RESUMEN
Several factors affect muscle protein synthesis (MPS) in the postabsorptive state. Extreme physical inactivity (e.g., bedrest) may reduce basal MPS, whereas walking may augment basal MPS. We hypothesized that outpatients would have a higher postabsorptive MPS than inpatients. To test this hypothesis, we conducted a retrospective analysis. We compared 152 outpatient participants who arrived at the research site the morning of the MPS assessment with 350 Inpatient participants who had an overnight stay in the hospital unit before the MPS assessment the following morning. We used stable isotopic methods and collected vastus lateralis biopsies â¼2 to 3 h apart to assess mixed MPS. MPS was â¼12% higher (P < 0.05) for outpatients than inpatients. Within a subset of participants, we discovered that after instruction to limit activity, outpatients (n = 13) took 800 to 900 steps in the morning to arrive at the unit, seven times more steps than inpatients (n = 12). We concluded that an overnight stay in the hospital as an inpatient is characterized by reduced morning activity and causes a slight but significant reduction in MPS compared with participants studied as outpatients. Researchers should be aware of physical activity status when designing and interpreting MPS results.NEW & NOTEWORTHY The postabsorptive muscle protein synthesis rate is lower in the morning after an overnight inpatient hospital stay compared with an outpatient visit. Although only a minimal amount of steps was conducted by outpatients (â¼900), this was enough to increase postabsorptive muscle protein synthesis rate.
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Pacientes Internos , Proteínas Musculares , Humanos , Pacientes Ambulatorios , Estudios Retrospectivos , Biosíntesis de ProteínasRESUMEN
BACKGROUND: Regulation of mechanistic target of rapamycin complex 1 (mTORC1) plays an important role in aging and nutrition. For example, caloric restriction reduces mTORC1 signaling and extends lifespan, whereas nutrient abundance and obesity increase mTORC1 signaling and reduce lifespan. Skeletal muscle-specific knockout (KO) of DEP domain-containing 5 protein (DEPDC5) results in constitutively active mTORC1 signaling, muscle hypertrophy and an increase in mitochondrial respiratory capacity. The metabolic profile of skeletal muscle, in the setting of hyperactive mTORC1 signaling, is not well known. OBJECTIVES: To determine the metabolomic and lipidomic signature in skeletal muscle from female and male wild-type (WT) and DEPDC5 KO mice. METHODS: Tibialis anterior (TA) muscles from WT and transgenic (conditional skeletal muscle-specific DEPDC5 KO) were obtained from female and male adult mice. Polar metabolites and lipids were extracted using a Bligh-Dyer extraction from 5 samples per group and identified and quantified by LC-MS/MS. Resulting analyte peak areas were analyzed with t-test, analysis of variance, and Volcano plots for group comparisons (e.g., WT compared with KO) and multivariate statistical analysis for genotype and sex comparisons. RESULTS: A total of 162 polar metabolites (organic acids, amino acids, and amines and acyl carnitines) and 1141 lipid metabolites were detected in TA samples by LC-MS/MS. Few polar metabolites showed significant differences in KO muscles compared with WT within the same sex group. P-aminobenzoic acid, ß-alanine, and dopamine were significantly higher in KO male muscle whereas erythrose-4-phosphate and oxoglutaric acid were significantly reduced in KO females. The lipidomic profile of the KO groups revealed an increase of muscle phospholipids and reduced triacylglycerol and diacylglycerol compared with the WT groups. CONCLUSIONS: Sex differences were detected in polar metabolome and lipids were dependent on genotype. The metabolomic profile of mice with hyperactive skeletal muscle mTORC1 is consistent with an upregulation of mitochondrial function and amino acid utilization for protein synthesis.
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Lipidómica , Espectrometría de Masas en Tándem , Femenino , Masculino , Ratones , Animales , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Cromatografía Liquida , Músculo Esquelético/metabolismo , Ratones Noqueados , LípidosRESUMEN
INTRODUCTION: Mitochondrial dysfunction is implicated in the metabolic myopathy accompanying peripheral artery disease (PAD) and critical limb ischemia (CLI). Type-2 diabetes mellitus (T2DM) is a major risk factor for PAD development and progression to CLI and may also independently be related to mitochondrial dysfunction. We set out to determine the effect of T2DM in the relationship between CLI and muscle mitochondrial respiratory capacity and coupling control. METHODS: We studied CLI patients undergoing revascularization procedures or amputation, and non-CLI patients with or without T2DM of similar age. Mitochondrial respiratory capacity and function were determined in lower limb permeabilized myofibers by high-resolution respirometry. RESULTS: Fourteen CLI patients (65 ± 10y) were stratified into CLI patients with (n = 8) or without (n = 6) T2DM and were compared to non-CLI patients with (n = 18; 69 ± 5y) or without (n = 19; 71 ± 6y) T2DM. Presence of CLI but not T2DM had a marked impact on all mitochondrial respiratory states in skeletal muscle, adjusted for the effects of sex. Leak respiration (State 2, P < 0.025 and State 4o, P < 0.01), phosphorylating respiration (P < 0.001), and maximal respiration in the uncoupled state (P < 0.001), were all suppressed in CLI patients, independent of T2DM. T2DM had no significant effect on mitochondrial respiratory capacity and function in adults without CLI. CONCLUSIONS: Skeletal muscle mitochondrial respiratory capacity was blunted by â¼35% in patients with CLI. T2DM was not associated with muscle oxidative capacity and did not moderate the relationship between muscle mitochondrial respiratory capacity and CLI.
