to control muscle contraction via the regulation of myosin motors, as mutations lead to debilitating disease. We use a combination of mechanics and small-angle X-ray diffraction to study the immediate and selective removal of the MyBP-CC1C7 domains of fast MyBP-C in permeabilized skeletal muscle. We show that cleavage leads to alterations in crossbridge kinetics and passive structural signatures of myofilaments that are indicative of a shift of myosin heads towards the ON state, highlighting the importance of MyBP-CC1C7 to myofilament force production and regulation.

DOI: https://doi.org/10.1038/s41467-024-46957-7
J Cachexia Sarcopenia Muscle. 2024 Mar 27.

ADAR2 deficiency ameliorates non-alcoholic fatty liver disease and muscle atrophy through modulating serum amyloid A1.

Mei-Lang Kung, Tai-Hua Yang, Chia-Chi Lin, Jia-Yun Ho, Tzu-Chi Hung, Chih-Hsiang Chang, Kuan-Wen Huang, Chien-Chin Chen, Yun-Wen Chen.

   BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. Sarcopenia is a syndrome characterized by progressive and generalized loss of skeletal muscle mass and strength, which is commonly associated with NAFLD. Adenosine-to-inosine editing, catalysed by adenosine deaminase acting on RNA (ADAR), is an important post-transcriptional modification of genome-encoded RNA transcripts. Three ADAR gene family members, including ADAR1, ADAR2 and ADAR3, have been identified. However, the functional role of ADAR2 in obesity-associated NAFLD and sarcopenia remains unclear.
METHODS: ADAR2+/+/GluR-BR/R mice (wild type [WT]) and ADAR2-/-/GluR-BR/R mice (ADAR2 knockout [KO]) were subjected to feeding with standard chow or high-fat diet (HFD) for 20 weeks at the age of 5 weeks. The metabolic parameters, hepatic lipid droplet, grip strength test, rotarod test, muscle weight, fibre cross-sectional area (CSA), fibre types and protein associated with protein degradation were examined. Systemic and local tissues serum amyloid A1 (SAA1) were measured. The effects of SAA1 on C2C12 myotube atrophy were investigated.
RESULTS: ADAR2 KO mice fed with HFD exhibited lower body weight (-7.7%, P < 0.05), lower liver tissue weight (-20%, P < 0.05), reduced liver lipid droplets in concert with a decrease in hepatic triglyceride content (-24%, P < 0.001) and liver injury (P < 0.01). ADAR2 KO mice displayed protection against HFD-induced glucose intolerance, insulin resistance and dyslipidaemia. Skeletal muscle mass (P < 0.01), muscle strength (P < 0.05), muscle endurance (P < 0.001) and fibre size (CSA; P < 0.0001) were improved in ADAR2 KO mice fed with HFD compared with WT mice fed with HFD. Muscle atrophy-associated transcripts, such as forkhead box protein O1, muscle atrophy F-box/atrogin-1 and muscle RING finger 1/tripartite motif-containing 63, were decreased in ADAR2 KO mice fed with HFD compared with WT mice fed with HFD. ADAR2 deficiency attenuates HFD-induced local liver and skeletal muscle tissue inflammation. ADAR2 deficiency abolished HFD-induced systemic (P < 0.01), hepatic (P < 0.0001) and muscular (P < 0.001) SAA1 levels. C2C12 myotubes treated with recombinant SAA1 displayed a decrease in myotube length (-37%, P < 0.001), diameter (-20%, P < 0.01), number (-39%, P < 0.001) and fusion index (-46%, P < 0.01). Myogenic markers (myosin heavy chain and myogenin) were decreased in SAA1-treated myoblast C2C12 cells.
CONCLUSIONS: These results provide novel evidence that ADAR2 deficiency may be important in obesity-associated sarcopenia and NAFLD. Increased SAA1 might be involved as a regulatory factor in developing sarcopenia in NAFLD.

Keywords:  ADAR2; NAFLD; SAA1; diabetes; inflammation; muscle atrophy

DOI:  https://doi.org/10.1002/jcsm.13460
Biomolecules. 2024 Mar 07. pii: 316. [Epub ahead of print]14(3):

Mitochondrial Transplantation Therapy Ameliorates Muscular Dystrophy in mdx Mouse Model.

Mikhail V Dubinin, Irina B Mikheeva, Anastasia E Stepanova, Anastasia D Igoshkina, Alena A Cherepanova, Alena A Semenova, Vyacheslav A Sharapov, Igor I Kireev, Konstantin N Belosludtsev.

