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PURPOSE: Approximately 30% of people infected with COVID-19 require hospitalization, and 20% of them are admitted to an intensive care unit (ICU). Most of these patients experience symptoms of fatigue weeks post-ICU, so understanding the factors associated with fatigue in this population is crucial. METHODS: Fifty-nine patients (38-78 yr) hospitalized in ICU for COVID-19 infection for 32 (6-80) d, including 23 (3-57) d of mechanical ventilation, visited the laboratory on two separate occasions. The first visit occurred 52 ± 15 d after discharge and was dedicated to questionnaires, blood sampling, and cardiopulmonary exercise testing, whereas measurements of the knee extensors neuromuscular function and performance fatigability were performed in the second visit 7 ± 2 d later. RESULTS: Using the FACIT-F questionnaire, 56% of patients were classified as fatigued. Fatigued patients had worse lung function score than non-fatigued (i.e., 2.9 ± 0.8 L vs 3.6 ± 0.8 L; 2.4 ± 0.7 L vs 3.0 ± 0.7 L for forced vital capacity and forced expiratory volume in 1 s, respectively), and forced vital capacity was identified as a predictor of being fatigued. Maximal voluntary activation was lower in fatigued patients than non-fatigued patients (82% ± 14% vs 91% ± 3%) and was the only neuromuscular variable that discriminated between fatigued and non-fatigued patients. Patient-reported outcomes also showed differences between fatigued and non-fatigued patients for sleep, physical activity, depression, and quality of life ( P < 0.05). CONCLUSIONS: COVID-19 survivors showed altered respiratory function 4 to 8 wk after discharge, which was further deteriorated in fatigued patients. Fatigue was also associated with lower voluntary activation and patient-reported impairments (i.e., sleep satisfaction, quality of life, or depressive state). The present study reinforces the importance of exercise intervention and rehabilitation to counteract cardiorespiratory and neuromuscular impairments of COVID-19 patients admitted in ICU, especially individuals experiencing fatigue.
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COVID-19 , Fatiga , Unidades de Cuidados Intensivos , Sobrevivientes , Humanos , COVID-19/complicaciones , COVID-19/fisiopatología , Persona de Mediana Edad , Masculino , Femenino , Anciano , Adulto , SARS-CoV-2 , Prueba de Esfuerzo , Capacidad Vital , Encuestas y Cuestionarios , Respiración ArtificialRESUMEN
Adult skeletal muscle stem cells (MuSC) are the regenerative precursors of myofibers and also have an important role in myofiber growth, adaptation, and maintenance by fusing to the myofibers-a process referred to as "myonuclear accretion." Due to a focus on MuSC function during regeneration, myofibers remain a largely overlooked component of the MuSC niche influencing MuSC fate. Here, we describe a method to directly measure the rate of myonuclear accretion in vitro and in vivo using ethynyl-2'-deoxyuridine (EdU)-based tracing of MuSC progeny. This method supports the dissection of MuSC intrinsic and myofiber-derived factors influencing myonuclear accretion as an alternative fate of MuSCs supporting myofiber homeostasis and plasticity.
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Diabetes represents a major public health concern with a considerable impact on human life and healthcare expenditures. It is now well established that diabetes is characterized by a severe skeletal muscle pathology that limits functional capacity and quality of life. Increasing evidence indicates that diabetes is also one of the most prevalent disorders characterized by impaired skeletal muscle regeneration, yet underlying mechanisms and therapeutic treatments remain poorly established. In this review, we describe the cellular and molecular alterations currently known to occur during skeletal muscle regeneration in people with diabetes and animal models of diabetes, including its associated comorbidities, e.g., obesity, hyperinsulinemia, and insulin resistance. We describe the role of myogenic and non-myogenic cell types on muscle regeneration in conditions with or without diabetes. Therapies for skeletal muscle regeneration and gaps in our knowledge are also discussed, while proposing future directions for the field.
