bims-musmir 2024-09-08 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2024–09–08
fourteen papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

Neuromuscular impairment at different stages of human sarcopenia.
Tic-tac-mito: The relationship between the biological clock with mitochondria dynamics and skeletal muscle function in humans.
Fibre-specific mitochondrial protein abundance is linked to resting and post-training mitochondrial content in the muscle of men.
Gut-muscle axis mechanism of exercise prevention of sarcopenia.
Amyotrophic Lateral Sclerosis and swim training affect copper metabolism in skeletal muscle in a mouse model of disease.
Mechanical Loading Modulates AMPK and mTOR Signaling in Muscle Cells.
Ectopic expression of Myomaker and Myomixer in slow muscle cells induces slow muscle fusion and myofiber death.
Unacylated Ghrelin Protects Against Age-Related Loss of Muscle Mass and Contractile Dysfunction in Skeletal Muscle.
Can non-invasive motor unit analysis reveal distinct neural strategies of force production in young with uncomplicated type 1 diabetes?
Artificial neural network inference analysis identified novel genes and gene interactions associated with skeletal muscle aging.
Identification of selective and non-selective C9ORF72 targeting in vivo active siRNAs.
Nitric oxide in modulating oxidative stress mediated skeletal muscle insulin resistance.
Myosin ATPase inhibition fails to rescue the metabolically dysregulated proteome of nebulin-deficient muscle.
A 2-hydroxybutyrate-mediated feedback loop regulates muscular fatigue.

J Cachexia Sarcopenia Muscle. 2024 Sep 05.

Neuromuscular impairment at different stages of human sarcopenia.

Fabio Sarto, Martino V Franchi, Jamie S McPhee, Daniel W Stashuk, Matteo Paganini, Elena Monti, Maira Rossi, Giuseppe Sirago, Sandra Zampieri, Evgeniia S Motanova, Giacomo Valli, Tatiana Moro, Antonio Paoli, Roberto Bottinelli, Maria A Pellegrino, Giuseppe De Vito, Helen M Blau, Marco V Narici.

   BACKGROUND: Degeneration of the motoneuron and neuromuscular junction (NMJ) and loss of motor units (MUs) contribute to age-related muscle wasting and weakness associated with sarcopenia. However, these features have not been comprehensively investigated in humans. This study aimed to compare neuromuscular system integrity and function at different stages of sarcopenia, with a particular focus on NMJ stability and MU properties.
METHODS: We recruited 42 young individuals (Y) (aged 25.98 ± 4.6 years; 57% females) and 88 older individuals (aged 75.9 ± 4.7 years; 55% females). The older group underwent a sarcopenia screening according to the revised guidelines of the European Working Group on Sarcopenia in Older People 2. In all groups, knee extensor muscle force was evaluated by isometric dynamometry, muscle morphology by ultrasound and MU potential properties by intramuscular electromyography (iEMG). MU number estimate (iMUNE) and blood samples were obtained. Muscle biopsies were collected in a subgroup of 16 Y and 52 older participants.
RESULTS: Thirty-nine older individuals were non-sarcopenic (NS), 31 pre-sarcopenic (PS) and 18 sarcopenic (S). A gradual decrease in quadriceps force, cross-sectional area and appendicular lean mass was observed across the different stages of sarcopenia (for all P < 0.0001). Handgrip force and the Short Physical Performance Battery score also showed a diminishing trend. iEMG analyses revealed elevated near fibre segment jitter in NS, PS and S compared with Y (Y vs. NS and S: P < 0.0001; Y vs. PS: P = 0.0169), suggestive of age-related impaired NMJ transmission. Increased C-terminal agrin fragment (P < 0.0001) and altered caveolin 3 protein expression were consistent with age-related NMJ instability in all the older groups. The iMUNE was lower in all older groups (P < 0.0001), confirming age-related loss of MUs. An age-related increase in MU potential complexity was also observed. These observations were accompanied by increased muscle denervation and axonal damage, evinced by the increase in neural cell adhesion molecule-positive fibres (Y vs. NS: P < 0.0001; Y vs. S: P = 0.02) and the increase in serum concentration of neurofilament light chain (P < 0.0001), respectively. Notably, most of these MU and NMJ parameters did not differ when comparing older individuals with or without sarcopenia.
CONCLUSIONS: Alterations in MU properties, axonal damage, an altered innervation profile and NMJ instability are prominent features of the ageing of the neuromuscular system. These neuromuscular alterations are accompanied by muscle wasting and weakness; however, they appear to precede clinically diagnosed sarcopenia, as they are already detectable in older NS individuals.