  Duchenne muscular dystrophy is caused by loss of the dystrophin protein. This pathology is accompanied by mitochondrial dysfunction contributing to muscle fiber instability. It is known that mitochondria-targeted in vivo therapy mitigates pathology and improves the quality of life of model animals. In the present work, we applied mitochondrial transplantation therapy (MTT) to correct the pathology in dystrophin-deficient mdx mice. Intramuscular injections of allogeneic mitochondria obtained from healthy animals into the hind limbs of mdx mice alleviated skeletal muscle injury, reduced calcium deposits in muscles and serum creatine kinase levels, and improved the grip strength of the hind limbs and motor activity of recipient mdx mice. We noted normalization of the mitochondrial ultrastructure and sarcoplasmic reticulum/mitochondria interactions in mdx muscles. At the same time, we revealed a decrease in the efficiency of oxidative phosphorylation in the skeletal muscle mitochondria of recipient mdx mice accompanied by a reduction in lipid peroxidation products (MDA products) and reduced calcium overloading. We found no effect of MTT on the expression of mitochondrial signature genes (Drp1, Mfn2, Ppargc1a, Pink1, Parkin) and on the level of mtDNA. Our results show that systemic MTT mitigates the development of destructive processes in the quadriceps muscle of mdx mice.

Keywords:  Duchenne muscular dystrophy; lipid peroxidation; mitochondrial dysfunction; mitochondrial transplantation; muscle force; skeletal muscle

DOI:  https://doi.org/10.3390/biom14030316
Pharmaceutics. 2024 Mar 05. pii: 363. [Epub ahead of print]16(3):

Pulsed Electric Fields Induce STING Palmitoylation and Polymerization Independently of Plasmid DNA Electrotransfer.

Amanda Sales Conniff, Julie Singh, Richard Heller, Loree C Heller.

  Gene therapy approaches may target skeletal muscle due to its high protein-expressing nature and vascularization. Intramuscular plasmid DNA (pDNA) delivery via pulsed electric fields (PEFs) can be termed electroporation or electrotransfer. Nonviral delivery of plasmids to cells and tissues activates DNA-sensing pathways. The central signaling complex in cytosolic DNA sensing is the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING). The effects of pDNA electrotransfer on the signaling of STING, a key adapter protein, remain incompletely characterized. STING undergoes several post-translational modifications which modulate its function, including palmitoylation. This study demonstrated that in mouse skeletal muscle, STING was constitutively palmitoylated at two sites, while an additional site was modified following electroporation independent of the presence of pDNA. This third palmitoylation site correlated with STING polymerization but not with STING activation. Expression of several palmitoyl acyltransferases, including zinc finger and DHHC motif containing 1 (zDHHC1), coincided with STING activation. Expression of several depalmitoylases, including palmitoyl protein thioesterase 2 (PPT2), was diminished in all PEF application groups. Therefore, STING may not be regulated by active modification by palmitate after electroporation but inversely by the downregulation of palmitate removal. These findings unveil intricate molecular changes induced by PEF application.

Keywords:  STING; electroporation; electrotransfer; palmitoylation; pulsed electric fields; skeletal muscle

DOI:  https://doi.org/10.3390/pharmaceutics16030363
bioRxiv. 2024 Feb 29. pii: 2024.02.29.582673. [Epub ahead of print]

DELE1 promotes translation-associated homeostasis, growth, and survival in mitochondrial myopathy.

Hsin-Pin Lin, Jennifer D Petersen, Alexandra J Gilsrud, Angelo Madruga, Theresa M D'Silva, Xiaoping Huang, Mario K Shammas, Nicholas P Randolph, Yan Li, Drew R Jones, Michael E Pacold, Derek P Narendra.

Mitochondrial dysfunction causes devastating disorders, including mitochondrial myopathy. Here, we identified that diverse mitochondrial myopathy models elicit a protective mitochondrial integrated stress response (mt-ISR), mediated by OMA1-DELE1 signaling. The response was similar following disruptions in mtDNA maintenance, from knockout of Tfam , and mitochondrial protein unfolding, from disease-causing mutations in CHCHD10 (G58R and S59L). The preponderance of the response was directed at upregulating pathways for aminoacyl-tRNA biosynthesis, the intermediates for protein synthesis, and was similar in heart and skeletal muscle but more limited in brown adipose challenged with cold stress. Strikingly, models with early DELE1 mt-ISR activation failed to grow and survive to adulthood in the absence of Dele1 , accounting for some but not all of OMA1's protection. Notably, the DELE1 mt-ISR did not slow net protein synthesis in stressed striated muscle, but instead prevented loss of translation-associated proteostasis in muscle fibers. Together our findings identify that the DELE1 mt-ISR mediates a stereotyped response to diverse forms of mitochondrial stress and is particularly critical for maintaining growth and survival in early-onset mitochondrial myopathy.

