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1.
Nat Commun ; 11(1): 5102, 2020 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-33037211

RESUMO

Skeletal muscle fibers are large syncytia but it is currently unknown whether gene expression is coordinately regulated in their numerous nuclei. Here we show by snRNA-seq and snATAC-seq that slow, fast, myotendinous and neuromuscular junction myonuclei each have different transcriptional programs, associated with distinct chromatin states and combinations of transcription factors. In adult mice, identified myofiber types predominantly express either a slow or one of the three fast isoforms of Myosin heavy chain (MYH) proteins, while a small number of hybrid fibers can express more than one MYH. By snRNA-seq and FISH, we show that the majority of myonuclei within a myofiber are synchronized, coordinately expressing only one fast Myh isoform with a preferential panel of muscle-specific genes. Importantly, this coordination of expression occurs early during post-natal development and depends on innervation. These findings highlight a previously undefined mechanism of coordination of gene expression in a syncytium.


Assuntos
Núcleo Celular/genética , Regulação da Expressão Gênica , Hibridização in Situ Fluorescente/métodos , Fibras Musculares Esqueléticas/citologia , Fibras Musculares Esqueléticas/fisiologia , Análise de Sequência de RNA/métodos , Animais , Feminino , Camundongos Endogâmicos C57BL , Músculo Esquelético/citologia , Músculo Esquelético/embriologia , Músculo Esquelético/crescimento & desenvolvimento , Cadeias Pesadas de Miosina/genética , Junção Neuromuscular/citologia , Análise de Célula Única , Tendões/citologia , Transcrição Genética
2.
Sports Health ; 12(6): 579-586, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32866081

RESUMO

CONTEXT: Distinct from the muscle atrophy that develops from inactivity or disuse, atrophy that occurs after traumatic joint injury continues despite the patient being actively engaged in exercise. Recognizing the multitude of factors and cascade of events that are present and negatively influence the regulation of muscle mass after traumatic joint injury will likely enable clinicians to design more effective treatment strategies. To provide sports medicine practitioners with the best strategies to optimize muscle mass, the purpose of this clinical review is to discuss the predominant mechanisms that control muscle atrophy for disuse and posttraumatic scenarios, and to highlight how they differ. EVIDENCE ACQUISITION: Articles that reported on disuse atrophy and muscle atrophy after traumatic joint injury were collected from peer-reviewed sources available on PubMed (2000 through December 2019). Search terms included the following: disuse muscle atrophy OR disuse muscle mass OR anterior cruciate ligament OR ACL AND mechanism OR muscle loss OR atrophy OR neurological disruption OR rehabilitation OR exercise. STUDY DESIGN: Clinical review. LEVEL OF EVIDENCE: Level 5. RESULTS: We highlight that (1) muscle atrophy after traumatic joint injury is due to a broad range of atrophy-inducing factors that are resistant to standard resistance exercises and need to be effectively targeted with treatments and (2) neurological disruptions after traumatic joint injury uncouple the nervous system from muscle tissue, contributing to a more complex manifestation of muscle loss as well as degraded tissue quality. CONCLUSION: Atrophy occurring after traumatic joint injury is distinctly different from the muscle atrophy that develops from disuse and is likely due to the broad range of atrophy-inducing factors that are present after injury. Clinicians must challenge the standard prescriptive approach to combating muscle atrophy from simply prescribing physical activity to targeting the neurophysiological origins of muscle atrophy after traumatic joint injury.


Assuntos
Lesões do Ligamento Cruzado Anterior/complicações , Atrofia Muscular/etiologia , Lesões do Ligamento Cruzado Anterior/patologia , Lesões do Ligamento Cruzado Anterior/fisiopatologia , Citocinas/sangue , Exercício Físico/fisiologia , Humanos , Fibras Musculares Esqueléticas/fisiologia , Proteínas Musculares/biossíntese , Músculo Esquelético/inervação , Músculo Esquelético/metabolismo , Atrofia Muscular/metabolismo , Miostatina/fisiologia , Proteólise , Células Satélites de Músculo Esquelético/fisiologia
3.
Nat Commun ; 11(1): 4479, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32900999

RESUMO

The giant protein titin is thought to be required for sarcomeric integrity in mature myocytes, but direct evidence for this hypothesis is limited. Here, we describe a mouse model in which Z-disc-anchored TTN is depleted in adult skeletal muscles. Inactivation of TTN causes sarcomere disassembly and Z-disc deformations, force impairment, myocyte de-stiffening, upregulation of TTN-binding mechanosensitive proteins and activation of protein quality-control pathways, concomitant with preferential loss of thick-filament proteins. Interestingly, expression of the myosin-bound Cronos-isoform of TTN, generated from an alternative promoter not affected by the targeting strategy, does not prevent deterioration of sarcomere formation and maintenance. Finally, we demonstrate that loss of Z-disc-anchored TTN recapitulates muscle remodeling in critical illness 'myosinopathy' patients, characterized by TTN-depletion and loss of thick filaments. We conclude that full-length TTN is required to integrate Z-disc and A-band proteins into the mature sarcomere, a function that is lost when TTN expression is pathologically lowered.