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Diabetes Mellitus , Músculo Esquelético , Regeneración , Humanos , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Animales , Diabetes Mellitus/terapia , Diabetes Mellitus/metabolismo , Desarrollo de Músculos , Resistencia a la InsulinaRESUMEN
Nemaline myopathies are the most common form of congenital myopathies. Variants in ACTA1 (NEM3) comprise 15-25% of all nemaline myopathy cases. Patients harboring variants in ACTA1 present with a heterogeneous disease course characterized by stable or progressive muscle weakness and, in severe cases, respiratory failure and death. To date, no specific treatments are available. Since NEM3 is an actin-based thin filament disease, we tested the ability of tirasemtiv, a fast skeletal muscle troponin activator, to improve skeletal muscle function in a mouse model of NEM3, harboring the patient-based p.Asp286Gly variant in Acta1. Acute and long-term tirasemtiv treatment significantly increased muscle contractile capacity at submaximal stimulation frequencies in both fast-twitch extensor digitorum longus and gastrocnemius muscle, and intermediate-twitch diaphragm muscle in vitro and in vivo. Additionally, long-term tirasemtiv treatment in NEM3 mice resulted in a decreased respiratory rate with preserved minute volume, suggesting more efficient respiration. Altogether, our data support the therapeutic potential of fast skeletal muscle troponin activators in alleviating skeletal muscle weakness in a mouse model of NEM3 caused by the Acta1:p.Asp286Gly variant.
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Imidazoles , Miopatías Nemalínicas , Pirazinas , Humanos , Animales , Ratones , Miopatías Nemalínicas/tratamiento farmacológico , Miopatías Nemalínicas/genética , Tono Muscular , Actinas/genética , Músculo Esquelético , Modelos Animales de Enfermedad , TroponinaRESUMEN
Due to the post-mitotic nature of skeletal muscle fibers, adult muscle maintenance relies on dedicated muscle stem cells (MuSCs). In most physiological contexts, MuSCs support myofiber homeostasis by contributing to myonuclear accretion, which requires a coordination of cell-type specific events between the myofiber and MuSCs. Here, we addressed the role of the kinase AMPKα2 in the coordination of these events supporting myonuclear accretion. We demonstrate that AMPKα2 deletion impairs skeletal muscle regeneration. Through in vitro assessments of MuSC myogenic fate and EdU-based cell tracing, we reveal a MuSC-specific role of AMPKα2 in the regulation of myonuclear accretion, which is mediated by phosphorylation of the non-metabolic substrate BAIAP2. Similar cell tracing in vivo shows that AMPKα2 knockout mice have a lower rate of myonuclear accretion during regeneration, and that MuSC-specific AMPKα2 deletion decreases myonuclear accretion in response to myofiber contraction. Together, this demonstrates that AMPKα2 is a MuSC-intrinsic regulator of myonuclear accretion.
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After injury, skeletal muscle regenerates thanks to the key role of satellite cells (SC). The regeneration process is supported and coordinated by other cell types among which immune cells. Among the mechanisms involved in skeletal muscle regeneration, a sexual dimorphism, involving sex hormones and more particularly estrogens, has been suggested. However, the role of sexual dimorphism on skeletal muscle regeneration is not fully understood, likely to the use of various experimental settings in both animals and human. This review aims at addressing how sex and estrogens regulate both the SC and the inflammatory response during skeletal muscle regeneration by considering the different experimental designs used in both animal models (i.e., ovarian hormone deficiency, estrogen replacement or supplementation, treatments with estrogen receptors agonists/antagonists and models knockout for estrogen receptors) and human (hormone therapy replacement, pre vs. postmenopausal, menstrual cycle variation ).
