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De novo capillarization is a primary muscular adaptation to endurance exercise training and is crucial to improving performance. Excess training load, however, impedes such beneficial adaptations, yet we recently demonstrated that such downregulation may be counteracted by ketone ester ingestion (KE) post-exercise. Therefore, we investigated whether KE could increase pro-angiogenic factors and thereby stimulate muscular angiogenesis during a 3-week endurance training-overload period involving 10 training sessions/week in healthy, male volunteers. Subjects received either 25 g of a ketone ester (KE, n = 9) or a control drink (CON, n = 9) immediately after each training session and before sleep. In KE, but not in CON, the training intervention increased the number of capillary contacts and the capillary-to-fibre perimeter exchange index by 44% and 42%, respectively. Furthermore, KE also substantially increased vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) expression both at the protein and at the mRNA level. Serum erythropoietin concentration was concomitantly increased by 26%. Conversely, in CON the training intervention increased only the protein content of eNOS. These data indicate that intermittent exogenous ketosis during endurance overload training stimulates muscular angiogenesis. This likely resulted from a direct stimulation of muscle angiogenesis, which may be at least partly due to stimulation of erythropoietin secretion and elevated VEGF activity, and/or an inhibition of the suppressive effect of overload training on the normal angiogenic response to training. This study provides novel evidence to support the potential of exogenous ketosis to benefit endurance training-induced muscular adaptation. KEY POINTS: Increased capillarization is a primary muscular adaptation to endurance exercise training. However, excess training load may impede such response. We previously observed that intermittent exogenous ketosis by post-exercise and pre-sleep ketone ester ingestion (KE) counteracted physiological dysregulations induced by endurance overload training. Therefore, we investigated whether KE could increase pro-angiogenic factors thereby stimulating muscular angiogenesis during a 3-week endurance training overload period. We show that the overload training period in the presence, but not in the absence, of KE markedly increased muscle capillarization (+40%). This increase was accompanied by higher circulating erythropoietin concentration and stimulation of the pro-angiogenic factors vascular endothelial growth factor and endothelial nitric oxide synthase in skeletal muscle. Collectively, our data indicate that intermittent exogenous ketosis may evolve as a potent nutritional strategy to facilitate recovery from strenuous endurance exercise, thereby stimulating beneficial muscular adaptations.
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Treino Aeróbico , Eritropoetina , Cetose , Humanos , Masculino , Fator A de Crescimento do Endotélio Vascular/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Neovascularização Fisiológica/fisiologia , Eritropoetina/metabolismo , Músculo Esquelético/fisiologia , Cetonas/farmacologia , Cetose/metabolismo , Ésteres/farmacologia , Resistência Física/fisiologiaRESUMO
KEY POINTS: Overload training is required for sustained performance gain in athletes (functional overreaching). However, excess overload may result in a catabolic state which causes performance decrements for weeks (non-functional overreaching) up to months (overtraining). Blood ketone bodies can attenuate training- or fasting-induced catabolic events. Therefore, we investigated whether increasing blood ketone levels by oral ketone ester (KE) intake can protect against endurance training-induced overreaching. We show for the first time that KE intake following exercise markedly blunts the development of physiological symptoms indicating overreaching, and at the same time significantly enhances endurance exercise performance. We provide preliminary data to indicate that growth differentiation factor 15 (GDF15) may be a relevant hormonal marker to diagnose the development of overtraining. Collectively, our data indicate that ketone ester intake is a potent nutritional strategy to prevent the development of non-functional overreaching and to stimulate endurance exercise performance. ABSTRACT: It is well known that elevated blood ketones attenuate net muscle protein breakdown, as well as negate catabolic events, during energy deficit. Therefore, we hypothesized that oral ketones can blunt endurance training-induced overreaching. Fit male subjects participated in two daily training sessions (3 weeks, 6 days/week) while receiving either a ketone ester (KE, n = 9) or a control drink (CON, n = 9) following each session. Sustainable training load in week 3 as well as power output in the final 30 min of a 2-h standardized endurance session were 15% higher in KE than in CON (both P < 0.05). KE inhibited the training-induced increase in nocturnal adrenaline (P < 0.01) and noradrenaline (P < 0.01) excretion, as well as blunted the decrease in resting (CON: -6 ± 2 bpm; KE: +2 ± 3 bpm, P < 0.05), submaximal (CON: -15 ± 3 bpm; KE: -7 ± 2 bpm, P < 0.05) and maximal (CON: -17 ± 2 bpm; KE: -10 ± 2 bpm, P < 0.01) heart rate. Energy balance during the training period spontaneously turned negative in CON (-2135 kJ/day), but not in KE (+198 kJ/day). The training consistently increased growth differentiation factor 15 (GDF15), but â¼2-fold more in CON than in KE (P < 0.05). In addition, delta GDF15 correlated with the training-induced drop in maximal heart rate (r = 0.60, P < 0.001) and decrease in osteocalcin (r = 0.61, P < 0.01). Other measurements such as blood ACTH, cortisol, IL-6, leptin, ghrelin and lymphocyte count, and muscle glycogen content did not differentiate KE from CON. In conclusion, KE during strenuous endurance training attenuates the development of overreaching. We also identify GDF15 as a possible marker of overtraining.