Assuntos
Fibras Musculares Esqueléticas/fisiologia , Proteínas Quinases/fisiologia , Sarcômeros/fisiologia , Animais , Fenômenos Biomecânicos , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Eletrônica de Transmissão , Força Muscular/fisiologia , Atrofia Muscular/etiologia , Atrofia Muscular/patologia , Atrofia Muscular/fisiopatologia , Doenças Musculares/patologia , Doenças Musculares/fisiopatologia , Miosinas/metabolismo , Proteínas Quinases/deficiência , Proteínas Quinases/genética , Sarcômeros/patologia , Ubiquitinação
4.
Mol Pharmacol ; 98(4): 351-363, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32764093

RESUMO

Ryanodine receptor (RYR) mutations confer stress-triggered malignant hyperthermia (MH) susceptibility. Dietary caffeine (CAF) is the most commonly consumed psychoactive compound by humans. CAF-triggered Ca2+ release and its influences on skeletal muscle contractility are widely used as experimental tools to study RYR function/dysfunction and diagnose MH susceptibility. We hypothesize that dietary CAF achieving blood levels measured in human plasma exacerbates the penetrance of RYR1 MH susceptibility mutations triggered by gaseous anesthetic, affecting both central and peripheral adverse responses. Heterozygous R163C-RYR1 (HET) MH susceptible mice are used to investigate the influences of dietary CAF on both peripheral and central responses before and after induction of halothane (HAL) maintenance anesthesia under experimental conditions that maintain normal core body temperature. HET mice receiving CAF (plasma CAF 893 ng/ml) have significantly shorter times to respiratory arrest compared with wild type, without altering blood chemistry or displaying hyperthermia or muscle rigor. Intraperitoneal bolus dantrolene before HAL prolongs time to respiratory arrest. A pilot electrographic study using subcutaneous electrodes reveals that dietary CAF does not alter baseline electroencephalogram (EEG) total power, but significantly shortens delay to isoelectric EEG, which precedes respiratory and cardiac arrest. CAF ± HAL are studied on RYR1 single-channel currents and HET myotubes to define molecular mechanisms of gene-by-environment synergism. Strong pharmacological synergism between CAF and HAL is demonstrated in both single-channel and myotube preparations. Central and peripheral nervous systems mediate adverse responses to HAL in a HET model of MH susceptibility exposed to dietary CAF, a modifiable lifestyle factor that may mitigate risks of acute and chronic diseases associated with RYR1 mutations. SIGNIFICANCE STATEMENT: Dietary caffeine at a human-relevant dose synergizes adverse peripheral and central responses to anesthesia in malignant hyperthermia susceptible mice. Synergism of these drugs can be attributed to their actions at ryanodine receptors.


Assuntos
Cafeína/efeitos adversos , Dantroleno/efeitos adversos , Halotano/efeitos adversos , Hipertermia Maligna/fisiopatologia , Fibras Musculares Esqueléticas/fisiologia , Mutação , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Animais , Cafeína/farmacologia , Dantroleno/administração & dosagem , Modelos Animais de Doenças , Sinergismo Farmacológico , Eletroencefalografia/instrumentação , Feminino , Halotano/administração & dosagem , Heterozigoto , Humanos , Injeções Intraperitoneais , Masculino , Hipertermia Maligna/genética , Camundongos , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo
5.
Am J Sports Med ; 48(10): 2429-2437, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32631074

RESUMO

BACKGROUND: Anterior cruciate ligament (ACL) injuries and reconstruction (ACLR) promote quadriceps muscle atrophy and weakness that can persist for years, suggesting the need for more effective rehabilitation programs. Whether neuromuscular electrical stimulation (NMES) can be used to prevent maladaptations in skeletal muscle size and function is unclear. PURPOSE: To examine whether early NMES use, started soon after an injury and maintained through 3 weeks after surgery, can preserve quadriceps muscle size and contractile function at the cellular (ie, fiber) level in the injured versus noninjured leg of patients undergoing ACLR. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: Patients (n = 25; 12 men/13 women) with an acute, first-time ACL rupture were randomized to NMES (5 d/wk) or sham (simulated microcurrent electrical nerve stimulation; 5 d/wk) treatment to the quadriceps muscles of their injured leg. Bilateral biopsies of the vastus lateralis were performed 3 weeks after surgery to measure skeletal muscle fiber size and contractility. Quadriceps muscle size and strength were assessed 6 months after surgery. RESULTS: A total of 21 patients (9 men/12 women) completed the trial. ACLR reduced single muscle fiber size and contractility across all fiber types (P < .01 to P < .001) in the injured compared with noninjured leg 3 weeks after surgery. NMES reduced muscle fiber atrophy (P < .01) through effects on fast-twitch myosin heavy chain (MHC) II fibers (P < .01 to P < .001). NMES preserved contractility in slow-twitch MHC I fibers (P < .01 to P < .001), increasing maximal contractile velocity (P < .01) and preserving power output (P < .01), but not in MHC II fibers. Differences in whole muscle strength between groups were not discerned 6 months after surgery. CONCLUSION: Early NMES use reduced skeletal muscle fiber atrophy in MHC II fibers and preserved contractility in MHC I fibers. These results provide seminal, cellular-level data demonstrating the utility of the early use of NMES to beneficially modify skeletal muscle maladaptations to ACLR. CLINICAL RELEVANCE: Our results provide the first comprehensive, cellular-level evidence to show that the early use of NMES mitigates early skeletal muscle maladaptations to ACLR. REGISTRATION: NCT02945553 (ClinicalTrials.gov identifier).