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Receptores de Estrógenos , Células Satélite del Músculo Esquelético , Animales , Femenino , Humanos , Receptores de Estrógenos/metabolismo , Caracteres Sexuales , Músculo Esquelético/metabolismo , Regeneración , Estrógenos/farmacología , Células Satélite del Músculo Esquelético/metabolismoRESUMEN
Post-injury skeletal muscle regeneration requires interactions between myogenic and non-myogenic cells. Our knowledge on the regeneration process is mainly based on models using toxic, chemical, or physical (e.g., based on either muscle freezing or crushing) injury. Strikingly, the time course and magnitude of changes in the number of cells involved in muscle regeneration have been poorly described in relation to mild and severe muscle damage induced by electrically-evoked lengthening contractions. We investigated for the first time the kinetics and magnitude of changes in mononuclear cells in relation to the extent of muscle damage. Mild and severe injury were induced in vivo in the mouse gastrocnemius muscle by 1 and 30 electrically-evoked lengthening contractions, respectively. Several days after muscle damage, functional analysis of maximal torque production and histological investigations were performed to assess the related cellular changes. Torque recovery was faster after mild injury than after severe muscle damage. More necrotic and regenerating myofibers were observed after severe muscle damage as compared with mild injury, illustrating an association between functional and histological alterations. The kinetics of changes in muscle stem cells (total, proliferating, and differentiating), endothelial cells, fibro-adipogenic progenitors (FAPs), and macrophages in the regenerating muscle was similar in mild and severe models. However, the magnitude of changes in the number of differentiating muscle stem cells, hematopoietic cells, among which macrophages, and FAPs was higher in severe muscle damage. Collectively, our results show that the amount of myogenic and non-myogenic cells varies according to the extent of skeletal muscle injury to ensure efficient skeletal muscle regeneration while the kinetics of changes is independent of muscle tissue alterations. The possibility to experimentally modulate the extent of muscle damage will be useful to further investigate the cellular and molecular events involved in muscle regeneration.
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Células Endoteliales , Músculo Esquelético , Ratones , Animales , Cinética , Músculo Esquelético/patología , Contracción Muscular , AdipogénesisRESUMEN
PURPOSE: The effectiveness of a neuromuscular electrical stimulation (NMES) program is proportional to the level of evoked torque, which can be achieved with either conventional or wide-pulse stimulations. The aim of this study was to compare evoked torque, objective fatigability, and related peripheral and central alterations, as well as changes in central nervous system (CNS) excitability induced by an acute session of conventional versus wide-pulse NMES. METHODS: Seventeen young men underwent three 20-min NMES sessions: conventional (0.2 ms/50 Hz), wide-pulse at 50 Hz (1 ms/50 Hz), and wide-pulse at 100 Hz (1 ms/100 Hz). Neuromuscular measurements (i.e., maximal voluntary contraction, voluntary activation, evoked responses to femoral nerve stimulation, and CNS excitability) were performed on the right quadriceps femoris muscle before and after each NMES session. CNS excitability was measured using transcranial magnetic, thoracic, and transcutaneous spinal cord stimulations. RESULTS: The level of evoked torque was not significantly different between conventional and wide-pulse protocols applied at the maximal tolerable current intensity. All NMES protocols induced objective fatigability (~14% decrease in maximal voluntary contraction torque, p < 0.001) associated with peripheral (decrease in doublet torque and potentiated M-wave amplitude, p = 0.002 and p < 0.001, respectively) but not central (unchanged voluntary activation, p = 0.79) alterations. However, these acute changes did not differ between NMES protocols and none of the NMES protocols modified markers of CNS excitability. CONCLUSION: These results may allow to conjecture that chronic effects and treatment effectiveness could be comparable between conventional and wide-pulse NMES.