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Diabetes Mellitus , Enfermedad Arterial Periférica , Adulto , Humanos , Isquemia Crónica que Amenaza las Extremidades , Músculo Esquelético , Enfermedad Arterial Periférica/complicaciones , Factores de Riesgo , Metabolismo Energético , Isquemia/complicaciones , Isquemia/metabolismo , Resultado del Tratamiento , Recuperación del MiembroRESUMEN
Activating transcription factor 4 (ATF4) is a multifunctional transcription regulatory protein in the basic leucine zipper superfamily. ATF4 can be expressed in most if not all mammalian cell types, and it can participate in a variety of cellular responses to specific environmental stresses, intracellular derangements, or growth factors. Because ATF4 is involved in a wide range of biological processes, its roles in human health and disease are not yet fully understood. Much of our current knowledge about ATF4 comes from investigations in cultured cell models, where ATF4 was originally characterized and where further investigations continue to provide new insights. ATF4 is also an increasingly prominent topic of in vivo investigations in fully differentiated mammalian cell types, where our current understanding of ATF4 is less complete. Here, we review some important high-level concepts and questions concerning the basic biology of ATF4. We then discuss current knowledge and emerging questions about the in vivo role of ATF4 in one fully differentiated cell type, mammalian skeletal muscle fibers.
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Factor de Transcripción Activador 4 , Atrofia Muscular , Factor de Transcripción Activador 4/genética , Factor de Transcripción Activador 4/metabolismo , Animales , Biología , Diferenciación Celular , Humanos , Mamíferos , Fibras Musculares Esqueléticas/metabolismo , Atrofia Muscular/etiologíaRESUMEN
mTORC1 regulates protein synthesis and in turn is regulated by growth factors, energy status, and amino acid availability. In kidney cell (HEK293-T) culture, the GAP activity toward RAG (GATOR1) protein complex suppresses activation of the RAG A/B-RAG C/D heterodimer when amino acids are insufficient. During amino acid sufficiency, the RAG heterodimer recruits mTORC1 to the lysosomal membrane where its interaction with Ras homolog enriched in brain (Rheb) stimulates mTORC1's kinase activity. The DEP domain containing 5 (DEPDC5) protein, a GATOR1 subunit, causes familial focal epilepsy when mutated, and global knockout of the Depdc5 gene is embryonically lethal. To study the function of DEPDC5 in skeletal muscle, we generated a muscle-specific inducible Depdc5 knockout mouse, hypothesizing that knocking out Depdc5 in muscle would make mTORC1 constitutively active, causing hypertrophy and improving muscle function. Examining mTORC1 signaling, morphology, mitochondrial respiratory capacity, contractile function, and applied physical function (e.g. rotarod, treadmill, grip test, and wheel running), we observed that mTORC1 activity was significantly higher in knockout (KO) mice, indicated by the increased phosphorylation of mTOR and its downstream effectors (by 118% for p-mTOR/mTOR, 114% for p-S6K1/S6K1, and 35% for p-4E-BP1/4E-BP1). The KO animals also exhibited soleus muscle cell hypertrophy and a 2.5-fold increase in mitochondrial respiratory capacity. However, contrary to our hypothesis, neither physical nor contractile function improved. In conclusion, DEPDC5 depletion in adult skeletal muscle removes GATOR1 inhibition of mTORC1, resulting in muscle hypertrophy and increased mitochondrial respiration, but does not improve overall muscle quality and function.
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Proteínas Activadoras de GTPasa/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Mitocondrias/metabolismo , Músculo Esquelético/metabolismo , Animales , Células Cultivadas , Proteínas Activadoras de GTPasa/deficiencia , Células HEK293 , Humanos , Ratones , Ratones Noqueados , Ratones Transgénicos , Músculo Esquelético/patología , Transducción de SeñalRESUMEN
Older adults undergoing age-related decrements in muscle health can benefit substantially from resistance exercise training, a potent stimulus for whole muscle and myofiber hypertrophy, neuromuscular performance gains, and improved functional mobility. With the use of advancing technologies, research continues to elucidate the mechanisms of and heterogeneity in adaptations to resistance exercise training beyond differences in exercise prescription. This review highlights the current knowledge in these areas and emphasizes knowledge gaps that require future attention of the field.