Keywords:  electromyography; fibre denervation; motoneuron; motor units; muscle atrophy; neuromuscular junction

DOI:  https://doi.org/10.1002/jcsm.13531
J Physiol. 2024 Sep 02.

Tic-tac-mito: The relationship between the biological clock with mitochondria dynamics and skeletal muscle function in humans.

Itamar C G Jesus, Flavia M Araujo.



Keywords:  biological clock; metabolism; mitochondria; protein synthesis; skeletal muscle

DOI:  https://doi.org/10.1113/JP287210
Nat Commun. 2024 Sep 03. 15(1): 7677

Fibre-specific mitochondrial protein abundance is linked to resting and post-training mitochondrial content in the muscle of men.

Elizabeth G Reisman, Javier Botella, Cheng Huang, Ralf B Schittenhelm, David A Stroud, Cesare Granata, Owala S Chandrasiri, Georg Ramm, Viola Oorschot, Nikeisha J Caruana, David J Bishop.

Analyses of mitochondrial adaptations in human skeletal muscle have mostly used whole-muscle samples, where results may be confounded by the presence of a mixture of type I and II muscle fibres. Using our adapted mass spectrometry-based proteomics workflow, we provide insights into fibre-specific mitochondrial differences in the human skeletal muscle of men before and after training. Our findings challenge previous conclusions regarding the extent of fibre-type-specific remodelling of the mitochondrial proteome and suggest that most baseline differences in mitochondrial protein abundances between fibre types reported by us, and others, might be due to differences in total mitochondrial content or a consequence of adaptations to habitual physical activity (or inactivity). Most training-induced changes in different mitochondrial functional groups, in both fibre types, were no longer significant in our study when normalised to changes in markers of mitochondrial content.

DOI: https://doi.org/10.1038/s41467-024-50632-2
Front Nutr. 2024 ;11 1418778

Gut-muscle axis mechanism of exercise prevention of sarcopenia.

Tao Li, Danyang Yin, Rengfei Shi.

  Sarcopenia refers to an age-related systemic skeletal muscle disorder, which is characterized by loss of muscle mass and weakening of muscle strength. Gut microbiota can affect skeletal muscle through a variety of mechanisms. Gut microbiota present distinct features among elderly people and sarcopenia patients, including a decrease in microbial diversity, which might be associated with the quality and function of the skeletal muscle. There might be a gut-muscle axis; where gut microbiota and skeletal muscle may affect each other bi-directionally. Skeletal muscle can affect the biodiversity of the gut microbiota, and the latter can, in turn, affect the anabolism of skeletal muscle. This review examines recent studies exploring the relationship between gut microbiota and skeletal muscle, summarizes the effects of exercise on gut microbiota, and discusses the possible mechanisms of the gut-muscle axis.

Keywords:  SCFAs; exercise; gut microbiota; gut-muscle axis; sarcopenia

DOI:  https://doi.org/10.3389/fnut.2024.1418778
Muscle Nerve. 2024 Sep 03.

Amyotrophic Lateral Sclerosis and swim training affect copper metabolism in skeletal muscle in a mouse model of disease.

Emilia Białobrodzka, Damian Jozef Flis, Banu Akdogan, Andzelika Borkowska, Mariusz Roman Wieckowski, Jedrzej Antosiewicz, Hans Zischka, Katarzyna Patrycja Dzik, Jan Jacek Kaczor, Wieslaw Ziolkowski.