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Contracción Muscular , Músculo Cuádriceps , Masculino , Humanos , Músculo Cuádriceps/fisiología , Estimulación Eléctrica/métodos , Contracción Muscular/fisiología , Fatiga Muscular/fisiología , Sistema Nervioso Central , Músculo Esquelético/fisiología , ElectromiografíaRESUMEN
Skeletal muscle is a plastic tissue that regenerates ad integrum after injury and adapts to raise mechanical loading/contractile activity by increasing its mass and/or myofiber size, a phenomenon commonly refers to as skeletal muscle hypertrophy. Both muscle regeneration and hypertrophy rely on the interactions between muscle stem cells and their neighborhood, which include inflammatory cells, and particularly macrophages. This review first summarizes the role of macrophages in muscle regeneration in various animal models of injury and in response to exercise-induced muscle damage in humans. Then, the potential contribution of macrophages to skeletal muscle hypertrophy is discussed on the basis of both animal and human experiments. We also present a brief comparative analysis of the role of macrophages during muscle regeneration versus hypertrophy. Finally, we summarize the current knowledge on the impact of different immunomodulatory strategies, such as heat therapy, cooling, massage, nonsteroidal anti-inflammatory drugs and resolvins, on skeletal muscle regeneration and their potential impact on muscle hypertrophy.
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Músculo Esquelético , Regeneración , Animales , Antiinflamatorios , Humanos , Hipertrofia , Macrófagos , Músculo Esquelético/fisiología , PlásticosRESUMEN
OBJECTIVES: The aim of the current study was to investigate the level of cardiorespiratory fitness and neuromuscular function of ICU survivors after COVID-19 and to examine whether these outcomes are related to ICU stay/mechanical ventilation duration. DESIGN: Prospective nonrandomized study. SETTING: Patients hospitalized in ICU for COVID-19 infection. PATIENTS: Sixty patients hospitalized in ICU (mean duration: 31.9 ± 18.2 d) were recruited 4-8 weeks post discharge from ICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients visited the laboratory on two separate occasions. The first visit was dedicated to quality of life questionnaire, cardiopulmonary exercise testing, whereas measurements of the knee extensors neuromuscular function were performed in the second visit. Maximal oxygen uptake (V o2 max) was 18.3 ± 4.5 mL·min -1 ·kg -1 , representing 49% ± 12% of predicted value, and was significantly correlated with ICU stay/mechanical ventilation (MV) duration ( R = -0.337 to -0.446; p < 0.01 to 0.001), as were maximal voluntary contraction and electrically evoked peak twitch. V o2 max (either predicted or in mL· min -1 ·kg -1 ) was also significantly correlated with key indices of pulmonary function such as predicted forced vital capacity or predicted forced expiratory volume in 1 second ( R = 0.430-0.465; p ≤ 0.001) and neuromuscular function. Both cardiorespiratory fitness and neuromuscular function were correlated with self-reported physical functioning and general health status. CONCLUSIONS: V o2 max was on average only slightly above the 18 mL·min -1 ·kg -1 , that is, the cut-off value known to induce difficulty in performing daily tasks. Overall, although low physical capacities at admission in ICU COVID-19 patients cannot be ruled out to explain the association between V o2 max or neuromuscular function and ICU stay/MV duration, altered cardiorespiratory fitness and neuromuscular function observed in the present study may not be specific to COVID-19 disease but seem applicable to all ICU/MV patients of similar duration.
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COVID-19 , Capacidad Cardiovascular , Cuidados Posteriores , COVID-19/terapia , Humanos , Unidades de Cuidados Intensivos , Oxígeno , Alta del Paciente , Estudios Prospectivos , Calidad de Vida , Respiración ArtificialRESUMEN
Muscle stem cells (MuSCs) reside in a specialized niche that ensures their regenerative capacity. Although we know that innate immune cells infiltrate the niche in response to injury, it remains unclear how MuSCs adapt to this altered environment for initiating repair. Here, we demonstrate that inflammatory cytokine signaling from the regenerative niche impairs the ability of quiescent MuSCs to reenter the cell cycle. The histone H3 lysine 27 (H3K27) demethylase JMJD3, but not UTX, allowed MuSCs to overcome inhibitory inflammation signaling by removing trimethylated H3K27 (H3K27me3) marks at the Has2 locus to initiate production of hyaluronic acid, which in turn established an extracellular matrix competent for integrating signals that direct MuSCs to exit quiescence. Thus, JMJD3-driven hyaluronic acid synthesis plays a proregenerative role that allows MuSC adaptation to inflammation and the initiation of muscle repair.