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Adaptación Fisiológica , Envejecimiento , Fuerza Muscular , Músculo Esquelético/fisiología , Entrenamiento de Fuerza , Envejecimiento Saludable , Humanos , Músculo Esquelético/inervación , Músculo Esquelético/metabolismoRESUMEN
BACKGROUND: Muscle protein synthesis (MPS) can be stimulated by ingestion of protein sources, such as whey, casein, or soy. Protein supplementation can enhance muscle protein synthesis after exercise and may preserve skeletal muscle mass and function in aging adults. Therefore, identifying protein sources with higher anabolic potency is of high significance. OBJECTIVE: The aim of this study was to determine the anabolic potency and efficacy of a novel whey protein hydrolysate mixture (WPH) on mechanistic target of rapamycin complex 1 (mTORC1) signaling and skeletal MPS in healthy young subjects. METHODS: Ten young men (aged 28.7 ± 3.6 y, 25.2 ± 2.9 kg/m2 body mass index [BMI]) were recruited into a double-blind two-way crossover trial. Subjects were randomized to receive either 0.08 g/kg of body weight (BW) of WPH or an intact whey protein (WHEY) mixture during stable isotope infusion experiments. Fractional synthetic rate, leucine and phenylalanine kinetics, and markers of amino acid sensing were assessed as primary outcomes before and 1-3 h after protein ingestion using a repeated measures mixed model. RESULTS: Blood leucine concentration, delivery of leucine to muscle, transport of leucine from blood into muscle and intracellular muscle leucine concentration significantly increased to a similar extent 1 h after ingestion of both mixtures (P < 0.05). Phosphorylation of S6K1 (i.e. a marker of mTORC1 activation) increased equally by â¼20% 1-h postingestion (P < 0.05). Ingestion of WPH and WHEY increased mixed MPS similarly in both groups by â¼43% (P < 0.05); however, phenylalanine utilization for synthesis increased in both treatments 1-h postingestion but remained elevated 3-h postingestion only in the WPH group (P < 0.05). CONCLUSIONS: We conclude that a small dose of WPH effectively increases leucine transport into muscle, activating mTORC1 and stimulating MPS in young men. WPH anabolic potency and efficacy for promoting overall muscle protein anabolism is similar to WHEY, an intact protein source. This trial was registered at clinicaltrials.gov as NCT03313830.
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Aminoácidos/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Proteínas Musculares/biosíntesis , Músculo Esquelético/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Proteína de Suero de Leche/farmacología , Adulto , Aminoácidos/sangre , Glucemia/metabolismo , Estudios Cruzados , Método Doble Ciego , Humanos , Hidrólisis , Insulina/metabolismo , Ácido Láctico/metabolismo , Masculino , Músculo Esquelético/metabolismoRESUMEN
Background: The muscle protein anabolic response to contraction and feeding may be blunted in older adults. Acute bouts of exercise can improve the ability of amino acids to stimulate muscle protein synthesis (MPS) by activating mechanistic target of rapamycin complex 1 (mTORC1) signaling, but it is not known whether exercise training may improve muscle sensitivity to amino acid availability. Objective: The aim of this study was to determine if muscle protein anabolism is resistant to essential amino acids (EAAs) and whether resistance exercise training (RET) improves muscle sensitivity to EAA in healthy older adults. Methods: In a longitudinal study, 19 healthy older adults [mean ± SD age: 71 ± 4 y body mass index (kg/m2): 28 ± 3] were trained for 12 wk with a whole-body program of progressive RET (60-75% 1-repetition maximum). Body composition, strength, and metabolic health were measured pre- and posttraining. We also performed stable isotope infusion experiments with muscle biopsies pre- and posttraining to measure MPS and markers of amino acid sensing in the basal state and in response to 6.8 g of EAA ingestion. Results: RET increased muscle strength by 16%, lean mass by 2%, and muscle cross-sectional area by 27% in healthy older adults (P < 0.05). MPS and mTORC1 signaling (i.e., phosphorylation status of protein kinase B, 4E binding protein 1, 70-kDa S6 protein kinase, and ribosomal protein S6) increased after EAA ingestion (P < 0.05) pre- and posttraining. RET increased basal MPS by 36% (P < 0.05); however, RET did not affect the response of MPS and mTORC1 signaling to EAA ingestion. Conclusion: RET increases strength and basal MPS, promoting hypertrophy in healthy older adults. In these subjects, a small dose of EAAs stimulates muscle mTORC1 signaling and MPS, and this response to EAAs does not improve after RET. Our data indicate that anabolic resistance to amino acids may not be a problem in healthy older adults. This trial was registered at www.clinicaltrials.gov as NCT02999802.