   INTRODUCTION/AIMS: Swim training and regulation of copper metabolism result in clinical benefits in amyotrophic lateral sclerosis (ALS) mice. Therefore, the study aimed to determine whether swim training improves copper metabolism by modifying copper metabolism in the skeletal muscles of ALS mice.
METHODS: SOD1G93A mice (n = 6 per group) were used as the ALS model, and wild-type B6SJL (WT) mice as controls (n = 6). Mice with ALS were analyzed before the onset of ALS (ALS BEFORE), at baseline ALS (first disease symptoms, trained and untrained, ALS ONSET), and at the end of ALS (last stage disease, trained and untrained, ALS TERMINAL). Copper concentrations and the level of copper metabolism proteins in the skeletal muscles of the lower leg were determined.
RESULTS: ALS disease caused a reduction in the copper concentration in ALS TERMINAL untrained mice compared with the ALS BEFORE (10.43 ± 1.81 and 38.67 ± 11.50 μg/mg, respectively, p = .0213). The copper chaperon for SOD1 protein, which supplies copper to SOD1, and ATPase7a protein (copper exporter), increased at the terminal stage of disease by 57% (p = .0021) and 34% (p = .0372), while the CTR1 protein (copper importer) decreased by 45% (p = .002). Swim training moderately affected the copper concentration and the concentrations of proteins responsible for copper metabolism in skeletal muscles.
DISCUSSION: The results show disturbances in skeletal muscle copper metabolism associated with ALS progression, which is moderately affected by swim training. From a clinical point of view, exercise in water for ALS patients should be an essential element of rehabilitation for maintaining quality of life.

Keywords:  ALS; copper metabolism; copper transport; exercise; neurodegeneration

DOI:  https://doi.org/10.1002/mus.28237
J Proteome Res. 2024 Aug 30.

Mechanical Loading Modulates AMPK and mTOR Signaling in Muscle Cells.

Xin Zhou, Shaochun Zhu, Junhong Li, Andre Mateus, Chloe Williams, Jonathan Gilthorpe, Ludvig J Backman.

  Skeletal muscle adaptation to exercise involves various phenotypic changes that enhance the metabolic and contractile functions. One key regulator of these adaptive responses is the activation of AMPK, which is influenced by exercise intensity. However, the mechanistic understanding of AMPK activation during exercise remains incomplete. In this study, we utilized an in vitro model to investigate the effects of mechanical loading on AMPK activation and its interaction with the mTOR signaling pathway. Proteomic analysis of muscle cells subjected to static loading (SL) revealed distinct quantitative protein alterations associated with RNA metabolism, with 10% SL inducing the most pronounced response compared to lower intensities of 5% and 2% as well as the control. Additionally, 10% SL suppressed RNA and protein synthesis while activating AMPK and inhibiting the mTOR pathway. We also found that SRSF2, necessary for pre-mRNA splicing, is regulated by AMPK and mTOR signaling, which, in turn, is regulated in an intensity-dependent manner by SL with the highest expression in 2% SL. Further examination showed that the ADP/ATP ratio was increased after 10% SL compared to the control and that SL induced changes in mitochondrial biogenesis. Furthermore, Seahorse assay results indicate that 10% SL enhances mitochondrial respiration. These findings provide novel insights into the cellular responses to mechanical loading and shed light on the intricate AMPK-mTOR regulatory network in muscle cells.

Keywords:  ADP/ATP ratio; AMPK; RNA sequencing; exercise adaptation; mTOR; mechanical loading; mitochondrial biogenesis; protein synthesis; proteomics analysis; skeletal muscle

DOI:  https://doi.org/10.1021/acs.jproteome.4c00242
J Genet Genomics. 2024 Aug 27. pii: S1673-8527(24)00214-5. [Epub ahead of print]

Ectopic expression of Myomaker and Myomixer in slow muscle cells induces slow muscle fusion and myofiber death.

Pengzheng Yong, Zhanxiong Zhang, Shaojun Du.