Assuntos
Lesões do Ligamento Cruzado Anterior , Reconstrução do Ligamento Cruzado Anterior , Terapia por Estimulação Elétrica , Músculo Quadríceps/fisiologia , Lesões do Ligamento Cruzado Anterior/cirurgia , Feminino , Humanos , Masculino , Contração Muscular , Fibras Musculares Esqueléticas/fisiologia , Força Muscular , Tamanho do Órgão
6.
J Electromyogr Kinesiol ; 53: 102439, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32563844

RESUMO

Muscle fibre conduction velocity (MFCV) is a basic physiological parameter biophysically related to the diameter of muscle fibres and properties of the sarcolemma. The aim of this study was to assess the intersession reproducibility of the relation between voluntary force and estimates of average muscle fibre conduction velocity (MFCV) from multichannel high-density surface electromyographic recordings (HDsEMG). Ten healthy men performed six linearly increasing isometric ankle dorsiflexions on two separate experimental sessions, 4 weeks apart. Each session involved the recordings of voluntary force during maximal isometric (MViF) and submaximal ramp contractions at 35-50-70% of MViF. Concurrently, the HDsEMG activity was detected from the tibialis anterior muscle and MFCV estimates were derived in 250-ms epochs. Absolute and relative reproducibility of MFCV initial value (intercept) and rate of change (regression slope) as a function of force were assessed by within-subject coefficient of correlation (CVw) and with intraclass correlation coefficient (ICC). MFCV was positively correlated with voluntary force (R2 = 0.75 ± 0.12) in all individuals and test conditions (P < 0.001). Average CVw for MFCV intercept and slope were of 2.6 ± 2.0% and 11.9 ± 3.2% and ICC values of 0.96 and 0.94, respectively. Overall, MFCV regression coefficients showed a high degree of intersession reproducibility in both absolute and relative terms. These results may have important practical implications in the tracking of training-induced neuromuscular changes and/or in the monitoring of the progress of neuromuscular disorders when a full sEMG signal decomposition is problematic or not possible.


Assuntos
Eletromiografia/métodos , Contração Isométrica/fisiologia , Fibras Musculares Esqueléticas/fisiologia , Condução Nervosa/fisiologia , Adulto , Humanos , Masculino , Músculo Esquelético/fisiologia , Reprodutibilidade dos Testes , Adulto Jovem
7.
PLoS One ; 15(5): e0233531, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32453807

RESUMO

Several studies have investigated the use of invasive and non-invasive stimulation methods to enhance nerve regeneration, and varying degrees of effectiveness have been reported. However, due to the use of different parameters in these studies, a fair comparison between the effectiveness of invasive and non-invasive stimulation methods is not possible. The present study compared the effectiveness of invasive and non-invasive stimulation using similar parameters. Eighteen Sprague Dawley rats were classified into three groups: the iES group stimulated with fully implantable device, the tES group stimulated with transcutaneous electrical nerve stimulation (TENS), and the injury group (no stimulation). The iES and tES groups received stimulation for 6 weeks starting immediately after the injury. Motor function was evaluated using the sciatic functional index (SFI) every week. The SFI values increased over time in all groups; faster and superior functional recovery was observed in the iES group than in the tES group. Histological evaluation of the nerve sections and gastrocnemius muscle sections were performed every other week. The axon diameter and muscle fiber area in the iES group were larger, and the g-ratio in the iES group was closer to 0.6 than those in the tES group. To assess the cause of the difference in efficiency, a 3D rat anatomical model was used to simulate the induced electric fields in each group. A significantly higher concentration and intensity around the sciatic nerve was observed in the iES group than in the tES group. Vector field distribution showed that the field was orthogonal to the sciatic nerve spread in the tES group, whereas it was parallel in the iES group; this suggested that the tES group was less effective in nerve stimulation. The results indicated that even though rats in the TENS group showed better recovery than those in the injury group, it cannot replace direct stimulation yet because rats stimulated with the invasive method showed faster recovery and superior outcomes. This was likely attributable to the greater concentration and parallel distribution of electric field with respect to target nerve.