DOI: https://doi.org/10.1101/2024.02.29.582673
Mol Metab. 2024 Mar 23. pii: S2212-8778(24)00052-8. [Epub ahead of print] 101921

Salubrinal promotes phospho-eIF2α-dependent activation of UPR leading to autophagy-mediated attenuation of iron-induced insulin resistance.

Khang Nguyen, Jialing Tang, Sungji Cho, Fan Ying, Hye Kyoung Sung, Kostas Pantopoulos, Gary Sweeney.

Identification of new mechanisms mediating insulin sensitivity is important to allow validation of corresponding therapeutic targets. In this study, we first used a cellular model of skeletal muscle cell iron overload and found endoplasmic reticulum (ER) stress and insulin resistance occurred after iron treatment. Insulin sensitivity was assessed using cells engineered to express an Akt biosensor, based on nuclear FoxO localization, as well as western blotting for insulin signaling proteins. Use of salubrinal to elevate eIF2α phosphorylation and promote the unfolded protein response (UPR) attenuated iron-induced insulin resistance. Salubrinal induced autophagy flux and its beneficial effects on insulin sensitivity were not observed in autophagy-deficient cells generated by overexpressing a dominant-negative Atg5 mutant or via knockout of ATG7. This indicated the beneficial effect of salubrinal-induced UPR activation was autophagy-dependent. We translated these observations to an animal model of systemic iron overload-induced skeletal muscle insulin resistance where administration of salubrinal as pretreatment promoted eIF2α phosphorylation, enhanced autophagic flux in skeletal muscle and improved insulin responsiveness. Together, our results show that salubrinal elicited an eIF2α-autophagy axis leading to improved skeletal muscle insulin sensitivity both in vitro and in mice.

DOI: https://doi.org/10.1016/j.molmet.2024.101921
Acta Physiol (Oxf). 2024 Mar 29. e14128

Ruxolitinib: A new hope for ventilator-induced diaphragm dysfunction.

Alex B Addinsall, Nicola Cacciani, Noah Moruzzi, Hazem Akkad, Alice Maestri, Per-Olof Berggren, Anna Widegren, Jonas Bergquist, Tamara Tchkonia, James L Kirkland, Lars Larsson.

   AIM: Mechanical ventilation (MV) results in diminished diaphragm size and strength, termed ventilator-induced diaphragm dysfunction (VIDD). VID increases dependence, prolongs weaning, and increases discharge mortality rates. The Janus kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) pathway is implicated in VIDD, upregulated following MV. JAK/STAT inhibition alleviates chronic muscle wasting conditions. This study aimed to explore the therapeutic potential of Ruxolitinib, an FDA approved JAK1/2 inhibitor (JI) for the treatment of VIDD.
METHODS: Rats were subjected to 5 days controlled MV (CMV) with and without daily Ruxolitinib gavage. Muscle fiber size and function were assessed. RNAseq, mitochondrial morphology, respirometry, and mass spectrometry were determined.
RESULTS: CMV significantly reduced diaphragm size and specific force by 45% (p < 0.01), associated with a two-fold P-STAT3 upregulation (p < 0.001). CMV disrupted mitochondrial content and reduced the oxygen consumption rate (p < 0.01). Expression of the motor protein myosin was unaffected, however CMV alters myosin function via post-translational modifications (PTMs). Daily administration of JI increased animal survival (40% vs. 87%; p < 0.05), restricted P-STAT3 (p < 0.001), and preserved diaphragm size and specific force. JI was associated with preserved mitochondrial content and respiratory function (p < 0.01), and the reversal or augmentation of myosin deamidation PTMs of the rod and head region.
CONCLUSION: JI preserved diaphragm function, leading to increased survival in an experimental model of VIDD. Functional enhancement was associated with maintenance of mitochondrial content and respiration and the reversal of ventilator-induced PTMs of myosin. These results demonstrate the potential of repurposing Ruxolitinib for treatment of VIDD.

Keywords:  STAT3; VIDD; critical care; diaphragm; mitochondria; myosin; post‐translational modification

DOI:  https://doi.org/10.1111/apha.14128
Biochim Biophys Acta Mol Basis Dis. 2024 Mar 21. pii: S0925-4439(24)00120-0. [Epub ahead of print] 167131

A stagewise response to mitochondrial dysfunction in mitochondrial DNA maintenance disorders.