  Zebrafish embryos possess two major types of myofibers, the slow and fast fibers, with distinct patterns of cell fusion. The fast muscle cells can fuse, while the slow muscle cells cannot. Here, we show that myomaker is expressed in both slow and fast muscle precursors, while myomixer is exclusive to fast muscle cells. The loss of Prdm1a, a regulator of slow muscle differentiation, results in strong myomaker and myomixer expression and slow muscle cell fusion. This abnormal fusion is further confirmed by the direct ectopic expression of myomaker or myomixer in slow muscle cells of transgenic models. Using the transgenic models, we show that the heterologous fusion between slow and fast muscle cells can alter slow muscle cell migration and gene expression. Furthermore, the overexpression of myomaker and myomixer also disrupts membrane integrity, resulting in muscle cell death. Collectively, this study identifies that the fiber-type-specific expression of fusogenic proteins is critical for preventing inappropriate fusion between slow and fast fibers in fish embryos, highlighting the need for precise regulation of fusogenic gene expression to maintain muscle fiber integrity and specificity.

Keywords:  Fiber specificity; Muscle cell fusion; Myofiber death; Myomaker; Myomixer; Transgenic zebrafish model

DOI:  https://doi.org/10.1016/j.jgg.2024.08.006
Aging Cell. 2024 Sep 02. e14323

Unacylated Ghrelin Protects Against Age-Related Loss of Muscle Mass and Contractile Dysfunction in Skeletal Muscle.

Hyunyoung Kim, Rojina Ranjit, Dennis R Claflin, Constantin Georgescu, Jonathan D Wren, Susan V Brooks, Benjamin F Miller, Bumsoo Ahn.

  Sarcopenia, the progressive loss of muscle mass and function, universally affects older adults and is closely associated with frailty and reduced quality of life. Despite the inevitable consequences of sarcopenia and its relevance to healthspan, no pharmacological therapies are currently available. Ghrelin is a gut-released hormone that increases appetite and body weight through acylation. Acylated ghrelin activates its receptor, growth hormone secretagogue receptor 1a (GHSR1a), in the brain by binding to it. Studies have demonstrated that acyl and unacylated ghrelin (UnAG) both have protective effects against acute pathological conditions independent of receptor activation. Here, we investigated the long-term effects of UnAG in age-associated muscle atrophy and contractile dysfunction in mice. Four-month-old and 18-month-old mice were subjected to either UnAG or control treatment for 10 months. UnAG did not affect food consumption or body weight. Gastrocnemius and quadriceps muscle weights were reduced by 20%-30% with age, which was partially protected against by UnAG. Specific force, force per cross-sectional area, measured in isolated extensor digitorum longus muscle was diminished by 30% in old mice; however, UnAG prevented the loss of specific force. UnAG also protected from decreases in mitochondrial respiration and increases in hydrogen peroxide generation of skeletal muscle of old mice. Results of bulk mRNA-seq analysis and our contractile function data show that UnAG reversed neuromuscular junction impairment that occurs with age. Collectively, our data revealed the direct role of UnAG in mitigating sarcopenia in mice, independent of food consumption or body weight, implicating UnAG treatment as a potential therapy against sarcopenia.

Keywords:  loss of muscle mass; mitochondria; neurogenic atrophy; neuromuscular junction; protein synthesis and degradation; sarcopenia; unacylated ghrelin

DOI:  https://doi.org/10.1111/acel.14323
Eur J Appl Physiol. 2024 Aug 30.

Can non-invasive motor unit analysis reveal distinct neural strategies of force production in young with uncomplicated type 1 diabetes?

Giacomo Valli, Rui Wu, Dean Minnock, Giuseppe Sirago, Giosuè Annibalini, Andrea Casolo, Alessandro Del Vecchio, Luana Toniolo, Elena Barbieri, Giuseppe De Vito.

