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Mammalian Genome : Official Journal of... Dec 2016This review assesses the importance of proteostasis in skeletal muscle maintenance with a specific emphasis on autophagy. Skeletal muscle appears to be particularly... (Review)
Review
This review assesses the importance of proteostasis in skeletal muscle maintenance with a specific emphasis on autophagy. Skeletal muscle appears to be particularly vulnerable to genetic defects in basal and induced autophagy, indicating that autophagy is co-substantial to skeletal muscle maintenance and adaptation. We discuss emerging evidence that tension-induced protein unfolding may act as a direct link between mechanical stress and autophagic pathways. Mechanistic links between protein damage, autophagy and muscle hypertrophy, which is also induced by mechanical stress, are still poorly understood. However, some mouse models of muscle disease show ameliorated symptoms upon effective targeting of basal autophagy. These findings highlight the importance of autophagy as therapeutic target and suggest that elucidating connections between protein unfolding and mTOR-dependent or mTOR-independent hypertrophic responses is likely to reveal specific therapeutic windows for the treatment of muscle wasting disorders.
Topics: Adaptation, Physiological; Animals; Autophagy; Humans; Hypertrophy; Mice; Muscle, Skeletal; Muscular Diseases; Protein Unfolding; Proteostasis; Signal Transduction; Stress, Mechanical; TOR Serine-Threonine Kinases
PubMed: 27484057
DOI: 10.1007/s00335-016-9659-2 -
European Review For Medical and... 2016The association of bilateral hypertrophy of temporalis and masseteric muscles is a rare clinical entity. The origin of the condition is unclear, causing cosmetic... (Review)
Review
OBJECTIVE
The association of bilateral hypertrophy of temporalis and masseteric muscles is a rare clinical entity. The origin of the condition is unclear, causing cosmetic problems, pain, and functional impairment.
PATIENTS AND METHODS
In this paper we analyzed 15 patients treated at the Department of Maxillo-Facial Surgery of the University of Naples Federico II, from 2000 to 2013, for temporalis and/or masseteric muscle hypertrophy, and in particular, a rare case of a patient with a marked bilateral swelling of the temporalis and masseteric region, in conjunction with a review of the literature.
RESULTS
Fourteen patients have not any kind of postoperatively problems. The last patient had been aware of the swelling for many years and complained of recurrent headaches. We adopted a new protocol fort this patients and the patient was very pleased with the treatment results, and reported a reduction in headaches and a continuation of his well-being, in addition to greater self-confidence. The last follow-up was performed three years after the first treatment, and the patient showed a complete resolution of his symptoms, and just a small increase of the swelling.
CONCLUSIONS
The treatment of temporalis and masseteric hypertrophy with Botulin toxin could be an effective option compared to conservative treatment or surgical intervention, although the review of the literature shows that this is only a temporary treatment. In fact, surgery still remains the best option. The treatment must be repeated every 4/6 months for 2-3 consecutive years before having stable benefits. To overcome this problem, an association with a bite treatment allowed us to achieve more lasting and more stable results over time without a recurrence of symptoms between the treatments. Furthermore, this association has enabled us to obtain a more rapid reduction of the hypertrophy.
