Mechanisms of mechanical overload-induced skeletal muscle hypertrophy: current understanding and future directions

Physiological Reviews, Journal Year: 2023, Volume and Issue: 103(4), P. 2679 - 2757

Published: June 29, 2023

Mechanisms underlying mechanical overload-induced skeletal muscle hypertrophy have been extensively researched since the landmark report by Morpurgo (1897) of “work-induced hypertrophy” in dogs that were treadmill trained. Much preclinical rodent and human resistance training research to date supports involved mechanisms include enhanced mammalian/mechanistic target rapamycin complex 1 (mTORC1) signaling, an expansion translational capacity through ribosome biogenesis, increased satellite cell abundance myonuclear accretion, postexercise elevations protein synthesis rates. However, several lines past emerging evidence suggest additional feed into or are independent these processes also involved. This review first provides a historical account how mechanistic has progressed. A comprehensive list associated with is then outlined, areas disagreement involving presented. Finally, future directions many discussed proposed.

Language: Английский

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Skeletal muscle memory

AJP Cell Physiology, Journal Year: 2023, Volume and Issue: 324(6), P. C1274 - C1294

Published: May 8, 2023

Skeletal muscle memory is an exciting phenomenon gaining significant traction across several scientific communities, among exercise practitioners, and the public. Research has demonstrated that skeletal tissue can be “primed” by earlier positive encounters with training enhance adaptation to later retraining, even following periods of cessation or detraining. This review will describe discuss most recent research investigating underlying mechanisms memory: 1) “cellular” and, 2) “epigenetic” memory, as well emerging evidence how these theories may work in synergy. We both “positive” “negative” highlight importance for optimizing interventions programs development therapeutic strategies counteracting wasting conditions age-related loss. Finally, important directions field highlighted advance next generation studies into future.

Language: Английский

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Lineage tracing of nuclei in skeletal myofibers uncovers distinct transcripts and interplay between myonuclear populations

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Oct. 30, 2024

Language: Английский

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The role of MEGF10 in myoblast fusion and hypertrophic response to overload of skeletal muscle

Journal of Muscle Research and Cell Motility, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 18, 2025

Biallelic mutations in multiple EGF domain protein 10 (MEGF10) gene cause EMARDD (early myopathy, areflexia, respiratory distress and dysphagia) humans, a severe recessive associated with reduced numbers of PAX7 positive satellite cells. To better understand the role MEGF10 cells, we overexpressed human mouse H-2kb-tsA58 myoblasts found that it inhibited fusion. Addition purified extracellular domains MEGF10, (ECD) or without (EGF) N-terminal EMI to myoblasts, showed ECD was more effective at reducing myoblast adhesion fusion by day 7 differentiation, yet promoted non-adhesive surfaces, highlighting importance these behaviours. We additionally tested Megf10 vivo using transgenic mice (Megf10+/-) no (Megf10-/-) Megf10. extensor digitorum longus muscle had fewer anti-Pax7 stained cell nuclei less able undergo hypertrophy response overload concomitant lower level activation. Taken together, our data suggest may promote survival prevent premature helping explain its EMARDD.

Language: Английский

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Mitochondria Isolated From Bone Mesenchymal Stem Cells Restrain Muscle Disuse Atrophy and Fatty Infiltration After Rotator Cuff Tears

The American Journal of Sports Medicine, Journal Year: 2025, Volume and Issue: unknown