   PURPOSE: to investigate the early consequences of type 1 diabetes (T1D) on the neural strategies of muscle force production.
METHODS: motor unit (MU) activity was recorded from the vastus lateralis muscle with High-Density surface Electromyography during isometric knee extension at 20 and 40% of maximum voluntary contraction (MVC) in 8 T1D (4 males, 4 females, 30.5 ± 3.6 years) and 8 matched control (4 males, 4 females, 27.3 ± 5.9 years) participants. Muscle biopsies were also collected from vastus lateralis for fiber type analysis, including myosin heavy chain (MyHC) isoform content via protein and mRNA expression.
RESULTS: MVC was comparable between groups as well as MU conduction velocity, action potentials' amplitude and proportions of MyHC protein isoforms. Nonetheless, MU discharge rate, relative derecruitment thresholds and mRNA expression of MyHC isoform I were lower in T1D.
CONCLUSIONS: young people with uncomplicated T1D present a different neural control of muscle force production. Furthermore, differences are detectable non-invasively in absence of any functional manifestation (i.e., force production and fiber type distribution). These novel findings suggest that T1D has early consequences on the neuromuscular system and highlights the necessity of a better characterization of neural control in this population.

Keywords:  Conduction velocity; High-density electromyography; Muscle biopsy; Myosin heavy chain

DOI:  https://doi.org/10.1007/s00421-024-05595-z
J Cachexia Sarcopenia Muscle. 2024 Aug 29.

Artificial neural network inference analysis identified novel genes and gene interactions associated with skeletal muscle aging.

Janelle Tarum, Graham Ball, Thomas Gustafsson, Mikael Altun, Lívia Santos.

   BACKGROUND: Sarcopenia is an age-related muscle disease that increases the risk of falls, disabilities, and death. It is associated with increased muscle protein degradation driven by molecular signalling pathways including Akt and FOXO1. This study aims to identify genes, gene interactions, and molecular pathways and processes associated with muscle aging and exercise in older adults that remained undiscovered until now leveraging on an artificial intelligence approach called artificial neural network inference (ANNi).
METHODS: Four datasets reporting the profile of muscle transcriptome obtained by RNA-seq of young (21-43 years) and older adults (63-79 years) were selected and retrieved from the Gene Expression Omnibus (GEO) data repository. Two datasets contained the transcriptome profiles associated to muscle aging and two the transcriptome linked to resistant exercise in older adults, the latter before and after 6 months of exercise training. Each dataset was individually analysed by ANNi based on a swarm neural network approach integrated into a deep learning model (Intelligent Omics). This allowed us to identify top 200 genes influencing (drivers) or being influenced (targets) by aging or exercise and the strongest interactions between such genes. Downstream gene ontology (GO) analysis of these 200 genes was performed using Metacore (Clarivate™) and the open-source software, Metascape. To confirm the differential expression of the genes showing the strongest interactions, real-time quantitative PCR (RT-qPCR) was employed on human muscle biopsies obtained from eight young (25 ± 4 years) and eight older men (78 ± 7.6 years), partaking in a 6-month resistance exercise training programme.
RESULTS: CHAD, ZDBF2, USP54, and JAK2 were identified as the genes with the strongest interactions predicting aging, while SCFD1, KDM5D, EIF4A2, and NIPAL3 were the main interacting genes associated with long-term exercise in older adults. RT-qPCR confirmed significant upregulation of USP54 (P = 0.005), CHAD (P = 0.03), and ZDBF2 (P = 0.008) in the aging muscle, while exercise-related genes were not differentially expressed (EIF4A2 P = 0.99, NIPAL3 P = 0.94, SCFD1 P = 0.94, and KDM5D P = 0.64). GO analysis related to skeletal muscle aging suggests enrichment of pathways linked to bone development (adj P-value 0.006), immune response (adj P-value <0.001), and apoptosis (adj P-value 0.01). In older exercising adults, these were ECM remodelling (adj P-value <0.001), protein folding (adj P-value <0.001), and proteolysis (adj P-value <0.001).
CONCLUSIONS: Using ANNi and RT-qPCR, we identified three strongly interacting genes predicting muscle aging, ZDBF2, USP54, and CHAD. These findings can help to inform the design of nonpharmacological and pharmacological interventions that prevent or mitigate sarcopenia.