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Aminoácidos Esenciales/farmacología , Proteínas Musculares/metabolismo , Músculo Esquelético/anatomía & histología , Músculo Esquelético/fisiología , Entrenamiento de Fuerza , Anciano , Aminoácidos Esenciales/metabolismo , Biomarcadores , Biopsia , Composición Corporal , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Estudios Longitudinales , Masculino , Músculo Esquelético/patología , Transducción de Señal , Técnicas de Cultivo de TejidosRESUMEN
PURPOSE: Acute bouts of resistance exercise and subsequent training alters protein turnover in skeletal muscle. The mechanisms responsible for the changes in basal post-absorptive protein turnover and its impact on muscle hypertrophy following resistance exercise training are unknown. Our goal was to determine whether post-absorptive muscle protein turnover following 12 weeks of resistance exercise training (RET) plays a role in muscle hypertrophy. In addition, we were interested in determining potential molecular mechanisms responsible for altering post-training muscle protein turnover. METHODS: Healthy young men (n = 31) participated in supervised whole body progressive RET at 60-80% 1 repetition maximum (1-RM), 3 days/week for 3 months. Pre- and post-training vastus lateralis muscle biopsies and blood samples taken during an infusion of 13C6 and 15N phenylalanine and were used to assess skeletal muscle protein turnover in the post-absorptive state. Lean body mass (LBM), muscle strength (determined by dynamometry), vastus lateralis muscle thickness (MT), myofiber type-specific cross-sectional area (CSA), and mRNA were assessed pre- and post-RET. RESULTS: RET increased strength (12-40%), LBM (~5%), MT (~15%) and myofiber CSA (~20%) (p < 0.05). Muscle protein synthesis (MPS) increased 24% while muscle protein breakdown (MPB) decreased 21%, respectively. These changes in protein turnover resulted in an improved net muscle protein balance in the basal state following RET. Further, the change in basal MPS is positively associated (r = 0.555, p = 0.003) with the change in muscle thickness. CONCLUSION: Post-absorptive muscle protein turnover is associated with muscle hypertrophy during resistance exercise training.
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Proteínas Musculares/metabolismo , Músculo Cuádriceps/metabolismo , Entrenamiento de Fuerza , Absorciometría de Fotón , Humanos , Masculino , Fuerza Muscular , Músculo Cuádriceps/diagnóstico por imagen , Músculo Cuádriceps/fisiología , Adulto JovenRESUMEN
KEY POINTS: Severe burns result in profound skeletal muscle atrophy that hampers recovery. The activity of skeletal muscle stem cells, satellite cells, acutely following a severe burn is unknown and may contribute to the recovery of lean muscle. Severe burn injury induces skeletal muscle regeneration and myonuclear apoptosis. Satellite cells undergo concurrent apoptosis and activation acutely following a burn, with a net reduction in satellite cell content compared to healthy controls. The activation and apoptosis of satellite cells probably impacts the recovery of lean tissue following a severe burn, contributing to prolonged frailty in burn survivors. ABSTRACT: Severe burns result in profound skeletal muscle atrophy; persistent muscle loss and weakness are major complications that hamper recovery from burn injury. Many factors contribute to the erosion of muscle mass following burn trauma and we propose that an impaired muscle satellite cell response is key in the aetiology of burn-induced cachexia. Muscle biopsies from the m. vastus lateralis were obtained from 12 male pediatric burn patients (>30% total body surface area burn) and 12 young, healthy male subjects. Satellite cell content, activation and apoptosis were determined via immunohistochemistry, as were muscle fibre regeneration and myonuclear apoptosis. Embryonic myosin heavy chain expression and central nucleation, indices of skeletal muscle regeneration, were elevated in burn patients (P < 0.05). Myonuclear apoptosis, quantified by TUNEL positive myonuclei and cleaved caspase-3 positive myonuclei, was also elevated in burn patients (P < 0.05). Satellite cell content was reduced in burn patients, with approximately 20% of satellite cells positive for TUNEL staining, indicating DNA damage associated with apoptosis (P < 0.05). Additionally, a significant percentage of satellite cells in burn patients expressed Ki67, a marker for cellular proliferation (P < 0.05). Satellite cell activation was also observed in burn patients with increased expression of MyoD compared to healthy controls (P < 0.05). Robust skeletal muscle atrophy occurs after burn injury, even in muscles located distally to the site of injury. The activation and apoptosis of satellite cells probably impacts the recovery of lean tissue following a severe burn, contributing to prolonged frailty in burn survivors.
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Apoptosis , Quemaduras/fisiopatología , Músculo Esquelético/fisiología , Células Satélite del Músculo Esquelético/fisiología , Adolescente , Adulto , Quemaduras/metabolismo , Caspasa 3/metabolismo , Niño , Humanos , Masculino , Músculo Esquelético/metabolismo , Proteína MioD/metabolismo , Cadenas Pesadas de Miosina/metabolismo , Factor de Transcripción PAX7/metabolismo , Regeneración , Células Satélite del Músculo Esquelético/metabolismo , Adulto JovenRESUMEN
Burn trauma results in prolonged hypermetabolism and skeletal muscle wasting. How hypermetabolism contributes to muscle wasting in burn patients remains unknown. We hypothesized that oxidative stress, cytosolic protein degradation, and mitochondrial stress as a result of hypermetabolism contribute to muscle cachexia postburn. Patients (n = 14) with burns covering >30% of their total body surface area were studied. Controls (n = 13) were young healthy adults. We found that burn patients were profoundly hypermetabolic at both the skeletal muscle and systemic levels, indicating increased oxygen consumption by mitochondria. In skeletal muscle of burn patients, concurrent activation of mTORC1 signaling and elevation in the fractional synthetic rate paralleled increased levels of proteasomes and elevated fractional breakdown rate. Burn patients had greater levels of oxidative stress markers as well as higher expression of mtUPR-related genes and proteins, suggesting that burns increased mitochondrial stress and protein damage. Indeed, upregulation of cytoprotective genes suggests hypermetabolism-induced oxidative stress postburn. In parallel to mtUPR activation postburn, mitochondrial-specific proteases (LONP1 and CLPP) and mitochondrial translocases (TIM23, TIM17B, and TOM40) were upregulated, suggesting increased mitochondrial protein degradation and transport of preprotein, respectively. Our data demonstrate that proteolysis occurs in both the cytosolic and mitochondrial compartments of skeletal muscle in severely burned patients. Increased mitochondrial protein turnover may be associated with increased protein damage due to hypermetabolism-induced oxidative stress and activation of mtUPR. Our results suggest a novel role for the mitochondria in burn-induced cachexia.