Published: March 15, 2025

Background: Rotator cuff tears (RCTs) commonly lead to muscle atrophy, fibrosis, and fatty infiltration, complicating treatment. Purpose: To investigate the use of mitochondria isolated from bone mesenchymal stem cells (BMSC-Mito) for mitigating complications after RCT, focusing on protection. Study Design: Controlled laboratory study. Methods: RCTs were induced by transecting tendons supraspinatus infraspinatus in Sprague-Dawley rats. In vivo, 90 rats randomized into 3 groups: sham (no intervention), treated with BMSC-Mito, phosphate-buffered saline. After 6 weeks intramuscular injections BMSC-Mito or saline, muscles harvested analysis. Evaluations included wet weight, fiber cross-sectional area, slow-fast myofiber types biomechanics, capillary density, respiratory chain complex activity, adenosine triphosphate (ATP) concentration, oxidative stress, mitochondrial ultrastructure. vitro experiments utilized primary rat skeletal pretreated rhodamine 6G induce dysfunction, assessing effects cell viability, membrane potential, stress levels. Results: can be effectively transplanted integrated local network. showed significant mass loss, reduced a shift slow fast types, which negatively affected biomechanics. These changes reversed BMSC-Mito. also preserved vascularity (CD31 α-SMA) impaired RCT. Additionally, notably improved disuse-induced changes, leading increased number COX IV expression; furthermore, protected morphology enhanced cytosolic superoxide dismutase activity. This treatment activity ATP reducing stress. vitro, maintained potential cells, restored its function Conclusion: findings suggest that might play role preventing atrophy infiltration RCT through protection promotion angiogenesis. Clinical Relevance: present promising therapeutic approach addressing rotator degeneration.

Language: Английский

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Functional specialisation and coordination of myonuclei

Biological reviews/Biological reviews of the Cambridge Philosophical Society, Journal Year: 2024, Volume and Issue: 99(4), P. 1164 - 1195

Published: March 13, 2024

ABSTRACT Myofibres serve as the functional unit for locomotion, with sarcomere fundamental subunit. Running entire length of this structure are hundreds myonuclei, located at periphery myofibre, juxtaposed to plasma membrane. Myonuclear specialisation and clustering centre ends fibre known be essential muscle contraction, yet molecular basis regionalisation has remained unclear. While ‘myonuclear domain hypothesis’ helped explain how myonuclei can independently govern large cytoplasmic territories, novel technologies have provided granularity on diverse transcriptional programs running simultaneously within syncytia added a new perspective communicate. Building upon this, we explore critical cellular sources heterogeneity myofibres, discussing impact intrinsic extrinsic factors myonuclear programs. This knowledge provides insights understanding development, repair, disease, but also opens avenues development precise therapeutic approaches.

Language: Английский

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Multinucleation as a buffer against gene expression noise in syncytial myofibres

The Journal of Physiology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 25, 2025