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Ácido Hialurónico , Inflamación , Histona Demetilasas con Dominio de Jumonji , Músculo Esquelético , Mioblastos Esqueléticos , Regeneración , Nicho de Células Madre , Animales , Ciclo Celular , Histonas , Humanos , Ácido Hialurónico/biosíntesis , Inflamación/metabolismo , Interferón gamma/metabolismo , Interleucina-6 , Histona Demetilasas con Dominio de Jumonji/genética , Histona Demetilasas con Dominio de Jumonji/metabolismo , Ratones , Músculo Esquelético/lesiones , Músculo Esquelético/fisiología , Mioblastos Esqueléticos/metabolismoRESUMEN
Sex differences in muscle fiber-type composition have been documented in several muscle groups while the hamstring muscle fiber-type composition has been poorly characterized. This study aimed to compare the semitendinosus muscle composition between men and women. Biopsy samples were obtained from the semitendinosus muscle of twelve men and twelve women during an anterior cruciate ligament reconstruction. SDH and ATPase activities as well as the size and the proportion of muscle fibers expressing myosin heavy chain (MyHC) isoforms were used to compare muscle composition between men and women. The proportion of SDH-positive muscle fibers was significantly lower (37.4 ± 11.2% vs. 49.3 ± 10.6%, p < 0.05), and the percentage of fast muscle fibers (i.e., based on ATPase activity) was significantly higher (65.8 ± 10.1% vs. 54.8 ± 8.3%, p < 0.05) in men versus women. Likewise, men muscles exhibited a lower percentage of the area that was occupied by MyHC-I labeling (35.6 ± 10.1% vs. 48.7 ± 8.9%; p < 0.05) and a higher percentage of the area that was occupied by MyHC-IIA (38.3 ± 6.7% vs. 32.5 ± 6.5%; p < 0.05) and MyHC-IIX labeling (26.1 ± 9.6% vs. 18.8 ± 8.5%; p = 0.06) as compared with women muscles. The cross-sectional area of MyHC-I, MyHC-IIA, and MyHC-IIX muscle fibers was 31%, 43%, and 50% larger in men as compared with women, respectively. We identified sex differences in semitendinosus muscle composition as illustrated by a faster phenotype and larger muscle size in men as compared with women. This sexual dimorphism might have functional consequences.
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Músculos Isquiosurales , Animales , Femenino , Masculino , Fibras Musculares Esqueléticas , Músculo Esquelético , Cadenas Pesadas de Miosina/genética , Isoformas de Proteínas , Caracteres SexualesRESUMEN
Skeletal muscles are composed of hundreds of multinucleated muscle fibers (myofibers) whose myonuclei are regularly positioned all along the myofiber's periphery except the few ones clustered underneath the neuromuscular junction (NMJ) at the synaptic zone. This precise myonuclei organization is altered in different types of muscle disease, including centronuclear myopathies (CNMs). However, the molecular machinery regulating myonuclei position and organization in mature myofibers remains largely unknown. Conversely, it is also unclear how peripheral myonuclei positioning is lost in the related muscle diseases. Here, we describe the microtubule-associated protein, MACF1, as an essential and evolutionary conserved regulator of myonuclei positioning and maintenance, in cultured mammalian myotubes, in Drosophila muscle, and in adult mammalian muscle using a conditional muscle-specific knockout mouse model. In vitro, we show that MACF1 controls microtubules dynamics and contributes to microtubule stabilization during myofiber's maturation. In addition, we demonstrate that MACF1 regulates the microtubules density specifically around myonuclei, and, as a consequence, governs myonuclei motion. Our in vivo studies show that MACF1 deficiency is associated with alteration of extra-synaptic myonuclei positioning and microtubules network organization, both preceding NMJ fragmentation. Accordingly, MACF1 deficiency results in reduced muscle excitability and disorganized triads, leaving voltage-activated sarcoplasmic reticulum Ca2+ release and maximal muscle force unchanged. Finally, adult MACF1-KO mice present an improved resistance to fatigue correlated with a strong increase in mitochondria biogenesis.