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Quemaduras/metabolismo , Caquexia/metabolismo , Mitocondrias Musculares/metabolismo , Músculo Esquelético/metabolismo , Estrés Oxidativo , Consumo de Oxígeno , ARN Mensajero/metabolismo , Proteasas ATP-Dependientes/genética , Proteasas ATP-Dependientes/metabolismo , Adolescente , Adulto , Western Blotting , Superficie Corporal , Quemaduras/complicaciones , Quemaduras/genética , Caquexia/etiología , Caquexia/genética , Estudios de Casos y Controles , Endopeptidasa Clp/genética , Endopeptidasa Clp/metabolismo , Femenino , Humanos , Masculino , Diana Mecanicista del Complejo 1 de la Rapamicina , Metabolismo , Persona de Mediana Edad , Mitocondrias/metabolismo , Proteínas de Transporte de Membrana Mitocondrial/genética , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Proteínas del Complejo de Importación de Proteínas Precursoras Mitocondriales , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Complejos Multiproteicos/genética , Complejos Multiproteicos/metabolismo , Proteínas Musculares/metabolismo , Complejo de la Endopetidasa Proteasomal/genética , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteolisis , Reacción en Cadena en Tiempo Real de la Polimerasa , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo , Regulación hacia Arriba , Adulto JovenRESUMEN
The goal of this critical review is to comprehensively assess the evidence for the molecular, physiologic, and phenotypic skeletal muscle responses to resistance exercise (RE) combined with the nutritional intervention of protein and/or amino acid (AA) ingestion in young adults. We gathered the literature regarding the translational response in human skeletal muscle to acute exposure to RE and protein/AA supplements and the literature describing the phenotypic skeletal muscle adaptation to RE and nutritional interventions. Supplementation of protein/AAs with RE exhibited clear protein dose-dependent effects on translational regulation (protein synthesis) through mammalian target of rapamycin complex 1 (mTORC1) signaling, which was most apparent through increases in p70 ribosomal protein S6 kinase 1 (S6K1) phosphorylation, compared with postexercise recovery in the fasted or carbohydrate-fed state. These acute findings were critically tested via long-term exposure to RE training (RET) and protein/AA supplementation, and it was determined that a diminishing protein/AA supplement effect occurs over a prolonged exposure stimulus after exercise training. Furthermore, we found that protein/AA supplements, combined with RET, produced a positive, albeit minor, effect on the promotion of lean mass growth (when assessed in >20 participants/treatment); a negligible effect on muscle mass; and a negligible to no additional effect on strength. A potential concern we discovered was that the majority of the exercise training studies were underpowered in their ability to discern effects of protein/AA supplementation. Regardless, even when using optimal methodology and large sample sizes, it is clear that the effect size for protein/AA supplementation is low and likely limited to a subset of individuals because the individual variability is high. With regard to nutritional intakes, total protein intake per day, rather than protein timing or quality, appears to be more of a factor on this effect during long-term exercise interventions. There were no differences in strength or mass/muscle mass on RET outcomes between protein types when a leucine threshold (>2 g/dose) was reached. Future research with larger sample sizes and more homogeneity in design is necessary to understand the underlying adaptations and to better evaluate the individual variability in the muscle-adaptive response to protein/AA supplementation during RET.
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Aminoácidos/farmacología , Proteínas en la Dieta/farmacología , Suplementos Dietéticos , Proteínas Musculares/biosíntesis , Músculo Esquelético/efectos de los fármacos , Biosíntesis de Proteínas , Entrenamiento de Fuerza , Aminoácidos/metabolismo , Proteínas en la Dieta/metabolismo , Humanos , Músculo Esquelético/metabolismoRESUMEN
BACKGROUND: To our knowledge the efficacy of soy-dairy protein blend (PB) supplementation with resistance exercise training (RET) has not been evaluated in a longitudinal study. OBJECTIVE: Our aim was to determine the effect of PB supplementation during RET on muscle adaptation. METHODS: In this double-blind randomized clinical trial, healthy young men [18-30 y; BMI (in kg/m(2)): 25 ± 0.5] participated in supervised whole-body RET at 60-80% 1-repetition maximum (1-RM) for 3 d/wk for 12 wk with random assignment to daily receive 22 g PB (n = 23), whey protein (WP) isolate (n = 22), or an isocaloric maltodextrin (carbohydrate) placebo [(MDP) n = 23]. Serum testosterone, muscle strength, thigh muscle thickness (MT), myofiber cross-sectional area (mCSA), and lean body mass (LBM) were assessed before and after 6 and 12 wk of RET. RESULTS: All treatments increased LBM (P < 0.001). ANCOVA did not identify an overall treatment effect at 12 wk (P = 0.11). There tended to be a greater change in LBM from baseline to 12 wk in the PB group than in the MDP group (0.92 kg; 95% CI: -0.12, 1.95 kg; P = 0.09); however, changes in the WP and MDP groups did not differ. Pooling data from combined PB and WP treatments showed a trend for greater change in LBM from baseline to 12 wk compared with MDP treatment (0.69 kg; 95% CI: -0.08, 1.46 kg; P = 0.08). Muscle strength, mCSA, and MT increased (P < 0.05) similarly for all treatments and were not different (P > 0.10) between treatments. Testosterone was not altered. CONCLUSIONS: PB supplementation during 3 mo of RET tended to slightly enhance gains in whole-body and arm LBM, but not leg muscle mass, compared with RET without protein supplementation. Although protein supplementation minimally enhanced gains in LBM of healthy young men, there was no enhancement of gains in strength. This trial was registered at clinicaltrials.gov as NCT01749189.