Assuntos
Lesões por Esmagamento/terapia , Regeneração Nervosa/fisiologia , Neuropatia Ciática/terapia , Estimulação Elétrica Nervosa Transcutânea , Animais , Axônios/efeitos da radiação , Lesões por Esmagamento/fisiopatologia , Lesões por Esmagamento/cirurgia , Modelos Animais de Doenças , Humanos , Fibras Musculares Esqueléticas/fisiologia , Fibras Musculares Esqueléticas/efeitos da radiação , Músculo Esquelético/fisiopatologia , Músculo Esquelético/efeitos da radiação , Compressão Nervosa/métodos , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica/fisiologia , Nervo Isquiático/crescimento & desenvolvimento , Nervo Isquiático/fisiopatologia , Nervo Isquiático/cirurgia , Neuropatia Ciática/fisiopatologia , Neuropatia Ciática/cirurgia
8.
Muscle Nerve ; 62(2): 284-288, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32367547

RESUMO

INTRODUCTION: The mechanism by which weakness develops in idiopathic inflammatory myopathies (IIMs) is still unclear. In this study we investigated the maximum force of single muscle fibers from patients with IIMs. METHODS: Permeabilized single muscle fibers from patients with IIMs and healthy controls were subjected to contractility measurements. Maximum force and specific force production (maximum force normalized to fiber size) and fiber type were determined for each isolated fiber. RESULTS: A total of 178 fibers were studied from five patients with IIMs and 95 fibers from four controls. Specific force production was significantly lower in the IIM group for all fiber types. DISCUSSION: The findings from this exploratory study suggest that weakness in IIMs may, in part, be caused by dysfunction of the contractile apparatus. These findings provide a basis for further studies into the mechanisms underlying weakness in IIMs.


Assuntos
Contração Muscular/fisiologia , Fibras Musculares de Contração Rápida/fisiologia , Fibras Musculares Esqueléticas/fisiologia , Fibras Musculares de Contração Lenta/fisiologia , Força Muscular/fisiologia , Miosite/fisiopatologia , Adulto , Biópsia , Estudos de Casos e Controles , Tamanho Celular , Dermatomiosite/metabolismo , Dermatomiosite/patologia , Dermatomiosite/fisiopatologia , Feminino , Humanos , Pessoa de Meia-Idade , Fibras Musculares de Contração Rápida/metabolismo , Fibras Musculares de Contração Rápida/patologia , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologia , Fibras Musculares de Contração Lenta/metabolismo , Fibras Musculares de Contração Lenta/patologia , Cadeias Pesadas de Miosina/metabolismo , Miosite/metabolismo , Miosite/patologia , Polimiosite/metabolismo , Polimiosite/patologia , Polimiosite/fisiopatologia , Adulto Jovem
9.
PLoS Genet ; 16(5): e1008754, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32365093

RESUMO

FSHD is characterized by the misexpression of DUX4 in skeletal muscle. Although DUX4 upregulation is thought to be the pathogenic cause of FSHD, DUX4 is lowly expressed in patient samples, and analysis of the consequences of DUX4 expression has largely relied on artificial overexpression. To better understand the native expression profile of DUX4 and its targets, we performed bulk RNA-seq on a 6-day differentiation time-course in primary FSHD2 patient myoblasts. We identify a set of 54 genes upregulated in FSHD2 cells, termed FSHD-induced genes. Using single-cell and single-nucleus RNA-seq on myoblasts and differentiated myotubes, respectively, we captured, for the first time, DUX4 expressed at the single-nucleus level in a native state. We identified two populations of FSHD myotube nuclei based on low or high enrichment of DUX4 and FSHD-induced genes ("FSHD-Lo" and "FSHD Hi", respectively). FSHD-Hi myotube nuclei coexpress multiple DUX4 target genes including DUXA, LEUTX and ZSCAN4, and also upregulate cell cycle-related genes with significant enrichment of E2F target genes and p53 signaling activation. We found more FSHD-Hi nuclei than DUX4-positive nuclei, and confirmed with in situ RNA/protein detection that DUX4 transcribed in only one or two nuclei is sufficient for DUX4 protein to activate target genes across multiple nuclei within the same myotube. DUXA (the DUX4 paralog) is more widely expressed than DUX4, and depletion of DUXA suppressed the expression of LEUTX and ZSCAN4 in late, but not early, differentiation. The results suggest that the DUXA can take over the role of DUX4 to maintain target gene expression. These results provide a possible explanation as to why it is easier to detect DUX4 target genes than DUX4 itself in patient cells and raise the possibility of a self-sustaining network of gene dysregulation triggered by the limited DUX4 expression.