Skeletal muscle fibres, or myofibres, are exceptional for their vast size and complex multinucleated structure. Formed by the fusion of individual myoblasts, these syncytial cells contain hundreds even thousands nuclei that collectively coordinate synthesis essential proteins, ensuring can grow, repair maintain strength (Hansson & Eftestol, 2023). With some fibres extending up to 42 cm in length achieving diameters exceeding 100 µm, myofibers possess a cellular volume approximately 4000 times greater than human oocyte et al., 2020a). This extraordinary scale, coupled with elongated, cylindrical-like morphology, raises fundamental question: Why has evolution selected multinucleation cells, what specific advantages does this structural arrangement confer? The predominant hypothesis argues facilitates expansion cytoplasmic myofibres. By adding nuclei, cell increases its DNA content, which turn provides enhanced biosynthetic regulatory capacity support high demands protein maintenance increase nuclear may drive enlargement cytoplasm, allowing myofibres achieve size. While explanation is compelling, scale functional suggest serve purposes beyond simply enabling expansion, including regulation spatial metabolic homeostasis. Importantly, not unique skeletal fibres. Comparisons other polyploid systems highlight intriguing parallels, suggesting broader significance adaptation. For instance, fungus Ashbya gossypii relies on extensive hyphal networks, require coordinated enzymatic activity across large distances (Mayer 2024). Similarly, binucleated hepatocytes sustain liver function (Darmasaputra 2024; Guidotti 2003), whereas osteoclasts efficiently secrete digestive enzymes resorb areas bone (Ono Nakashima, 2018). Additionally, maturation Drosophila oocytes supported surrounding nurse multiple copies genome. These directly transfer components, mRNA, proteins materials, during development. enables grow while circumventing limitations would likely arise from relying single set genomic such mononuclear (Spradling 2022). Together, examples illustrate how evolved as versatile strategy address challenges maintaining homeostasis functionally specialized cells. evolutionary emergence appears be convergent phenomenon, arising independently diverse taxa (Peterson Fox, 2021). convergence underscores adaptive advantages, increased scalability potential buffer stochastic fluctuations gene expression. Studying alongside uncover shared principles regulation, organization noise reduction, well lineage-specific adaptations tailored distinct biological demands. I propose only addresses logistical supporting but also serves critical mechanism mitigate fluctuations, commonly referred 'noise' Gene expression noise, variability transcription translation, results random mRNA levels (Raj van Oudenaarden, 2008; Sanchez Golding, 2013), disrupt function. In mononucleated significantly impair However, distribution transcriptional form decentralized network independent units. could averaging them out, stable consistent cell. proposed noise-buffering homeostasis, adaptation physiological stress. article will explore mathematical foundations hypothesis, examining might noise. It discuss implications biology experimental approaches investigate relationship between offering insights into aspect organization. Multinucleated like many centres volume, uniquely equipped against If each nucleus acts an unit, achieves cumulative reducing relative impact enhancing overall SNR. Therefore, distributed myonuclei suppress stabilizing manner single-nucleus cannot achieve. When small number molecules transcribed – at low rates mean level low, thus (σmRNA) becomes relatively compared mean. leads shows increases, decreases. inverse square-root dependence implies particularly prone production cause variations levels. words, distributing reduce expression, resulting more volume. Thus, decreases following 1/ N $\sqrt $ scaling. framework strengthens central opinion piece, total buffers out bursts, reliable production, contributing robustness Empirical evidence abundance, present challenge As result, genes adopt different strategies based susceptibility Comparative studies species, Saccharomyces cerevisiae, Mus musculus Homo sapiens, have shown most actually favour higher translation over (Hausser 2019). there exceptions, Escherichia coli, where encoding ribosomal exhibit both rates, rare, balance processes finely tuned gene's role sensitivity Low-abundance often tolerate because transient spikes sufficient functions, signalling Despite localized mechanisms control still presence within myofibre solution stability varying rates. One key factor half-life. Longer half-lives, assuming quality, stabilize pool available remains time without need continuous transcription. preventing rapid degradation, longer half-lives otherwise lead abundance. addition, localization plays minimizing myonuclear domains. Myonuclei strategically positioned along fibre localize mRNAs nearby regions, products translated close respective domains prevents becoming diluted degraded, occur if they were dispersed throughout concentrating discrete domains, optimize process, steady supply when needed. molecular diffusion cytoplasm introduces another layer stochasticity molecules, concentration 2020b), system. localizing effects local abundance caused diffusion, thereby likelihood degradation dilution. closer proximity transcribing myonucleus translational machinery, synthesis. it reduces risk shortages energy-efficient, solely thermal energy being effective short distances, active transport complement (Denes 2021; Pinheiro 2021), addressing demand rendering less discrete, discussed (Prasad Millay, Bagley 2023; Hansson Moreover, heterogeneity among further contributes compartmentalized (Dos Santos 2020; Kim Petrany 2020), same patterns reflecting roles regions control. genetic material donated newly fused stem existing resident divergent (Sun 2024), highlighting complexity provide organizing controlling stability, ensure efficient, robust, adaptable changing conditions. conclusion, concept offers compelling extends well-known scaling match Multinucleation help noise-reduction effect compartmentalization ensures fine-tuned regions. To test combination required. Single-nucleus imaging analysis using advanced techniques smFISH live-cell real-time influences variability. Mathematical modelling, incorporating parameters predict Genetic manipulations alter state direct stability. types, certain fungi, offer regulating exploring inter-nuclear communication synchronize computational determine whether reduction indeed driving force behind systems, significant engineering, development, disease. Please note: publisher responsible content functionality any information supplied authors. Any queries (other missing content) should directed corresponding author article. None declared. K.-A.H.: Conception design work, drafting work revising critically important intellectual final approval version published agreement accountable all aspects work. None.