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Treino Aeróbico , Ésteres/farmacologia , Cetonas/farmacologia , Adolescente , Adulto , Bebidas , Ciclismo , Biomarcadores/sangue , Método Duplo-Cego , Fator 15 de Diferenciação de Crescimento/sangue , Humanos , Cetonas/urina , Masculino , Adulto JovemRESUMO
PURPOSE: The myocellular response to hypoxia is primarily regulated by hypoxia-inducible factors (HIFs). HIFs thus conceivably are implicated in muscular adaptation to altitude training. Therefore, we investigated the effect of hypoxic versus normoxic training during a period of prolonged hypoxia ('living high') on muscle HIF activation during acute ischaemia. METHODS: Ten young male volunteers lived in normobaric hypoxia for 5 weeks (5 days per week, ~ 15.5 h per day, FiO2: 16.4-14.0%). One leg was trained in hypoxia (TRHYP, 12.3% FiO2) whilst the other leg was trained in normoxia (TRNOR, 20.9% FiO2). Training sessions (3 per week) consisted of intermittent unilateral knee extensions at 20-25% of the 1-repetition maximum. Before and after the intervention, a 10-min arterial occlusion and reperfusion of the leg was performed. Muscle oxygenation status was continuously measured by near-infrared spectroscopy. Biopsies were taken from m. vastus lateralis before and at the end of the occlusion. RESULTS: Irrespective of training, occlusion elevated the fraction of HIF-1α expressing myonuclei from ~ 54 to ~ 64% (P < 0.05). However, neither muscle HIF-1α or HIF-2α protein abundance, nor the expression of HIF-1α or downstream targets selected increased in any experimental condition. Training in both TRNOR and TRHYP raised muscular oxygen extraction rate upon occlusion by ~ 30%, whilst muscle hyperperfusion immediately following the occlusion increased by ~ 25% in either group (P < 0.05). CONCLUSION: Ten minutes of arterial occlusion increased HIF-1α-expressing myonuclei. However, neither normoxic nor hypoxic training during 'living high' altered muscle HIF translocation, stabilisation, or transcription in response to acute hypoxia induced by arterial occlusion.
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Fator 1 Induzível por Hipóxia/metabolismo , Hipóxia/metabolismo , Músculo Esquelético/metabolismo , Consumo de Oxigênio/fisiologia , Adulto , Altitude , Treinamento Intervalado de Alta Intensidade/métodos , Humanos , Masculino , RNA Mensageiro/metabolismoRESUMO
In humans, nutrient deprivation and extreme endurance exercise both activate autophagy. We hypothesized that cumulating fasting and cycling exercise would potentiate activation of autophagy in skeletal muscle. Well-trained athletes were divided into control (n = 8), low-intensity (LI, n = 8), and high-intensity (HI, n = 7) exercise groups and submitted to fed and fasting sessions. Muscle biopsy samples were obtained from the vastus lateralis before, at the end, and 1 h after a 2 h LI or HI bout of exercise. Phosphorylation of ULK1(Ser317) was higher after exercise (P < 0.001). In both the fed and the fasted states, LC3bII protein level and LC3bII/I were decreased after LI and HI (P < 0.05), while p62/SQSTM1 was decreased only 1 h after HI (P < 0.05), indicating an increased autophagic flux after HI. The autophagic transcriptional program was also activated, as evidenced by the increased level of LC3b, p62/SQSTM1, GabarapL1, and Cathepsin L mRNAs observed after HI but not after LI. The increased autophagic flux after HI exercise could be due to increased AMP-activated protein kinase α (AMPKα) activity, as both AMPKα(Thr172) and ACC(Ser79) had a higher phosphorylation state after HI (P < 0.001). In summary, the most effective strategy to activate autophagy in human skeletal muscle seems to rely on exercise intensity more than diet.