Topics: Adult; Aged; Botulinum Toxins, Type A; Female; Humans; Hypertrophy; Injections, Intramuscular; Male; Masseter Muscle; Middle Aged; Neuromuscular Agents; Temporal Muscle; Treatment Outcome
PubMed: 26813447
DOI: No ID Found -
European Journal of Sport Science Aug 2019Skeletal muscle has indispensable roles in regulating whole body health (e.g. glycemic control, energy consumption) and, in being central in locomotion, is crucial in... (Review)
Review
Skeletal muscle has indispensable roles in regulating whole body health (e.g. glycemic control, energy consumption) and, in being central in locomotion, is crucial in maintaining quality-of-life. Therefore, understanding the regulation of muscle mass is of significant importance. Resistance exercise training (RET) combined with supportive nutrition is an effective strategy to achieve muscle hypertrophy by driving chronic elevations in muscle protein synthesis (MPS). The regulation of muscle protein synthesis is a coordinated process, in requiring ribosomes to translate mRNA and sufficient myonuclei density to provide the platform for ribosome and mRNA transcription; as such MPS is determined by both translational efficiency (ribosome activity) and translational capacity (ribosome number). Moreover, as the muscle protein pool expands during hypertrophy, translation capacity (i.e. ribosomes and myonuclei content) could theoretically become rate-limiting such that an inability to expand these pools through ribosomal biogenesis and satellite cell (SC) mediated myonuclear addition could limit growth potential. Simple measures of RNA (ribosome content) and DNA (SC/Myonuclei number) concentrations reveal that these pools do increase with hypertrophy; yet whether these adaptations are a pre-requisite or a limiting factor for hypertrophy is unresolved and highly debated. This is primarily due to methodological limitations and many assumptions being made on static measures or correlative associations. However recent advances within the field using stable isotope tracers shows promise in resolving these questions in muscle adaptation.
Topics: Humans; Hypertrophy; Muscle Development; Muscle, Skeletal; Protein Biosynthesis; Resistance Training; Ribosomes; Signal Transduction
PubMed: 30741116
DOI: 10.1080/17461391.2019.1569726 -
STAR Protocols Mar 2022The skeletal muscle system is the major organ associated with movement of the body. Myogenesis and regeneration induced post-injury contribute to muscle formation and...
The skeletal muscle system is the major organ associated with movement of the body. Myogenesis and regeneration induced post-injury contribute to muscle formation and maintenance. Here, we provide detailed protocol for the accelerated repair of injured skeletal muscles and generation of hypertrophic muscle fibers. This protocol includes cardiotoxin induced muscle injury and also describes isolation of satellite cells from skeletal muscle tissues of mice. This protocol can be used to study the mechanisms associated with accelerated muscle repair and hypertrophy. For complete details on the use and execution of this protocol, please refer to Ray et al. (2021).
Topics: Animals; Hypertrophy; Mice; Mice, Inbred C57BL; Muscle, Skeletal; Muscular Diseases; Regeneration
PubMed: 35118424
DOI: 10.1016/j.xpro.2021.101111 -
Skeletal Muscle Dec 2018β-adrenergic receptors (βARs) are the target of catecholamines and play fundamental roles in cardiovascular, pulmonary, and skeletal muscle physiology. An important...
BACKGROUND
β-adrenergic receptors (βARs) are the target of catecholamines and play fundamental roles in cardiovascular, pulmonary, and skeletal muscle physiology. An important action of βAR stimulation on skeletal muscle is anabolic growth, which has led to the use of agonists such as clenbuterol by athletes to enhance muscle performance. While previous work has demonstrated that βARs can engage distinct signaling and functional cascades mediated by either G proteins or the multifunctional adaptor protein, β-arrestin, the precise role of β-arrestin in skeletal muscle physiology is not known. Here, we tested the hypothesis that agonist activation of the βAR by clenbuterol would engage β-arrestin as a key transducer of anabolic skeletal muscle growth.
METHODS
The contractile force of isolated extensor digitorum longus muscle (EDL) and calcium signaling in isolated flexor digitorum brevis (FDB) fibers were examined from the wild-type (WT) and β-arrestin 1 knockout mice (βarr1KO) followed by chronic administration of clenbuterol (1 mg/kg/d). Hypertrophic responses including fiber composition and fiber size were examined by immunohistochemical imaging. We performed a targeted phosphoproteomic analysis on clenbuterol stimulated primary cultured myoblasts from WT and βarr1KO mice. Statistical significance was determined by using a two-way analysis with Sidak's or Tukey's multiple comparison test and the Student's t test.
RESULTS
Chronic administration of clenbuterol to WT mice enhanced the contractile force of EDL muscle and calcium signaling in isolated FDB fibers. In contrast, when administered to βarr1KO mice, the effect of clenbuterol on contractile force and calcium influx was blunted. While clenbuterol-induced hypertrophic responses were observed in WT mice, this response was abrogated in mice lacking β-arrestin 1. In primary cultured myoblasts, clenbuterol-stimulated phosphorylation of multiple pro-hypertrophy proteins required the presence of β-arrestin 1.