Amy E Vincent, Chun Chen, Tiago Bernardino Gomes, Valeria Di Leo, Tuomas Laalo, Kamil Pabis, Rodrick Capaldi, Michael F Marusich, David McDonald, Andrew Filby, Andrew Fuller, Diana Lehmann Urban, Stephan Zierz, Marcus Deschauer, Doug Turnbull, Amy K Reeve, Conor Lawless.

  Mitochondrial DNA (mtDNA) deletions which clonally expand in skeletal muscle of patients with mtDNA maintenance disorders, impair mitochondrial oxidative phosphorylation dysfunction. Previously we have shown that these mtDNA deletions arise and accumulate in perinuclear mitochondria causing localised mitochondrial dysfunction before spreading through the muscle fibre. We believe that mito-nuclear signalling is a key contributor in the accumulation and spread of mtDNA deletions, and that knowledge of how muscle fibres respond to mitochondrial dysfunction is key to our understanding of disease mechanisms. To understand the contribution of mito-nuclear signalling to the spread of mitochondrial dysfunction, we use imaging mass cytometry. We characterise the levels of mitochondrial Oxidative Phosphorylation proteins alongside a mitochondrial mass marker, in a cohort of patients with mtDNA maintenance disorders. Our expanded panel included protein markers of key signalling pathways, allowing us to investigate cellular responses to different combinations of oxidative phosphorylation dysfunction and ragged red fibres. We find combined Complex I and IV deficiency to be most common. Interestingly, in fibres deficient for one or more complexes, the remaining complexes are often upregulated beyond the increase of mitochondrial mass typically observed in ragged red fibres. We further find that oxidative phosphorylation deficient fibres exhibit an increase in the abundance of proteins involved in proteostasis, e.g. HSP60 and LONP1, and regulation of mitochondrial metabolism (including oxidative phosphorylation and proteolysis, e.g. PHB1). Our analysis suggests that the cellular response to mitochondrial dysfunction changes depending on the combination of deficient oxidative phosphorylation complexes in each fibre.

Keywords:  Cell signalling; Mitochondrial DNA deletion; Mitochondrial disease; Myopathy; OXPHOS

DOI:  https://doi.org/10.1016/j.bbadis.2024.167131
Life (Basel). 2024 Mar 20. pii: 412. [Epub ahead of print]14(3):

Aerobic Exercise Modulates Proteomic Profiles in Gastrocnemius Muscle of db/db Mice, Ameliorating Sarcopenia.

Yen-Chun Huang, Monika Renuka Sanotra, Chi-Chang Huang, Yi-Ju Hsu, Chen-Chung Liao.

  Type-2 diabetes mellitus (T2DM)-induced sarcopenia is intertwined with diminished insulin sensitivity and extracellular matrix (ECM) remodeling in skeletal muscle and other organs. Physical activities such as aerobic exercise play a crucial role in regulating blood glucose levels, insulin sensitivity, metabolic pathways, oxidative stress, fibrosis, ECM remodeling, and muscle regeneration by modulating differentially expressed protein (DEP) levels. The objectives of our research were to investigate the effect of six weeks of aerobic exercise on the gastrocnemius and soleus muscle of db/db mice's DEP levels compared to those of sedentary db/db mice. A total of eight db/db mice were divided into two groups (n = 4 per group), namely sedentary mice (SED) and exercise-trained mice (ET), of which the latter were subjected to six weeks of a moderate-intensity aerobic exercise intervention for five days per week. After the exercise intervention, biochemical tests, including analyses of blood glucose and HbA1c levels, were performed. Histological analysis using H & E staining on tissue was performed to compare morphological characters. Gastrocnemius and soleus muscles were dissected and processed for proteomic analysis. Data were provided and analyzed based on the DEPs using the label-free quantification (LFQ) algorithm. Functional enrichment analysis and Ingenuity Pathway Analysis (IPA) were employed as bioinformatics tools to elucidate the molecular mechanisms involved in the DEPs and disease progression. Significantly reduced blood glucose and HbA1c levels and an increased cross-sectional area (CSA) of gastrocnemius muscle fibers were seen in the ET group after the exercise interventions due to upregulations of metabolic pathways. Using proteomics data analysis, we found a significant decrease in COL1A1, COL4A2, ENG, and LAMA4 protein levels in the ET gastrocnemius, showing a significant improvement in fibrosis recovery, ECM remodeling, and muscle regeneration via the downregulation of the TGF-β signaling pathway. Upregulated metabolic pathways due to ET-regulated DEPs in the gastrocnemius indicated increased glucose metabolism, lipid metabolism, muscle regeneration, and insulin sensitivity, which play a crucial role in muscle regeneration and maintaining blood glucose and lipid levels. No significant changes were observed in the soleus muscle due to the type of exercise and muscle fiber composition. Our research suggests that engaging in six weeks of aerobic exercise may have a positive impact on the recovery of T2DM-induced sarcopenia, which might be a potential candidate for mitigation, prevention, and therapeutic treatment in the future.