Language: Английский

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FRET‐Based Sensor Zebrafish Reveal Muscle Cells Do Not Undergo Apoptosis in Starvation or Natural Aging‐Induced Muscle Atrophy

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 4, 2025

Abstract Muscle atrophy occurs during natural aging and under disease conditions. cell apoptosis is considered one of the main causes muscle atrophy, while several recent studies argued that cells do not die atrophy. Here, sensor zebrafish are generated to visualize engulfment dead by macrophages. Using these zebrafish, starvation, aging‐induced models established. The data showed diameters decreased in both models; however, found process In starvation‐induced it also number nuclei remained constant, there no increase macrophages tissues, which further confirmed die. models, transcriptional analysis pathway down‐regulated, autophagy protein degradation pathways up‐regulated. All indicated although a great reduction mass starvation or apoptosis. These findings provide new insights into can benefit treatments for atrophy‐related diseases.

Language: Английский

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A primer on global molecular responses to exercise in skeletal muscle: Omics in focus

Journal of sport and health science/Journal of Sport and Health Science, Journal Year: 2025, Volume and Issue: unknown, P. 101029 - 101029

Published: Feb. 1, 2025

Advances in skeletal muscle omics has expanded our understanding of exercise-induced adaptations at the molecular level. Over past 2 decades, transcriptome studies have detailed acute and chronic responses to resistance, endurance, concurrent exercise, focusing on variables such as training status, nutrition, age, sex, metabolic health profile. Multi-omics approaches, integration transcriptomic epigenetic data, along with emerging ribosomal RNA sequencing advancements, further provided insights into how adapts exercise across lifespan. Downstream transcriptome, proteomic phosphoproteomic identified novel regulators adaptations, while single-cell/nucleus spatial technologies promise evolve cellular specialization communication around cells. This narrative review highlights (a) historical foundations muscle, (b) current research 3 layers cascade (DNA, RNA, protein), (c) applications single-cell study adaptation exercise. Further elaboration muscle's global footprint using multi-omics methods will help researchers practitioners develop more effective targeted approaches improve well athletic performance.

Language: Английский

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A satellite cell‐dependent epigenetic fingerprint in skeletal muscle identity genes after lifelong physical activity

The FASEB Journal, Journal Year: 2025, Volume and Issue: 39(5)

Published: March 6, 2025

Satellite cells comprise a small proportion of mononuclear in adult skeletal muscle. Despite their relative rarity, satellite have critical functions muscle adaptation, particularly during prolonged exercise training. The mechanisms by which mediate responsiveness to physical activity throughout the lifespan are still being defined, but epigenetic regulation may play role. To explore this possibility, we analyzed global DNA methylation patterns tissue from female mice that engaged lifelong voluntary unweighted wheel running with or without cells. were ablated adulthood using tamoxifen-inducible Pax7-DTA model. Compared sedentary mice, for 13 months caused differences promoter regions numerous fiber-enriched genes-Cacgn1, Dnm2, Mlip, Myl1, Myom2, Mstn, Sgca, Sgcg, Tnnc1, Tnni2, Tpm1, and Ttn-only when present. These genes relate fiber identity, cytoarchitecture, size as well overall function. Epigenetic alterations such consistent previously observed histological vivo impairments adaptation after cell depletion these same mice. Musk region was affected only absence sedentary; dovetails work showing influence innervation. Defining effects on identity fibers provides new directions how rare stem can promote function lifespan.

Language: Английский

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