CONCLUSIONS
We have identified a previously unappreciated role for β-arrestin 1 in mediating βAR-stimulated skeletal muscle growth and strength. We propose these findings could have important implications in the design of future pharmacologic agents aimed at reversing pathological conditions associated with skeletal muscle wasting.
Topics: Adrenergic beta-2 Receptor Agonists; Animals; Calcium Signaling; Cells, Cultured; Clenbuterol; Female; Hypertrophy; Male; Mice; Mice, Inbred C57BL; Muscle Contraction; Muscle Fibers, Skeletal; Muscle Strength; Receptors, Adrenergic, beta-2; beta-Arrestin 1
PubMed: 30591079
DOI: 10.1186/s13395-018-0184-8 -
Scientific Reports Sep 2017Some of the Chronic Obstructive Pulmonary Disease (COPD) patients engaged in exercise-based muscle rehabilitation programs are unresponsive. To unravel the respective...
Some of the Chronic Obstructive Pulmonary Disease (COPD) patients engaged in exercise-based muscle rehabilitation programs are unresponsive. To unravel the respective role of chronic hypoxia and pulmonary inflammation on soleus muscle hypertrophic capacities, we challenged male Wistar rats to repeated lipopolysaccharide instillations, associated or not with a chronic hypoxia exposure. Muscle hypertrophy was initiated by bilateral ablation of soleus agonists 1 week before sacrifice. To understand the role played by the histone acetylation, we also treated our animals with an inhibitor of bromodomains and extra terminal proteins (I-BET) during the week after surgery. Pulmonary inflammation totally inhibited this hypertrophy response under both normoxic and hypoxic conditions (26% lower than control surgery, p < 0.05), consistent with the S6K1 and myogenin measurements. Changes in histone acetylation and class IIa histone deacetylases expression, following pulmonary inflammation, suggested a putative role for histone acetylation signaling in the altered hypertrophy response. The I-BET drug restored the hypertrophy response suggesting that the non-response of muscle to a hypertrophic stimulus could be modulated by epigenetic mechanisms, including histone-acetylation dependant pathways. Drugs targeting such epigenetic mechanisms may open therapeutic perspectives for COPD patients with systemic inflammation who are unresponsive to rehabilitation.
Topics: Acetylation; Animals; Heterocyclic Compounds, 4 or More Rings; Histones; Humans; Hypertrophy; Hypoxia; Male; Muscle, Skeletal; Muscular Diseases; Pneumonia; Protein Domains; Pulmonary Disease, Chronic Obstructive; Rats, Wistar
PubMed: 28935884
DOI: 10.1038/s41598-017-12112-0 -
Physiological Reports Jan 2021Magnetic resonance imaging (MRI) is the current gold standard for measuring changes in muscle size (cross-sectional area [CSA] and volume) but can be cost-prohibitive...
Magnetic resonance imaging (MRI) is the current gold standard for measuring changes in muscle size (cross-sectional area [CSA] and volume) but can be cost-prohibitive and resource-intensive. We evaluated the validity of B-mode ultrasonography (US) as a low-cost alternative to MRI for measuring muscle hypertrophy and atrophy in response to resistance training and immobilization, respectively. Fourteen young men performed 10wk of unilateral resistance training (RT) to induce muscle hypertrophy. In the final two weeks of the 10wk, the subjects' contralateral leg was immobilized (IMB). The cross-sectional area of the vastus lateralis (VLCSA) was measured at the mid-thigh before and after each intervention using MRI (VLCSA ) and US (VLCSA ). The relationship and agreement between methods were assessed. Reliability of US measurements ranged from good to excellent in all comparisons (ICC >0.67). VLCSA significantly increased after 10 weeks of RT (VLCSA : 7.9 ± 3.8%; VLCSA : 7.8 ± 4.5%) and decreased after 2 weeks of IMB (VLCSA : -8.2%±5.8%; VLCSA : -8.7 ± 6.1%). Significant correlations were identified between MRI and US at each time point measured (all r > 0.85) and, importantly, between MRI- and US-derived changes in VLCSA. Bland-Altman analysis revealed minimal bias in US measurements relative to the MRI (-0.5 ± 3.0%) and all measurements were within the upper and lower limits of agreement. Our data suggest that B-mode ultrasonography can be a suitable alternative to MRI for measuring changes in muscle size in response to increased and decreased muscle loading in young men.