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Proteínas Quinases Ativadas por AMP/metabolismo , Autofagia/fisiologia , Exercício Físico/fisiologia , Músculo Quadríceps/metabolismo , Músculo Quadríceps/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Catepsina L/metabolismo , Jejum/metabolismo , Jejum/fisiologia , Humanos , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Musculares/metabolismo , Fosforilação/fisiologia , Resistência Física/fisiologia , RNA Mensageiro/metabolismo , Proteína Sequestossoma-1 , Transdução de Sinais/fisiologiaRESUMO
Hypoxia-induced muscle wasting is a phenomenon often described with prolonged stays at high altitude, which has been attributed to altered protein metabolism. We hypothesized that acute normobaric hypoxia would induce a negative net protein balance by repressing anabolic and activating proteolytic signaling pathways at rest and postexercise and that those changes could be partially genetically determined. Eleven monozygotic twins participated in an experimental trial in normoxia and hypoxia (10.7% O2). Muscle biopsy samples were obtained before and after a 20-min moderate cycling exercise. In hypoxia at rest, autophagic flux was increased, as indicated by an increased microtubule-associated protein 1 light chain 3 type II/I (LC3-II/I) ratio (+25%) and LC3-II expression (+60%) and decreased p62/SQSTM1 expression (-25%; P<0.05), whereas exercise reversed those changes to a level similar to that with normoxia except for p62/SQSTM1, which was further decreased (P<0.05). Hypoxia also increased Bnip3 (+34%) and MAFbx (+18%) mRNA levels as well as REDD1 expression (+439%) and AMP-activated protein kinase phosphorylation (+22%; P<0.05). Among the molecular responses to hypoxia and/or exercise, high monozygotic similarity was found for REDD1, LC3-II, and LC3-II/I (P<0.05). Our results indicate that environmental hypoxia modulates protein metabolism at rest and after moderate exercise by primarily increasing markers of protein breakdown and, more specifically, markers of the autophagy-lysosomal system, with a modest genetic contribution.
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Autofagia/fisiologia , Hipóxia/fisiopatologia , Proteínas Associadas aos Microtúbulos/metabolismo , Fatores de Transcrição/metabolismo , Adulto , Western Blotting , Exercício Físico/fisiologia , Genótipo , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteínas Associadas aos Microtúbulos/genética , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Ligases SKP Culina F-Box/genética , Proteínas Ligases SKP Culina F-Box/metabolismo , Fatores de Transcrição/genética , Adulto JovemAssuntos
Treino Aeróbico , Exercício Físico , Suplementos Nutricionais , Humanos , Hidrocortisona , CetonasRESUMO
INTRODUCTION: Strenuous eccentric exercise (EE) induces microstructural muscle damage, which decreases muscle performance. Palmitoylethanolamide (PEA) exerts analgesic and anti-inflammatory effects in clinical pain conditions and preclinical models of experimentally induced-inflammation. This might hold clues for improved recovery from EE. Therefore, the current study evaluates the effect of PEA supplementation on functional and molecular responses to a single EE bout. METHODS: Eleven healthy male participants were included in a double-blind crossover study in which they received PEA (350 mg Levagen+) or placebo (maltodextrin) supplements, in a randomized order. In each experimental condition participants performed an acute bout of EE (24x10 eccentric contractions of the knee extensors on an isokinetic dynamometer). At baseline, 24 (D1), 48 (D2), 72 (D3) and 120 h (D5) following EE, maximal voluntary contraction and jump height were measured. Blood samples were collected at baseline and on D1-D5, and muscle biopsies were collected at baseline and on D2. Perceived muscle soreness, sleep quality and food intake were recorded daily. RESULTS: Muscle strength and jump height decreased following EE (up to ~40 and ~ 17% respectively; Ptime < 0.05) in both conditions. This drop was accompanied by an increase in plasma creatine kinase and perceived muscle soreness (Ptime < 0.05). Furthermore, EE, but not PEA, increased the expression of the myogenic marker Pax7 and of the catabolic markers p-FoxO1-3a, p62 and LC3BII/I (Ptime < 0.05). CONCLUSIONS: PEA supplementation does not improve muscle soreness, muscle strength and jump performance following a single EE bout. Additionally, PEA supplementation had no effect on local or systemic markers of muscle damage, catabolism or regeneration.