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Suplementos Dietéticos , Ejercicio Físico , Músculo Esquelético/efectos de los fármacos , Entrenamiento de Fuerza , Proteína de Suero de Leche/administración & dosificación , Adaptación Fisiológica , Adolescente , Adulto , Composición Corporal , Índice de Masa Corporal , Peso Corporal , Método Doble Ciego , Humanos , Masculino , Fuerza Muscular/efectos de los fármacos , Testosterona/sangre , Adulto JovenRESUMEN
BACKGROUND: Previous work demonstrated that a soy-dairy protein blend (PB) prolongs hyperaminoacidemia and muscle protein synthesis in young adults after resistance exercise. OBJECTIVE: We investigated the effect of PB in older adults. We hypothesized that PB would prolong hyperaminoacidemia, enhancing mechanistic target of rapamycin complex 1 (mTORC1) signaling and muscle protein anabolism compared with a whey protein isolate (WPI). METHODS: This double-blind, randomized controlled trial studied men 55-75 y of age. Subjects consumed 30 g protein from WPI or PB (25% soy, 25% whey, and 50% casein) 1 h after leg extension exercise (8 sets of 10 repetitions at 70% one-repetition maximum). Blood and muscle amino acid concentrations and basal and postexercise muscle protein turnover were measured by using stable isotopic methods. Muscle mTORC1 signaling was assessed by immunoblotting. RESULTS: Both groups increased amino acid concentrations (P < 0.05) and mTORC1 signaling after protein ingestion (P < 0.05). Postexercise fractional synthesis rate (FSR; P ≥ 0.05), fractional breakdown rate (FBR; P ≥ 0.05), and net balance (P = 0.08) did not differ between groups. WPI increased FSR by 67% (mean ± SEM: rest: 0.05% ± 0.01%; postexercise: 0.09% ± 0.01%; P < 0.05), decreased FBR by 46% (rest: 0.17% ± 0.01%; postexercise: 0.09% ± 0.03%; P < 0.05), and made net balance less negative (P < 0.05). PB ingestion did not increase FSR (rest: 0.07% ± 0.03%; postexercise: 0.09% ± 0.01%; P ≥ 0.05), tended to decrease FBR by 42% (rest: 0.25% ± 0.08%; postexercise: 0.15% ± 0.08%; P = 0.08), and made net balance less negative (P < 0.05). Within-group percentage of change differences were not different between groups for FSR, FBR, or net balance (P ≥ 0.05). CONCLUSIONS: WPI and PB ingestion after exercise in older men induced similar responses in hyperaminoacidemia, mTORC1 signaling, muscle protein synthesis, and breakdown. These data add new evidence for the use of whey or soy-dairy PBs as targeted nutritional interventions to counteract sarcopenia. This trial was registered at clinicaltrials.gov as NCT01847261.
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Complejos Multiproteicos/metabolismo , Músculo Esquelético/metabolismo , Transducción de Señal/fisiología , Proteínas de Soja/farmacología , Serina-Treonina Quinasas TOR/metabolismo , Proteína de Suero de Leche/farmacología , Anciano , Envejecimiento , Bebidas/análisis , Método Doble Ciego , Ejercicio Físico , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/fisiología , Humanos , Masculino , Diana Mecanicista del Complejo 1 de la Rapamicina , Persona de Mediana Edad , Complejos Multiproteicos/genética , Músculo Esquelético/efectos de los fármacos , Proteínas de Soja/química , Serina-Treonina Quinasas TOR/genéticaRESUMEN
Mitochondrial health is critical to physiological function, particularly in tissues with high ATP turnover, such as striated muscle. It has been postulated that derangements in skeletal muscle mitochondrial function contribute to impaired physical function in older adults. Here, we determined mitochondrial respiratory capacity and coupling control in skeletal muscle biopsies obtained from young and older adults. Twenty-four young (28 ± 7 yr) and thirty-one older (62 ± 8 yr) adults were studied. Mitochondrial respiration was determined in permeabilized myofibers from the vastus lateralis after the addition of substrates oligomycin and CCCP. Thereafter, mitochondrial coupling control was calculated. Maximal coupled respiration (respiration linked to ATP production) was lower in muscle from older vs. young subjects (P < 0.01), as was maximal uncoupled respiration (P = 0.06). Coupling control in response to the ATP synthase inhibitor oligomycin was lower in older adults (P < 0.05), as was the mitochondria flux control ratio, coupled respiration normalized to maximal uncoupled respiration (P < 0.05). Calculation of respiratory function revealed lower respiration linked to ATP production (P < 0.001) and greater reserve respiration (P < 0.01); i.e., respiratory capacity not used for phosphorylation in muscle from older adults. We conclude that skeletal muscle mitochondrial respiratory capacity and coupling control decline with age. Lower respiratory capacity and coupling efficiency result in a reduced capacity for ATP production in skeletal muscle of older adults.