Topics: Adult; Humans; Hypertrophy; Male; Muscle, Skeletal; Muscular Atrophy; Quadriceps Muscle; Resistance Training; Ultrasonography
PubMed: 33403796
DOI: 10.14814/phy2.14683 -
Physiological Research Aug 2023G protein-coupled receptor 81 (GPR81), a selective receptor for lactate, expresses in skeletal muscle cells, but the physiological role of GPR81 in skeletal muscle has...
G protein-coupled receptor 81 (GPR81), a selective receptor for lactate, expresses in skeletal muscle cells, but the physiological role of GPR81 in skeletal muscle has not been fully elucidated. As it has been reported that the lactate administration induces muscle hypertrophy, the stimulation of GPR81 has been suggested to mediate muscle hypertrophy. To clarify the contribution of GPR81 activation in skeletal muscle hypertrophy, in the present study, we investigated the effect of GPR81 agonist administration on skeletal muscle mass in mice. Male C57BL/6J mice were randomly divided into control group and GPR81 agonist-administered group that received oral administration of the specific GPR81 agonist 3-Chloro-5-hydroxybenzoic acid (CHBA). In both fast-twitch plantaris and slow-twitch soleus muscles of mice, the protein expression of GPR81 was observed. Oral administration of CHBA to mice significantly increased absolute muscle weight and muscle weight relative to body weight in the two muscles. Moreover, both absolute and relative muscle protein content in the two muscles were significantly increased by CHBA administration. CHBA administration also significantly upregulated the phosphorylation level of p42/44 extracellular signal-regulated kinase-1/2 (ERK1/2) and p90 ribosomal S6 kinase (p90RSK). These observations suggest that activation of GRP81 stimulates increased the mass of two types of skeletal muscle in mice in vivo. Lactate receptor GPR81 may positively affect skeletal muscle mass through activation of ERK pathway.
Topics: Mice; Male; Animals; Lactic Acid; Mice, Inbred C57BL; Muscle, Skeletal; Muscle Fibers, Skeletal; Receptors, G-Protein-Coupled; Hypertrophy
PubMed: 37795889
DOI: 10.33549/physiolres.935004 -
Skeletal Muscle Oct 2019Skeletal muscle mass and strength are crucial determinants of health. Muscle mass loss is associated with weakness, fatigue, and insulin resistance. In fact, it is...
BACKGROUND
Skeletal muscle mass and strength are crucial determinants of health. Muscle mass loss is associated with weakness, fatigue, and insulin resistance. In fact, it is predicted that controlling muscle atrophy can reduce morbidity and mortality associated with diseases such as cancer cachexia and sarcopenia.
METHODS
We analyzed gene expression data from muscle of mice or human patients with diverse muscle pathologies and identified LMCD1 as a gene strongly associated with skeletal muscle function. We transiently expressed or silenced LMCD1 in mouse gastrocnemius muscle or in mouse primary muscle cells and determined muscle/cell size, targeted gene expression, kinase activity with kinase arrays, protein immunoblotting, and protein synthesis levels. To evaluate force, calcium handling, and fatigue, we transduced the flexor digitorum brevis muscle with a LMCD1-expressing adenovirus and measured specific force and sarcoplasmic reticulum Ca release in individual fibers. Finally, to explore the relationship between LMCD1 and calcineurin, we ectopically expressed Lmcd1 in the gastrocnemius muscle and treated those mice with cyclosporine A (calcineurin inhibitor). In addition, we used a luciferase reporter construct containing the myoregulin gene promoter to confirm the role of a LMCD1-calcineurin-myoregulin axis in skeletal muscle mass control and calcium handling.