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AIMS: Eighteen patients with asthma were evaluated during preparation to climb to extreme altitude in order to study the effects of low fractional inspired oxygen (FiO(2)), prolonged exposure to cold air and high altitude on lung function, asthma control and airway inflammation. METHODS: Spirometry and airway inflammation (fractional exhaled nitric oxide (FeNO) and induced sputum) were studied under different test conditions: hypoxic (FiO(2)=11%) exercise test, 24-hour cold exposure (-5°C) and before, during and after an expedition that involved climbing the Aconcagua mountain (6965 m). RESULTS: Forced expiratory volume in 1 s (FEV(1)) and FeNO values were slightly lower (p<0.04) after 1 h of normobaric hypoxia. FEV(1) decreased (p=0.009) after 24-hour cold exposure, accompanied by increased sputum neutrophilia (p<0.01). During the expedition FEV(1) and forced vital capacity decreased (maximum FEV(1) decrease of 12.3% at 4300 m) and asthma symptoms slightly increased. After the expedition the Asthma Control Test score and prebronchodilator FEV(1) were reduced (p<0.02), sputum neutrophil count was increased (p=0.04) and sputum myeloperoxidase levels, sputum interleukin 17 mRNA, serum and sputum vascular endothelial growth factor A levels were significantly higher compared with baseline. Patients with asthma with the lowest oxygen saturation during the hypoxic exercise test were more prone to develop acute mountain sickness. CONCLUSIONS: Exposure to environmental conditions at high altitude (hypoxia, exercise, cold) was associated with a moderate loss of asthma control, increased airway obstruction and neutrophilic airway inflammation. The cold temperature is probably the most important contributing factor as 24-hour cold exposure by itself induced similar effects.
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Doença da Altitude/fisiopatologia , Altitude , Asma/fisiopatologia , Temperatura Baixa/efeitos adversos , Exercício Físico/fisiologia , Hipóxia/complicações , Inflamação/fisiopatologia , Óxido Nítrico/metabolismo , Adulto , Doença da Altitude/etiologia , Teste de Esforço , Expedições , Feminino , Volume Expiratório Forçado , Humanos , Hipóxia/fisiopatologia , Masculino , Pessoa de Meia-Idade , Espirometria , EscarroRESUMO
AIM: Histidine-containing dipeptides (HCDs) are pleiotropic homeostatic molecules with potent antioxidative and carbonyl quenching properties linked to various inflammatory, metabolic, and neurological diseases, as well as exercise performance. However, the distribution and metabolism of HCDs across tissues and species are still unclear. METHODS: Using a sensitive UHPLC-MS/MS approach and an optimized quantification method, we performed a systematic and extensive profiling of HCDs in the mouse, rat, and human body (in n = 26, n = 25, and n = 19 tissues, respectively). RESULTS: Our data show that tissue HCD levels are uniquely produced by carnosine synthase (CARNS1), an enzyme that was preferentially expressed by fast-twitch skeletal muscle fibres and brain oligodendrocytes. Cardiac HCD levels are remarkably low compared to other excitable tissues. Carnosine is unstable in human plasma, but is preferentially transported within red blood cells in humans but not rodents. The low abundant carnosine analogue N-acetylcarnosine is the most stable plasma HCD, and is enriched in human skeletal muscles. Here, N-acetylcarnosine is continuously secreted into the circulation, which is further induced by acute exercise in a myokine-like fashion. CONCLUSION: Collectively, we provide a novel basis to unravel tissue-specific, paracrine, and endocrine roles of HCDs in human health and disease.