Assuntos
Núcleo Celular/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Distrofia Muscular Facioescapuloumeral , RNA-Seq/métodos , Análise de Célula Única/métodos , Estudos de Casos e Controles , Diferenciação Celular , Núcleo Celular/química , Núcleo Celular/classificação , Núcleo Celular/patologia , Células Cultivadas , Regulação da Expressão Gênica , Células HEK293 , Humanos , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Fibras Musculares Esqueléticas/patologia , Fibras Musculares Esqueléticas/fisiologia , Fibras Musculares Esqueléticas/ultraestrutura , Distrofia Muscular Facioescapuloumeral/genética , Distrofia Muscular Facioescapuloumeral/metabolismo , Distrofia Muscular Facioescapuloumeral/patologia , Mioblastos/metabolismo , Mioblastos/fisiologia , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Sequenciamento Completo do Exoma
10.
Am J Physiol Endocrinol Metab ; 319(2): E265-E275, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32459525

RESUMO

Saturated fatty acids (SFAs) are implicated in muscle inflammation/cell stress and insulin resistance, but the catalog of factors involved is incomplete. SFA derivatives that accumulate with mismatched FA availability and FA oxidation (FAO) are likely involved, and evidence has emerged that select acylcarnitines should be considered. To understand if excessive long-chain acylcarnitine accumulation and limited FAO associate with lipotoxicity, carnitine palmitoyltransferase 2 knockout C2C12 cells were generated (CPT2 KO). CPT2 KO was confirmed by Western blot, increased palmitoylcarnitine accumulation, and loss of FAO capacity. There was no effect of CPT2 KO on palmitic acid (PA) concentration-dependent increases in media IL-6 or adenylate kinase. PA at 200 and 500 µM did not trigger cell stress responses (phospho-Erk, -JNK, or -p38) above that of vehicle in WT or CPT2 KO cells. In contrast, loss of CPT2 exacerbated PA-induced insulin resistance (acute phospho-Akt; 10 or 100 nM insulin) by as much as ~50-96% compared with WT. Growing cells in carnitine-free media abolished differences between WT and CPT2 KO, but this did not fully rescue PA-induced insulin resistance. The results suggest that PA-induced insulin resistance stems in part from palmitoylcarnitine accumulation, further supporting the hypothesis that select acylcarnitines participate in cell signaling and, when in excess, can compromise cell function. Since carnitine-free conditions could not fully rescue insulin signaling, and CPT2 KO did not alter cell stress responses, the majority of PA-induced "lipotoxicity" in C2C12 myotubes cannot be attributed to palmitoylcarnitine alone.


Assuntos
Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/fisiologia , Técnicas de Inativação de Genes , Resistência à Insulina/fisiologia , Fibras Musculares Esqueléticas/fisiologia , Ácido Palmítico/farmacologia , Animais , Linhagem Celular , Camundongos , Fibras Musculares Esqueléticas/citologia , Fibras Musculares Esqueléticas/efeitos dos fármacos , Palmitoilcarnitina/metabolismo , Transdução de Sinais/fisiologia
11.
Int J Sports Med ; 41(11): 709-719, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32365388

RESUMO

This two-part narrative review aims to provide an insight into the age-related mechanical and neuromuscular factors contributing to: (1) decreased maximal muscle strength and power; (2) decreased force control; and (3) increased fatigability. Structural and functional changes from the macro-level of the muscle-tendon unit to the micro-level of the single muscle fibre have been reviewed and are described. At the muscle-tendon unit level, muscle volume, thickness and cross-sectional area, as well as pennation angle and fascicle length all decrease as part of the natural ageing process. These changes negatively affect muscle quality, muscle and tendon stiffness and Young's modulus and account for impairment in motor performance. A progressive age-related alteration in neuromuscular function is also well-established, with reduction in number and firing rate of the motor unit, contractile velocity and specific tension of muscle fibres, and stability of neuromuscular junction. These could be the result of structural alterations in the: (i) motor neuron, with number reduced, size and collateral sprouting increased; (ii) neuromuscular junction, with decreased post-synaptic junctional fold and density of active zones and increased pre-synaptic branching and post-synaptic area; and (iii) muscle fibre, with decreased number and size and increased type I and co-expression of myosin heavy chain.


Assuntos
Envelhecimento/fisiologia , Músculo Esquelético/fisiologia , Humanos , Neurônios Motores/citologia , Neurônios Motores/fisiologia , Fadiga Muscular/fisiologia , Fibras Musculares Esqueléticas/citologia , Fibras Musculares Esqueléticas/fisiologia , Força Muscular/fisiologia , Músculo Esquelético/anatomia & histologia , Músculo Esquelético/inervação , Junção Neuromuscular/anatomia & histologia , Junção Neuromuscular/fisiologia , Qualidade de Vida , Tendões/anatomia & histologia , Tendões/fisiologia
12.
Am J Chin Med ; 48(3): 631-650, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32329640