Keywords:  ECM remodeling; T2DM-induced sarcopenia; aerobic exercise; db/db mice; gastrocnemius muscle; metabolic pathways; muscle regeneration; proteomic profiling

DOI:  https://doi.org/10.3390/life14030412
J Vis Exp. 2024 Mar 08.

Stimulated Single Fiber Electromyography (SFEMG) for Assessing Neuromuscular Junction Transmission in Rodent Models.

Arsh Ketabforoush, Meifang Wang, W David Arnold.

As the final connection between the nervous system and muscle, transmission at the neuromuscular junction (NMJ) is crucial for normal motor function. Single fiber electromyography (SFEMG) is a clinically relevant and sensitive technique that measures single muscle fiber action potential responses during voluntary contractions or nerve stimulations to assess NMJ transmission. The assessment and quantification of NMJ transmission involves two parameters: jitter and blocking. Jitter refers to the variability in timing (latency) between consecutive single-fiber action potentials (SFAPs). Blocking signifies the failure of NMJ transmission to initiate an SFAP response. Although SFEMG is a well-established and sensitive test in clinical settings, its application in preclinical research has been relatively infrequent. This report outlines the steps and criteria employed in performing stimulated SFEMG to quantify jitter and blocking in rodent models. This technique can be used in preclinical and clinical studies to gain insights into NMJ function in the context of health, aging, and disease.

DOI: https://doi.org/10.3791/66452
Aging Cell. 2024 Mar 27. e14156

Prevention of age-related neuromuscular junction degeneration in sarcopenia by low-magnitude high-frequency vibration.

Zhengyuan Bao, Can Cui, Chaoran Liu, Yufeng Long, Ronald Man Yeung Wong, Senlin Chai, Ling Qin, Clinton Rubin, Benjamin Hon Kei Yip, Zhihong Xu, Qing Jiang, Simon Kwoon-Ho Chow, Wing-Hoi Cheung.

  Neuromuscular junction (NMJ) degeneration is one of pathological factors of sarcopenia. Low-magnitude high-frequency vibration (LMHFV) was reported effective in alleviating the sarcopenia progress. However, no previous study has investigated treatment effects of LMHFV targeting NMJ degeneration in sarcopenia. We first compared morphological differences of NMJ between sarcopenic and non-sarcopenic subjects, as well as young and old C57BL/6 mice. We then systematically characterized the age-related degeneration of NMJ in SAMP8 against its control strain, SAMR1 mice, from 3 to 12 months old. We also investigated effects of LMHFV in SAMP8 on the maintenance of NMJ during the onset of sarcopenia with respect to the Agrin-LRP4-MuSK-Dok7 pathway and investigated the mechanism related to ERK1/2 signaling. We observed sarcopenic/old NMJ presented increased acetylcholine receptors (AChRs) cluster fragmentation and discontinuity than non-sarcopenic/young NMJ. In SAMP8, NMJ degeneration (morphologically at 6 months and functionally at 8 months) was observed associated with the sarcopenia onset (10 months). SAMR1 showed improved NMJ morphology and function compared with SAMP8 at 10 months. Skeletal muscle performance was improved at Month 4 post-LMHFV treatment. Vibration group presented improved NMJ function at Months 2 and 6 posttreatment, accompanied with alleviated morphological degeneration at Month 4 posttreatment. LMHFV increased Dok7 expression at Month 4 posttreatment. In vitro, LMHFV could promote AChRs clustering in myotubes by increasing Dok7 expression through suppressing ERK1/2 phosphorylation. In conclusion, NMJ degeneration was observed associated with the sarcopenia onset in SAMP8. LMHFV may attenuate NMJ degeneration and sarcopenia progression by increasing Dok7 expression through suppressing ERK1/2 phosphorylation.

Keywords:  Dok7; ERK1/2; neuromuscular junction; sarcopenia; vibration

DOI:  https://doi.org/10.1111/acel.14156