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Carnosina , Dipeptídeos , Humanos , Ratos , Camundongos , Animais , Dipeptídeos/química , Dipeptídeos/metabolismo , Dipeptídeos/farmacologia , Carnosina/metabolismo , Carnosina/farmacologia , Histidina/química , Histidina/metabolismo , Espectrometria de Massas em Tandem , AntioxidantesRESUMO
Old skeletal muscle exhibits decreased anabolic sensitivity, eventually contributing to muscle wasting. Besides anabolism, also muscle inflammation and catabolism are critical players in regulating the old skeletal muscle's sensitivity. Omega-3 fatty acids (ω-3) are an interesting candidate to reverse anabolic insensitivity via anabolic actions. Yet, it remains unknown whether ω-3 also attenuates muscle inflammation and catabolism. The present study investigates the effect of ω-3 supplementation on muscle inflammation and metabolism (anabolism/catabolism) upon resistance exercise (RE). Twenty-three older adults (65-84 years; 8â) were randomized to receive ω-3 (~3 g/d) or corn oil (placebo [PLAC]) and engaged in a 12-week RE program (3×/wk). Before and after intervention, muscle volume, strength, and systemic inflammation were assessed, and muscle biopsies were analyzed for markers of anabolism, catabolism, and inflammation. Isometric knee-extensor strength increased in ω-3 (+12.2%), but not in PLAC (-1.4%; pinteraction = .015), whereas leg press strength improved in both conditions (+27.1%; ptime < .001). RE, but not ω-3, decreased inflammatory (p65NF-κB) and catabolic (FOXO1, LC3b) markers, and improved muscle quality. Yet, muscle volume remained unaffected by RE and ω-3. Accordingly, muscle anabolism (mTORC1) and plasma C-reactive protein remained unchanged by RE and ω-3, whereas serum IL-6 tended to decrease in ω-3 (pinteraction = .07). These results show that, despite no changes in muscle volume, RE-induced gains in isometric strength can be further enhanced by ω-3. However, ω-3 did not improve RE-induced beneficial catabolic or inflammatory adaptations. Irrespective of muscle volume, gains in strength (primary criterion for sarcopenia) might be explained by changes in muscle quality due to muscle inflammatory or catabolic signaling.
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Suplementos Nutricionais , Ácidos Graxos Ômega-3 , Contração Isométrica/fisiologia , Força Muscular/fisiologia , Músculo Esquelético/metabolismo , Treinamento Resistido , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Método Duplo-Cego , Feminino , Humanos , Perna (Membro) , Masculino , Transdução de SinaisRESUMO
Exercise training is a powerful strategy to prevent and combat cardiovascular and metabolic diseases, although the integrative nature of the training-induced adaptations is not completely understood. We show that chronic blockade of histamine H1/H2 receptors led to marked impairments of microvascular and mitochondrial adaptations to interval training in humans. Consequently, functional adaptations in exercise capacity, whole-body glycemic control, and vascular function were blunted. Furthermore, the sustained elevation of muscle perfusion after acute interval exercise was severely reduced when H1/H2 receptors were pharmaceutically blocked. Our work suggests that histamine H1/H2 receptors are important transducers of the integrative exercise training response in humans, potentially related to regulation of optimal post-exercise muscle perfusion. These findings add to our understanding of how skeletal muscle and the cardiovascular system adapt to exercise training, knowledge that will help us further unravel and develop the exercise-is-medicine concept.