RESUMO

The loss of skeletal muscle mass and function is a serious consequence of chronic diseases and aging. BST204 is a purified ginseng (the root of Panax ginseng) extract that has been processed using ginsenoside-ß-glucosidase and acid hydrolysis to enrich ginsenosides Rg3 and Rh2 from the crude ginseng. BST204 has a broad range of health benefits, but its effects and mechanism on muscle atrophy are currently unknown. In this study, we have examined the effects and underlying mechanisms of BST204 on myotube formation and myotube atrophy induced by tumor necrosis factor-α (TNF-α). BST204 promotes myogenic differentiation and multinucleated myotube formation through Akt activation. BST204 prevents myotube atrophy induced by TNF-α through the activation of Akt/mTOR signaling and down-regulation of muscle-specific ubiquitin ligases, MuRF1, and Atrogin-1. Furthermore, BST204 treatment in atrophic myotubes suppresses mitochondrial reactive oxygen species (ROS) production and regulates mitochondrial transcription factors such as NRF1 and Tfam, through enhancing the activity and expression of peroxisome proliferator-activated receptor-γ coactivator1α (PGC1α). Collectively, our findings indicate that BST204 improves myotube formation and PGC1α-mediated mitochondrial function, suggesting that BST204 is a potential therapeutic or neutraceutical remedy to intervene muscle weakness and atrophy.


Assuntos
Desenvolvimento Muscular/efeitos dos fármacos , Fibras Musculares Esqueléticas/efeitos dos fármacos , Panax/química , Fitoterapia , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Animais , Atrofia/induzido quimicamente , Atrofia/tratamento farmacológico , Humanos , Mitocôndrias Musculares/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologia , Fibras Musculares Esqueléticas/fisiologia , Fator 1 Nuclear Respiratório/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Extratos Vegetais/isolamento & purificação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estimulação Química , Serina-Treonina Quinases TOR/metabolismo , Fator de Necrose Tumoral alfa
13.
Gen Comp Endocrinol ; 293: 113492, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32333912

RESUMO

Within the zebra finch song system, robust sex differences exist that enable singing behavior in males, but not females. Estradiol is a potent contributor to this process, but how and through which receptor(s) it acts is not clear. Historically, pharmacological manipulations of nuclear estrogen receptors have yielded conflicting results possibly due to method of drug delivery. More recently, the membrane bound G-protein coupled estrogen receptor 1 (GPER1) has also been identified as a potential candidate, but its function has not been fully described. To further investigate the role of GPER1, and the importance of the route of drug administration, a specific antagonist (G-15) was intramuscularly administered to zebra finches for 25 days, starting on the day of hatching. G-15 significantly decreased muscle fiber sizes of ventralis and dorsalis in the syrinx of males only. Dimorphic characteristics of the neural song system were unaffected by this manipulation in either sex. These results contrast with a study in which G-15 was intracranially delivered. In males, select song nuclei were decreased in volume, and in females, syrinx muscle fiber size was increased. Together, these results support the hypothesis that estrogens acting through GPER1 influence dimorphic development of the song system, and that method of drug administration is important in this species.


Assuntos
Encéfalo/fisiologia , Tentilhões/fisiologia , Músculos/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Caracteres Sexuais , Vocalização Animal/fisiologia , Animais , Receptor alfa de Estrogênio , Feminino , Masculino , Fibras Musculares Esqueléticas/fisiologia , Neurônios/fisiologia
14.
Life Sci ; 251: 117603, 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32240680

RESUMO

AIMS: The objective of this study was to establish a more accurate analytical model and method for grip strength test of mice and to investigate the beneficial effects of lifelong exercise training to prevent functional decline of muscle during aging. MAIN METHODS: Fifty randomly selected adult male BALB/c mice (24-56 week age) were used in grip strength testing periodically with short periods (3 s). Such method was used to detect a modified grip strength test. Then sixty-four male BALB/c mice (6 week age) were assigned into groups Sedentary (n = 32), Exercise (n = 32, lifelong treadmill training 3 days per week and 30 min per day). The muscle strength and morphology parameters were measured at the ages of 6, 12, 30 and 64 weeks, respectively. KEY FINDINGS: The grip strength (peak value and endurance) of sedentary group monotonically decreased in adult BALB/c mice during aging, while that of exercise group remained a relatively high level even slightly increased at aged period. Meanwhile, lifelong exercise training could slow down the loss of gastrocnemius muscle mass, myofiber cross-sectional area, myonuclear number and myonuclear domain. The number of myofibers was relatively stable in adult mice. SIGNIFICANCE: Modified analytical method for grip strength testing, with improved accuracy and reliability, may be an efficient substitute for conventional method in measuring the strength and endurance of mice and investigating the effect of lifelong exercise on muscle loss. Lifelong exercise training helps prevent muscle loss and muscle defunctionalization while aging.