RESULTS
Here, we identify LIM and cysteine-rich domains 1 (LMCD1) as a positive regulator of muscle mass, that increases muscle protein synthesis and fiber size. LMCD1 expression in vivo was sufficient to increase specific force with lower requirement for calcium handling and to reduce muscle fatigue. Conversely, silencing LMCD1 expression impairs calcium handling and force, and induces muscle fatigue without overt atrophy. The actions of LMCD1 were dependent on calcineurin, as its inhibition using cyclosporine A reverted the observed hypertrophic phenotype. Finally, we determined that LMCD1 represses the expression of myoregulin, a known negative regulator of muscle performance. Interestingly, we observed that skeletal muscle LMCD1 expression is reduced in patients with skeletal muscle disease.
CONCLUSIONS
Our gain- and loss-of-function studies show that LMCD1 controls protein synthesis, muscle fiber size, specific force, Ca handling, and fatigue resistance. This work uncovers a novel role for LMCD1 in the regulation of skeletal muscle mass and function with potential therapeutic implications.
Topics: Animals; Calcineurin; Calcineurin Inhibitors; Calcium; Cells, Cultured; Co-Repressor Proteins; Gene Expression Regulation; Humans; Hypertrophy; LIM Domain Proteins; Mice; Mice, Inbred C57BL; Mice, SCID; Mice, Transgenic; Muscle Fibers, Skeletal; Muscle Proteins; Muscle Strength; Muscle, Skeletal; Muscular Diseases; RNA, Messenger; Signal Transduction
PubMed: 31666122
DOI: 10.1186/s13395-019-0214-1 -
Journal of Applied Physiology... Mar 2017Skeletal muscle can adapt to increased mechanical loads by undergoing hypertrophy. Transient reductions in whole muscle force production have been reported during the...
Skeletal muscle can adapt to increased mechanical loads by undergoing hypertrophy. Transient reductions in whole muscle force production have been reported during the onset of hypertrophy, but contractile changes in individual muscle fibers have not been previously studied. Additionally, the extracellular matrix (ECM) stores and transmits forces from muscle fibers to tendons and bones, and determining how the ECM changes during hypertrophy is important in understanding the adaptation of muscle tissue to mechanical loading. Using the synergist ablation model, we sought to measure changes in muscle fiber contractility, collagen content, and cross-linking, and in the expression of several genes and activation of signaling proteins that regulate critical components of myogenesis and ECM synthesis and remodeling during muscle hypertrophy. Tissues were harvested 3, 7, and 28 days after induction of hypertrophy, and nonoverloaded rats served as controls. Muscle fiber specific force (sF), which is the maximum isometric force normalized to cross-sectional area, was reduced 3 and 7 days after the onset of mechanical overload, but returned to control levels by 28 days. Collagen abundance displayed a similar pattern of change. Nearly a quarter of the transcriptome changed over the course of overload, as well as the activation of signaling pathways related to hypertrophy and atrophy. Overall, this study provides insight into fundamental mechanisms of muscle and ECM growth, and indicates that although muscle fibers appear to have completed remodeling and regeneration 1 mo after synergist ablation, the ECM continues to be actively remodeling at this time point. This study utilized a rat synergist ablation model to integrate changes in single muscle fiber contractility, extracellular matrix composition, activation of important signaling pathways in muscle adaption, and corresponding changes in the muscle transcriptome to provide novel insight into the basic biological mechanisms of muscle fiber hypertrophy.
Topics: Adaptation, Physiological; Animals; Extracellular Matrix; Hypertrophy; Male; Muscle Fibers, Skeletal; Muscle Proteins; Muscle Strength; Muscle, Skeletal; Muscular Diseases; Myocardial Contraction; Rats; Rats, Sprague-Dawley; Transcriptome
PubMed: 27979985
DOI: 10.1152/japplphysiol.00719.2016