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Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Proteínas de Microfilamentos/metabolismo , Microtúbulos/metabolismo , Mitocondrias Musculares/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Mioblastos Esqueléticos/metabolismo , Unión Neuromuscular/metabolismo , Biogénesis de Organelos , Animales , Línea Celular , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Drosophila melanogaster/ultraestructura , Acoplamiento Excitación-Contracción , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas de Microfilamentos/genética , Microtúbulos/genética , Microtúbulos/ultraestructura , Mitocondrias Musculares/genética , Mitocondrias Musculares/ultraestructura , Fatiga Muscular , Fibras Musculares Esqueléticas/ultraestructura , Fuerza Muscular , Mioblastos Esqueléticos/ultraestructura , Unión Neuromuscular/genética , Unión Neuromuscular/ultraestructura , Factores de TiempoRESUMEN
Mitochondrial diseases are genetic disorders that lead to impaired mitochondrial function, resulting in exercise intolerance and muscle weakness. In patients, muscle fatigue due to defects in mitochondrial oxidative capacities commonly precedes muscle weakness. In mice, deletion of the fast-twitch skeletal muscle-specific Tfam gene (Tfam KO) leads to a deficit in respiratory chain activity, severe muscle weakness and early death. Here, we performed a time-course study of mitochondrial and muscular dysfunctions in 11- and 14-week-old Tfam KO mice, i.e. before and when mice are about to enter the terminal stage, respectively. Although force in the unfatigued state was reduced in Tfam KO mice compared to control littermates (wild type) only at 14â weeks, during repeated submaximal contractions fatigue was faster at both ages. During fatiguing stimulation, total phosphocreatine breakdown was larger in Tfam KO muscle than in wild-type muscle at both ages, whereas phosphocreatine consumption was faster only at 14â weeks. In conclusion, the Tfam KO mouse model represents a reliable model of lethal mitochondrial myopathy in which impaired mitochondrial energy production and premature fatigue occur before muscle weakness and early death.
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Fatiga Muscular , Debilidad Muscular , Animales , Proteínas de Unión al ADN/metabolismo , Proteínas del Grupo de Alta Movilidad/genética , Proteínas del Grupo de Alta Movilidad/metabolismo , Humanos , Ratones , Ratones Noqueados , Mitocondrias/metabolismo , Proteínas Mitocondriales/metabolismo , Fatiga Muscular/fisiología , Debilidad Muscular/complicaciones , Debilidad Muscular/metabolismo , Músculo Esquelético/metabolismo , Factores de Transcripción/metabolismoRESUMEN
OBJECTIVE: Although neuromuscular electrical stimulation (NMES) has been used as a safe and relevant complement to voluntary resistance training, its effectiveness in increasing quadriceps femoris muscle strength and mass in healthy young and older adults has not been determined. The aim of this scoping review was to assess the effects of NMES on quadriceps muscle strength and mass in healthy young and older adults. METHODS: CENTRAL, Pedro, MEDLINE, and PubMed were searched from inception to September 2019. Randomized controlled trials (RCTs) that compared NMES with control group or voluntary resistance training for healthy young and older adults were included. Study characteristics, primary and secondary outcome parameters, and details of the NMES intervention were extracted by 2 reviewers. Only studies for which full text was available in English were included. RESULTS: Thirty-two RCTs including 796 healthy participants were identified as being eligible for young adults, and 5 RCTs including 123 healthy participants were identified as being eligible for older adults. The available evidence strongly suggests that NMES improves quadriceps muscle strength compared with a control group in young adults, but its efficacy seems lower than that of voluntary resistance training. The available limited evidence regarding the effects of NMES on quadriceps muscle mass compared with control in young adults is inconclusive, with 3 RCTs showing positive effects and 3 RCTs not showing positive effects. The very limited available evidence from 5 RCTs in older adults suggests that NMES might be beneficial for increasing quadriceps muscle strength and mass. CONCLUSION: Overall, the evidence indicates that NMES is an efficacious method for increasing quadriceps muscle strength in young adults, whereas its impact on muscle mass requires further investigations. In addition, the effectiveness of NMES needs to be confirmed in older adults on the basis of more high-quality RCTs with larger sample sizes. IMPACT: This scoping review of 37 RCTs including 919 people is the first study, to the authors' knowledge, to show that the use of NMES increases quadriceps muscle strength in young adults and might improve quadriceps muscle strength compared with control interventions in older adults. In both young and older adults, the effects of NMES on quadriceps muscle mass are still unclear.