Keywords:  Aging; Artificial neural network; Exercise; Machine learning; Skeletal muscle

DOI:  https://doi.org/10.1002/jcsm.13562
Mol Ther Nucleic Acids. 2024 Sep 10. 35(3): 102291

Identification of selective and non-selective C9ORF72 targeting in vivo active siRNAs.

James W Gilbert, Zachary Kennedy, Bruno M D C Godinho, Ashley Summers, Alexandra Weiss, Dimas Echeverria, Brianna Bramato, Nicholas McHugh, David Cooper, Ken Yamada, Matthew Hassler, Hélène Tran, Fen Biao Gao, Robert H Brown, Anastasia Khvorova.

  A hexanucleotide (G4C2) repeat expansion (HRE) within intron one of C9ORF72 is the leading genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). C9ORF72 haploinsufficiency, formation of RNA foci, and production of dipeptide repeat (DPR) proteins have been proposed as mechanisms of disease. Here, we report the first example of disease-modifying siRNAs for C9ORF72 driven ALS/FTD. Using a combination of reporter assay and primary cortical neurons derived from a C9-ALS/FTD mouse model, we screened a panel of more than 150 fully chemically stabilized siRNAs targeting different C9ORF72 transcriptional variants. We demonstrate the lack of correlation between siRNA efficacy in reporter assay versus native environment; repeat-containing C9ORF72 mRNA variants are found to preferentially localize to the nucleus, and thus C9ORF72 mRNA accessibility and intracellular localization have a dominant impact on functional RNAi. Using a C9-ALS/FTD mouse model, we demonstrate that divalent siRNAs targeting C9ORF72 mRNA variants specifically or non-selectively reduce the expression of C9ORF72 mRNA and significantly reduce DPR proteins. Interestingly, siRNA silencing all C9ORF72 mRNA transcripts was more effective in removing intranuclear mRNA aggregates than targeting only HRE-containing C9ORF72 mRNA transcripts. Combined, these data support RNAi-based degradation of C9ORF72 as a potential therapeutic paradigm.

Keywords:  C9ORF72 amyotrophic lateral sclerosis, ALS; MT: Oligonucleotides: Therapies and Applications; dipeptide-repeat proteins; frontotemporal dementia, FTD; mRNA localization; oligonucleotide therapeutics; siRNA

DOI:  https://doi.org/10.1016/j.omtn.2024.102291
Mol Biol Rep. 2024 Aug 29. 51(1): 944

Nitric oxide in modulating oxidative stress mediated skeletal muscle insulin resistance.

Aamir Anwar, Shivang Shukla, Priya Pathak.

  Insulin resistance (IR) being the major cause behind different metabolic disorders, has attracted a lot of attention. Epidemiological data shows marked rise in the cases over a period of time. Nitric oxide (NO), produced from nitric oxide synthases (NOS), is involved in a variety of biological functions, alteration in which causes various disorders like hypertension, atherosclerosis, and angiogenesis-associated disorders. IR has been found to be a contributing factor, which is associated with abnormal NO signalling. Skeletal muscle is essential for metabolism, both for its role in glucose uptake and its importance in metabolic disease. In this article, we give an overview of the significance of NO in oxidative stress (OS) mediated IR, describing its role in different conditions that are associated with skeletal muscle IR. NO is found to be involved in the activation of insulin receptor downstream pathway, which suggests absence of NO could lead to reduced glucose uptake, and may ultimately result in IR.

Keywords:  Insulin resistance; Nitric oxide; Oxidative stress; Reactive oxygen species; Skeletal muscle

DOI:  https://doi.org/10.1007/s11033-024-09874-y
J Physiol. 2024 Aug 31.

Myosin ATPase inhibition fails to rescue the metabolically dysregulated proteome of nebulin-deficient muscle.