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Envejecimiento , Regulación hacia Abajo , Complejo II de Transporte de Electrones/metabolismo , Complejo I de Transporte de Electrón/metabolismo , Mitocondrias Musculares/metabolismo , Músculo Esquelético/crecimiento & desarrollo , Fosforilación Oxidativa , Adulto , Anciano , Anciano de 80 o más Años , Carbonil Cianuro m-Clorofenil Hidrazona/farmacología , Estudios de Cohortes , Regulación hacia Abajo/efectos de los fármacos , Complejo I de Transporte de Electrón/antagonistas & inhibidores , Complejo II de Transporte de Electrones/antagonistas & inhibidores , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mitocondrias Musculares/efectos de los fármacos , Mitocondrias Musculares/enzimología , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Miofibrillas/efectos de los fármacos , Miofibrillas/enzimología , Miofibrillas/metabolismo , Oligomicinas/farmacología , Fosforilación Oxidativa/efectos de los fármacos , Ionóforos de Protónes/farmacología , Músculo Cuádriceps/efectos de los fármacos , Músculo Cuádriceps/crecimiento & desarrollo , Músculo Cuádriceps/metabolismo , Desacopladores/farmacología , Adulto JovenRESUMEN
INTRODUCTION: In healthy individuals, strenuous exercise typically results in a transient increase in the inflammatory cytokine, interleukin-6 (IL-6). This increase in IL-6 is reported to have pleiotropic effects including increased glucose uptake, increased fat oxidation, and anti-inflammatory actions. PURPOSE: The purpose of this study was to determine if patients with a traumatic brain injury (TBI) have a differential cytokine response to exercise compared to healthy control subjects (CON). METHODS: Eight patients with a TBI and eight age- and sex-matched controls completed an exercise test to volitional exhaustion. Metabolic data were collected continuously, and blood was collected at baseline, immediately post-exercise, and every 10 min for an hour post-exercise. Serum was analyzed for IL-6, tumor necrosis factor-alpha, interleukin-10 (IL-10), and cortisol. RESULTS: Peak oxygen consumption (CON 33 ± 2 ml kg(-1) min(-1); TBI 29 ± 2 ml kg(-1) min(-1)) and respiratory exchange ratio during exercise were equivalent between groups. There were no baseline differences between groups for cytokine or cortisol concentrations. Exercise did not increase IL-6 in TBI, whereas IL-6 was elevated from baseline in CON at 0, 40, and 50 min post-exercise (p < 0.05). IL-10 and cortisol increased from baseline in CON at 40 min post-exercise (p < 0.05). CONCLUSIONS: These data indicate that patients recovering from TBI have blunted IL-6, IL-10, and cortisol responses following a peak exercise test compared to non-TBI controls. This lack of an exercise response may represent impaired hypothalamic-pituitary-adrenal axis function.
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Lesiones Encefálicas/metabolismo , Ejercicio Físico , Interleucina-10/sangre , Interleucina-6/sangre , Adulto , Estudios de Casos y Controles , Femenino , Humanos , Hidrocortisona/sangre , Masculino , Factor de Necrosis Tumoral alfa/sangreRESUMEN
Restriction of blood flow to a contracting muscle during low-intensity resistance exercise (BFR exercise) stimulates mTORC1 signaling and protein synthesis in human muscle within 3 h postexercise. However, there is a lack of mechanistic data to provide a direct link between mTORC1 activation and protein synthesis in human skeletal muscle following BFR exercise. Therefore, the primary purpose of this study was to determine whether mTORC1 signaling is necessary for stimulating muscle protein synthesis after BFR exercise. A secondary aim was to describe the 24-h time course response in muscle protein synthesis and breakdown following BFR exercise. Sixteen healthy young men were randomized to one of two groups. Both the control (CON) and rapamycin (RAP) groups completed BFR exercise; however, RAP was administered 16 mg of the mTOR inhibitor rapamycin 1 h prior to BFR exercise. BFR exercise consisted of four sets of leg extension exercise at 20% of 1 RM. Muscle biopsies were collected from the vastus lateralis before exercise and at 3, 6, and 24 h after BFR exercise. Mixed-muscle protein fractional synthetic rate increased by 42% at 3 h postexercise and 69% at 24 h postexercise in CON, whereas this increase was inhibited in the RAP group. Phosphorylation of mTOR (Ser(2448)) and S6K1 (Thr(389)) was also increased in CON but inhibited in RAP. Mixed-muscle protein breakdown was not significantly different across time or groups. We conclude that activation of mTORC1 signaling and protein synthesis in human muscle following BFR exercise is inhibited in the presence of rapamycin.