Assuntos
Envelhecimento/fisiologia , Força Muscular/fisiologia , Condicionamento Físico Animal/fisiologia , Comportamento Sedentário , Animais , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fibras Musculares Esqueléticas/fisiologia , Músculo Esquelético/metabolismo , Reprodutibilidade dos Testes
15.
J Vis Exp ; (156)2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-32150167

RESUMO

Although conventional nerve conduction studies (NCS) and electromyography (EMG) are suitable for the diagnosis of neuromuscular disorders, they provide limited information about muscle fiber membrane properties and underlying disease mechanisms. Muscle velocity recovery cycles (MVRCs) illustrate how the velocity of a muscle action potential depends on the time after a preceding action potential. MVRCs are closely related to changes in membrane potential that follow an action potential, thereby providing information about muscle fiber membrane properties. MVRCs may be recorded quickly and easily by direct stimulation and recording from multi-fiber bundles in vivo. MVRCs have been helpful in understanding disease mechanisms in several neuromuscular disorders. Studies in patients with channelopathies have demonstrated the different effects of specific ion channel mutations on muscle excitability. MVRCs have been previously tested in patients with neurogenic muscles. In this prior study, muscle relative refraction period (MRRP) was prolonged, and early supernormality (ESN) and late supernormality (LSN) were reduced in patients compared to healthy controls. Thereby, MVRCs can provide in vivo evidence of membrane depolarization in intact human muscle fibers that underlie their reduced excitability. The protocol presented here describes how to record MVRCs and analyze the recordings. MVRCs can serve as a fast, simple, and useful method for revealing disease mechanisms across a broad range of neuromuscular disorders.


Assuntos
Potenciais de Ação , Eletromiografia/instrumentação , Potenciais da Membrana , Contração Muscular , Fibras Musculares Esqueléticas/fisiologia , Músculo Esquelético/fisiologia , Recuperação de Função Fisiológica , Humanos
16.
PLoS One ; 15(3): e0229944, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32131083

RESUMO

Controlled mechanical ventilation (CMV) can cause diaphragmatic motionlessness to induce diaphragmatic dysfunction. Partial maintenance of spontaneous breathing (SB) can reduce ventilation-induced diaphragmatic dysfunction (VIDD). However, to what extent SB is maintained in CMV can attenuate or even prevent VIDD has been rarely reported. The current study aimed to investigate the relationship between SB intensity and VIDD and to identify what intensity of SB maintained in CMV can effectively avoid VIDD. Adult rats were randomly divided according to different SB intensities: SB (0% pressure controlled ventilation (PCV)), high-intensity SB (20% PCV), medium-intensity SB (40% PCV), medium-low intensity SB (60% PCV), low-intensity SB (80% PCV), and PCV (100% PCV). The animals underwent 24-h controlled mechanical ventilation (CMV). The transdiaphragmatic pressure (Pdi), the maximal Pdi (Pdi max) when phrenic nerves were stimulated, Pdi/Pdi max, and the diaphragmatic tonus under different frequencies of electric stimulations were determined. Calpain and caspase-3 were detected using ELISA and the cross-section areas (CSAs) of different types of muscle fibers were measured. The Pdi showed a significant decrease from 20% PCV and the Pdi max showed a significant decrease from 40% PCV (P<0.05). In vivo and vitro diaphragmatic tonus exhibited a significant decrease from 40% PCV and 20% PCV, respectively (P<0.05). From 20% PCV, the CSAs of types I, IIa, and IIb/x muscle fibers showed significant differences, which reached the lowest levels at 100% PCV. SB intensity is negatively associated with the development of VIDD. Maintenance of SB at an intensity of 60%-80% may effectively prevent the occurrence of VIDD.


Assuntos
Diafragma/fisiopatologia , Pulmão/fisiopatologia , Respiração Artificial/métodos , Respiração , Animais , Humanos , Ventilação com Pressão Positiva Intermitente , Fibras Musculares Esqueléticas/fisiologia , Ratos
17.
J Anim Sci ; 98(5)2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32175577

RESUMO

Satellite cells are the myogenic stem and progenitor population found in skeletal muscle. These cells typically reside in a quiescent state until called upon to support repair, regeneration, or muscle growth. The activities of satellite cells are orchestrated by systemic hormones, autocrine and paracrine growth factors, and the composition of the basal lamina of the muscle fiber. Several key intracellular signaling events are initiated in response to changes in the local environment causing exit from quiescence, proliferation, and differentiation. Signals emanating from Notch, wingless-type mouse mammary tumor virus integration site family members, and transforming growth factor-ß proteins mediate the reversible exit from growth 0 phase while those initiated by members of the fibroblast growth factor and insulin-like growth factor families direct proliferation and differentiation. Many of these pathways impinge upon the myogenic regulatory factors (MRF), myogenic factor 5, myogenic differentiation factor D, myogenin and MRF4, and the lineage determinate, Paired box 7, to alter transcription and subsequent satellite cell decisions. In the recent past, insight into mouse transgenic models has led to a firm understanding of regulatory events that control satellite cell metabolism and myogenesis. Many of these niche-regulated functions offer subtle differences from their counterparts in livestock pointing to the existence of species-specific controls. The purpose of this review is to examine the mechanisms that mediate large animal satellite cell activity and their relationship to those present in rodents.