Jenni Laitila, Robert A E Seaborne, Natasha Ranu, Justin S Kolb, Carina Wallgren-Pettersson, Nanna Witting, John Vissing, Juan Jesus Vilchez, Edmar Zanoteli, Johanna Palmio, Sanna Huovinen, Henk Granzier, Julien Ochala.

  Nemaline myopathy (NM) is a genetic muscle disease, primarily caused by mutations in the NEB gene (NEB-NM) and with muscle myosin dysfunction as a major molecular pathogenic mechanism. Recently, we have observed that the myosin biochemical super-relaxed state was significantly impaired in NEB-NM, inducing an aberrant increase in ATP consumption and remodelling of the energy proteome in diseased muscle fibres. Because the small-molecule Mavacamten is known to promote the myosin super-relaxed state and reduce the ATP demand, we tested its potency in the context of NEB-NM. We first conducted in vitro experiments in isolated single myofibres from patients and found that Mavacamten successfully reversed the myosin ATP overconsumption. Following this, we assessed its short-term in vivo effects using the conditional nebulin knockout (cNeb KO) mouse model and subsequently performing global proteomics profiling in dissected soleus myofibres. After a 4 week treatment period, we observed a remodelling of a large number of proteins in both cNeb KO mice and their wild-type siblings. Nevertheless, these changes were not related to the energy proteome, indicating that short-term Mavacamten treatment is not sufficient to properly counterbalance the metabolically dysregulated proteome of cNeb KO mice. Taken together, our findings emphasize Mavacamten potency in vitro but challenge its short-term efficacy in vivo. KEY POINTS: No cure exists for nemaline myopathy, a type of genetic skeletal muscle disease mainly derived from mutations in genes encoding myofilament proteins. Applying Mavacamten, a small molecule directly targeting the myofilaments, to isolated membrane-permeabilized muscle fibres from human patients restored myosin energetic disturbances. Treating a mouse model of nemaline myopathy in vivo with Mavacamten for 4 weeks, remodelled the skeletal muscle fibre proteome without any noticeable effects on energetic proteins. Short-term Mavacamten treatment may not be sufficient to reverse the muscle phenotype in nemaline myopathy.

Keywords:  Mavacamten; myosin; nebulin; nemaline myopathy; proteomics; skeletal muscle

DOI:  https://doi.org/10.1113/JP286870
Elife. 2024 Sep 03. pii: RP92707. [Epub ahead of print]12

A 2-hydroxybutyrate-mediated feedback loop regulates muscular fatigue.

Brennan J Wadsworth, Marina Leiwe, Eleanor A Minogue, Pedro P Cunha, Viktor Engman, Carolin Brombach, Christos Asvestis, Shiv K Sah-Teli, Emilia Marklund, Peppi Karppinen, Jorge L Ruas, Helene Rundqvist, Johanna T Lanner, Randall S Johnson.

  Several metabolites have been shown to have independent and at times unexpected biological effects outside of their metabolic pathways. These include succinate, lactate, fumarate, and 2-hydroxyglutarate. 2-Hydroxybutyrate (2HB) is a byproduct of endogenous cysteine synthesis, produced during periods of cellular stress. 2HB rises acutely after exercise; it also rises during infection and is also chronically increased in a number of metabolic disorders. We show here that 2HB inhibits branched-chain aminotransferase enzymes, which in turn triggers a SIRT4-dependent shift in the compartmental abundance of protein ADP-ribosylation. The 2HB-induced decrease in nuclear protein ADP-ribosylation leads to a C/EBPβ-mediated transcriptional response in the branched-chain amino acid degradation pathway. This response to 2HB exposure leads to an improved oxidative capacity in vitro. We found that repeated injection with 2HB can replicate the improvement to oxidative capacity that occurs following exercise training. Together, we show that 2-HB regulates fundamental aspects of skeletal muscle metabolism.

Keywords:  Exercise; biochemistry; chemical biology; metabolite; mouse; muscle fiber

DOI:  https://doi.org/10.7554/eLife.92707