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Ejercicio Físico/fisiología , Complejos Multiproteicos/metabolismo , Músculo Esquelético/irrigación sanguínea , Músculo Esquelético/efectos de los fármacos , Biosíntesis de Proteínas/efectos de los fármacos , Flujo Sanguíneo Regional/fisiología , Sirolimus/administración & dosificación , Serina-Treonina Quinasas TOR/metabolismo , Adolescente , Adulto , Constricción , Humanos , Masculino , Diana Mecanicista del Complejo 1 de la Rapamicina , Contracción Muscular/fisiología , Músculo Esquelético/metabolismo , Transducción de Señal/efectos de los fármacos , Adulto JovenRESUMEN
Elevated metabolic rate is a hallmark of the stress response to severe burn injury. This response is mediated in part by adrenergic stress and is responsive to changes in ambient temperature. We hypothesize that uncoupling of oxidative phosphorylation in skeletal muscle mitochondria contributes to increased metabolic rate in burn survivors. Here, we determined skeletal muscle mitochondrial function in healthy and severely burned adults. Indirect calorimetry was used to estimate metabolic rate in burn patients. Quadriceps muscle biopsies were collected on two separate occasions (11 ± 5 and 21 ± 8 days postinjury) from six severely burned adults (68 ± 19% of total body surface area burned) and 12 healthy adults. Leak, coupled, and uncoupled mitochondrial respiration was determined in permeabilized myofiber bundles. Metabolic rate was significantly greater than predicted values for burn patients at both time points (P < 0.05). Skeletal muscle oxidative capacity, citrate synthase activity, a marker of mitochondrial abundance, and mitochondrial sensitivity to oligomycin were all lower in burn patients vs. controls at both time points (P < 0.05). A greater proportion of maximal mitochondrial respiration was linked to thermogenesis in burn patients compared with controls (P < 0.05). Increased metabolic rate in severely burned adults is accompanied by derangements in skeletal muscle mitochondrial function. Skeletal muscle mitochondria from burn victims are more uncoupled, indicating greater heat production within skeletal muscle. Our findings suggest that skeletal muscle mitochondrial dysfunction contributes to increased metabolic rate in burn victims.
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Quemaduras/complicaciones , Quemaduras/metabolismo , Mitocondrias Musculares/fisiología , Enfermedades Mitocondriales/etiología , Músculo Esquelético/metabolismo , Adulto , Metabolismo Basal , Biopsia , Quemaduras/patología , Estudios de Casos y Controles , Respiración de la Célula , Humanos , Masculino , Persona de Mediana Edad , Enfermedades Mitocondriales/metabolismo , Enfermedades Mitocondriales/patología , Músculo Esquelético/patología , Músculo Esquelético/ultraestructura , Descanso , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
BACKGROUND: Postexercise protein or amino acid ingestion restores muscle protein synthesis in older adults and represents an important therapeutic strategy for aging muscle. However, the precise nutritional factors involved are unknown. OBJECTIVE: The purpose of this study was to determine the role of increased postexercise Leu ingestion on skeletal muscle myofibrillar protein synthesis (MyoPS), mammalian/mechanistic target of rapamycin complex 1 signaling, and amino acid transporter (AAT) mRNA expression in older men over a 24-h post-resistance exercise (RE) time course. METHODS: During a stable isotope infusion trial (l-[ring-(13)C6]Phe; l-[1-(13)C]Leu), older men performed RE and, at 1 h after exercise, ingested 10 g of essential amino acids (EAAs) containing either a Leu content similar to quality protein (control, 1.85 g of Leu, n = 7) or enriched Leu (LEU; 3.5 g of Leu, n = 8). Muscle biopsies (vastus lateralis) were obtained at rest and 2, 5, and 24 h after exercise. RESULTS: p70 S6 kinase 1 phosphorylation was increased in each group at 2 h (P < 0.05), whereas 4E binding protein 1 phosphorylation increased only in the LEU group (P < 0.05). MyoPS was similarly increased (â¼90%) above basal in each group at 5 h (P < 0.05) and remained elevated (â¼90%) at 24 h only in the LEU group (P < 0.05). The mRNA expression of select AATs was increased at 2 and 5 h in each group (P < 0.05), but AAT expression was increased at 24 h only in the LEU group (P < 0.05). CONCLUSIONS: Leu-enriched EAA ingestion after RE may prolong the anabolic response and sensitivity of skeletal muscle to amino acids in older adults. These data emphasize the potential importance of adequate postexercise Leu ingestion to enhance the response of aging muscle to preventive or therapeutic exercise-based rehabilitation programs. This trial was registered at clinicaltrials.gov as NCT00891696.