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Terapia por Estimulación Eléctrica/métodos , Debilidad Muscular/terapia , Educación y Entrenamiento Físico/métodos , Músculo Cuádriceps/fisiología , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Músculo Esquelético/fisiología , Adulto JovenRESUMEN
Low-frequency and high-frequency wide-pulse neuromuscular electrical stimulation (NMES) can generate extra torque (ET) via afferent pathways. Superimposing tendon vibration (TV) to NMES can increase the activation of these afferent pathways and favor ET generation. Knowledge of the characteristics of ET is essential to implement these stimulation paradigms in clinical practice. Thus, we aimed to investigate the effects of frequency and TV superimposition on the occurrence and magnitude of ET in response to wide-pulse NMES. NMES-induced isometric plantar flexion torque was recorded in 30 healthy individuals who performed five NMES protocols: wide-pulse low-frequency (1 ms; 20 Hz; WPLF) and wide-pulse high-frequency (1 ms; 100 Hz; WPHF) without and with superimposed TV (1 mm; 100 Hz) and conventional NMES (50 µs; 20 Hz; reference protocol). Each NMES protocol consisted of three 20-s trains interspersed by 90 s of rest, with NMES intensity being adjusted to reach 10% of maximal voluntary contraction. The ET occurrence was similar for WPLF and WPHF (P = 0.822). In the responders, the ET magnitude was greater for WPHF than WPLF (P < 0.001). There was no effect of superimposed TV on ET characteristics. This study reported an effect of NMES frequency on ET magnitude, whereas TV superimposition did not affect this parameter. In the context of our experimental design decisions, the present findings question the clinical use of wide-pulse NMES and its combination with superimposed TV. Yet, further research is needed to maximize force production through the occurrence and magnitude of ET.NEW & NOTEWORTHY This study is the first to assess the effect of stimulation frequency and superimposed tendon vibration on extra torque characteristics generated by wide-pulse neuromuscular electrical stimulation. The percentage of subjects showing extra torque (i.e., considered as responders) was similar for low-frequency and high-frequency wide-pulse neuromuscular electrical stimulation. In the responders, the extra torque was greater for high-frequency than for low-frequency wide-pulse neuromuscular electrical stimulation. The superimposition of tendon vibration had no effect on extra torque occurrence or magnitude.