Assuntos
Desenvolvimento Muscular , Fatores de Regulação Miogênica/metabolismo , Células Satélites de Músculo Esquelético/fisiologia , Animais , Diferenciação Celular , Gado , Camundongos , Fibras Musculares Esqueléticas/fisiologia , Músculo Esquelético/fisiologia , Fator Regulador Miogênico 5/metabolismo , Miogenina/metabolismo , Somatomedinas/metabolismo
18.
Rev. Asoc. Méd. Argent ; 133(1): 12-20, mar. 2020. graf, tab
Artigo em Espanhol | LILACS | ID: biblio-1097697

RESUMO

La rigidez cadavérica (rigor mortis) es un proceso no muy bien comprendido por la mayoría de los médicos. El conocimiento de la intimidad del proceso de la rigidez cadavérica es de vital importancia ya que es una de las variables que junto con las livideces (livor mortis) y la temperatura (algor mortis) del cadáver ayudan a determinar el cronotanatodiagnóstico, tanatocronodiagnóstico o intervalo postmortal del período inmediato de la muerte. Para entender el mecanismo de la rigidez y el espasmo cadavérico es preciso hacer un repaso de la contracción muscular fisiológica en el vivo. Hay que tener presente que el tipo de fibra muscular predominante modificará las características de la contracción muscular fisiológica en el vivo, y también la rigidez y el espasmo cadavérico. (AU)


The cadaveric rigidity (rigor mortis) is a process which is not very well understood by the majority of the doctors. The knowledge of the intimacy of the cadaveric stiffness process is of vital importance since it is one of the variables that, as well as the postmortem lividity (livor mortis) and the body temperature post mortem (algor mortis) help determine the chronotanatodiagnostic, tanatochronodiagnostic or postmortal interval of the immediate period of death. In order to understand the mechanism of stiffness and cadaveric spasm, it is necessary to review the physiological muscle contraction in vivo. We should keep in mind that the predominant type of muscle fiber will modify the characteristics of physiological muscle contraction in vivo, as well as stiffness and cadaveric spasm. (AU)


Assuntos
Humanos , Mudanças Depois da Morte , Rigor Mortis/fisiopatologia , Fibras Musculares Esqueléticas/fisiologia , Fatores de Tempo , Contração Muscular/fisiologia , Relaxamento Muscular/fisiologia
19.
Sci Rep ; 10(1): 4524, 2020 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-32161296

RESUMO

Motor neurons form specialized synapses with skeletal muscle fibers, called neuromuscular junctions (NMJs). Cultured myotubes are used as a simplified in vitro system to study the postsynaptic specialization of muscles. The stimulation of myotubes with the glycoprotein agrin or laminin-111 induces the clustering of postsynaptic machinery that contains acetylcholine receptors (AChRs). When myotubes are grown on laminin-coated surfaces, AChR clusters undergo developmental remodeling to form topologically complex structures that resemble mature NMJs. Needing further exploration are the molecular processes that govern AChR cluster assembly and its developmental maturation. Here, we describe an improved protocol for culturing muscle cells to promote the formation of complex AChR clusters. We screened various laminin isoforms and showed that laminin-221 was the most potent for inducing AChR clusters, whereas laminin-121, laminin-211, and laminin-221 afforded the highest percentages of topologically complex assemblies. Human primary myotubes that were formed by myoblasts obtained from patient biopsies also assembled AChR clusters that underwent remodeling in vitro. Collectively, these results demonstrate an advancement of culturing myotubes that can facilitate high-throughput screening for potential therapeutic targets for neuromuscular disorders.


Assuntos
Técnicas de Cultura de Células , Laminina , Fibras Musculares Esqueléticas/citologia , Fibras Musculares Esqueléticas/fisiologia , Densidade Pós-Sináptica , Animais , Linhagem Celular , Células Cultivadas , Imunofluorescência , Laminina/química , Camundongos , Modelos Biológicos , Mioblastos/citologia , Mioblastos/fisiologia , Junção Neuromuscular , Receptores Colinérgicos/metabolismo
20.
Comput Methods Biomech Biomed Engin ; 23(8): 312-322, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32031425

RESUMO

This study investigates mechanical cooperation among tongue muscles. Five volunteers were imaged using tagged magnetic resonance imaging to quantify spatiotemporal kinematics while speaking. Waveforms of strain in the line of action of fibers (SLAF) were estimated by projecting strain tensors onto a model of fiber directionality. SLAF waveforms were temporally aligned to determine consistency across subjects and correlation across muscles. The cohort exhibited consistent patterns of SLAF, and muscular extension-contraction was correlated. Volume-preserving tongue movement in speech generation can be achieved through multiple paths, but the study reveals similarities in motion patterns and muscular action-despite anatomical (and other) dissimilarities.


Assuntos
Fibras Musculares Esqueléticas/fisiologia , Fala/fisiologia , Estresse Mecânico , Língua/fisiologia , Adulto , Fenômenos Biomecânicos , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Fonética
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