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Músculo Esquelético , Vibración , Estimulación Eléctrica , Humanos , Contracción Muscular , Tendones , TorqueRESUMEN
Nemaline myopathy, a disease of the actin-based thin filament, is one of the most frequent congenital myopathies. To date, no specific therapy is available to treat muscle weakness in nemaline myopathy. We tested the ability of tirasemtiv, a fast skeletal troponin activator that targets the thin filament, to augment muscle force-both in vivo and in vitro-in a nemaline myopathy mouse model with a mutation (H40Y) in Acta1. In Acta1H40Y mice, treatment with tirasemtiv increased the force response of muscles to submaximal stimulation frequencies. This resulted in a reduced energetic cost of force generation, which increases the force production during a fatigue protocol. The inotropic effects of tirasemtiv were present in locomotor muscles and, albeit to a lesser extent, in respiratory muscles, and they persisted during chronic treatment, an important finding as respiratory failure is the main cause of death in patients with congenital myopathy. Finally, translational studies on permeabilized muscle fibers isolated from a biopsy of a patient with the ACTA1H40Y mutation revealed that at physiological Ca2+ concentrations, tirasemtiv increased force generation to values that were close to those generated in muscle fibers of healthy subjects. These findings indicate the therapeutic potential of fast skeletal muscle troponin activators to improve muscle function in nemaline myopathy due to the ACTA1H40Y mutation, and future studies should assess their merit for other forms of nemaline myopathy and for other congenital myopathies.
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Actinas , Miopatías Nemalínicas , Actinas/genética , Animales , Humanos , Imidazoles , Ratones , Músculo Esquelético/patología , Mutación , Miopatías Nemalínicas/tratamiento farmacológico , Miopatías Nemalínicas/genética , Pirazinas/uso terapéuticoRESUMEN
Around one third of intensive care unit (ICU) patients will develop severe neuromuscular alterations, known as intensive care unit-acquired weakness (ICUAW), during their stay. The diagnosis of ICUAW is difficult and often delayed as a result of sedation or delirium. Indeed, the clinical evaluation of both Medical Research Council score and maximal voluntary force (e.g., using handgrip and/or handheld dynamometers), two independent predictors of mortality, can be performed only in awake and cooperative patients. Transcutaneous electrical/magnetic stimulation applied over motor nerves combined with the development of dedicated ergometer have recently been introduced in ICU patients in order to propose an early and non-invasive measurement of evoked force. The aim of this narrative review is to summarize the different tools allowing bedside force evaluation in ICU patients and the related experimental protocols. We suggest that non-invasive electrical and/or magnetic evoked force measurements could be a relevant strategy to characterize muscle weakness in the early phase of ICU and diagnose ICUAW.
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Potenciales Evocados , Estudios Transversales , Ergometría/instrumentación , Fuerza de la Mano/fisiología , Humanos , Unidades de Cuidados Intensivos/organización & administración , Unidades de Cuidados Intensivos/tendencias , Debilidad Muscular/etiología , Debilidad Muscular/fisiopatología , NarraciónRESUMEN
Understanding the physiological/mechanical mechanisms leading to skeletal muscle damage remains one of the challenges in muscle physiology. This review presents the functional, structural, and cellular consequences of electrically evoked submaximal isometric contractions that can elicit severe and localized skeletal muscle damage. Hypotheses related to underlying physiological and mechanical processes involved in severe and localized muscle damage also are discussed.
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Contracción Muscular , Músculo Esquelético , Estimulación Eléctrica , Humanos , Contracción IsométricaRESUMEN
Understanding the circuits that promote an efficient resolution of inflammation is crucial to deciphering the molecular and cellular processes required to promote tissue repair. Macrophages play a central role in the regulation of inflammation, resolution, and repair/regeneration. Using a model of skeletal muscle injury and repair, herein we identified annexin A1 (AnxA1) as the extracellular trigger of macrophage skewing toward a pro-reparative phenotype. Brought into the injured tissue initially by migrated neutrophils, and then overexpressed in infiltrating macrophages, AnxA1 activated FPR2/ALX receptors and the downstream AMPK signaling cascade, leading to macrophage skewing, dampening of inflammation, and regeneration of muscle fibers. Mice lacking AnxA1 in all cells or only in myeloid cells displayed a defect in this reparative process. In vitro experiments recapitulated these properties, with AMPK-null macrophages lacking AnxA1-mediated polarization. Collectively, these data identified the AnxA1/FPR2/AMPK axis as an important pathway in skeletal muscle injury regeneration.