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Exercício Físico , Histamina , Exercício Físico/fisiologia , Histamina/farmacologia , Histamina/fisiologia , Humanos , Pulmão , Músculo Esquelético , TransdutoresRESUMO
INTRODUCTION: Ageing is associated with an attenuated hypertrophic response to resistance training and periods of training interruptions. Hence, elderly would benefit from the 'muscle memory' effects of resistance training on muscle strength and mass during detraining and retraining. As the underlying mechanisms are not yet clear, this study investigated the role of myonuclei during training, detraining and retraining by using PCM1 labelling in muscle cross-sections of six older men. METHODS: Knee extension strength and power were measured in 30 older men and 10 controls before and after 12 weeks resistance training and after detraining and retraining of similar length. In a subset, muscle biopsies from the vastus lateralis were taken for analysis of fibre size, fibre type distribution, Pax7+ satellite cell number and myonuclear domain size. RESULTS: Resistance training increased knee extension strength and power parameters (+10 to +36%, p < .001) and decreased the frequency of type IIax fibres by half (from 20 to 10%, p = .034). Detraining resulted in a modest loss of strength and power (-5 to -15%, p ≤ .004) and a trend towards a fibre-type specific decrease in type II fibre cross-sectional area (-17%, p = .087), type II satellite cell number (-30%, p = .054) and type II myonuclear number (-12%, p = .084). Less than eight weeks of retraining were needed to reach the post-training level of one-repetition maximum strength. Twelve weeks of retraining were associated with type II fibre hypertrophy (+29%, p = .050), which also promoted an increase in the number of satellite cells (+72%, p = .036) and myonuclei (+13%, p = .048) in type II fibres. Changes in the type II fibre cross-sectional area were positively correlated with changes in the myonuclear number (Pearson's r between 0.40 and 0.73), resulting in a stable myonuclear domain. CONCLUSION: Gained strength and power and fibre type changes were partially preserved following 12 weeks of detraining, allowing for a fast recovery of the 1RM performance following retraining. Myonuclear number tended to follow individual changes in type II fibre size, which is in support of the myonuclear domain theory.
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Treinamento Resistido , Células Satélites de Músculo Esquelético , Idoso , Humanos , Hipertrofia , Masculino , Fibras Musculares Esqueléticas , Força Muscular , Músculo EsqueléticoRESUMO
The aim of the study was to determine the effect of α-actinin-3 (ACTN3) deficiency (XX) on muscle damage induced by an eccentric exercise bout. In this purpose, 4 RR and 4 XX individuals performed an intensive eccentric knee flexion exercise on an isokinetic dynamometer. Muscle biopsies, blood and pain scores were taken before and after the exercise to determine the extent of the exercise-induced damage and the effect of the ACTN3 R577X polymorphism. Maximal isometric strength of the quadriceps and single fibre properties were compared before and after the exercise. The drop in maximal isometric strength of the quadriceps at 45° knee flexion following the eccentric exercise bout was on average 37% 24â h post-exercise. The decrease in force was also apparent in isolated type IIa fibres (8%; P = 0.02), but not in type I fibres (P = 0.88). Creatine kinase and myoglobin plasma levels increased in all participants at least by 55% and 87%, respectively (P < 0.05). In addition, mRNA levels of markers for muscle regeneration and muscle remodelling increased after the eccentric exercise (P < 0.05), however, independently from ACTN3 R577X genotype. The mRNA level of nuclear factor of activated T-cells 1 (NFATc1) decreased after the eccentric exercise only in XX genotypes (P < 0.05). The stiffness of type IIa, but not type I muscle fibres increased only in RR individuals after the eccentric exercise (P < 0.05). While no major effect of α-actinin-3 deficiency on susceptibility to muscle damage was found acutely, the increased stiffness response in fast RR fibres might be a protection mechanism from muscle damage during a subsequent eccentric exercise bout.
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Actinina/genética , Fibras Musculares de Contração Rápida/fisiologia , Músculo Quadríceps/lesões , Biópsia por Agulha , Creatina Quinase/sangue , Genótipo , Humanos , Masculino , Força Muscular , Dinamômetro de Força Muscular , Mioglobina/sangue , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Adulto JovemRESUMO
Purpose: Ketone bodies are energy substrates produced by the liver during prolonged fasting or low-carbohydrate diet. The ingestion of a ketone ester (KE) rapidly increases blood ketone levels independent of nutritional status. KE has recently been shown to improve exercise performance, but whether it can also promote post-exercise muscle protein or glycogen synthesis is unknown. Methods: Eight healthy trained males participated in a randomized double-blind placebo-controlled crossover study. In each session, subjects undertook a bout of intense one-leg glycogen-depleting exercise followed by a 5-h recovery period during which they ingested a protein/carbohydrate mixture. Additionally, subjects ingested a ketone ester (KE) or an isocaloric placebo (PL). Results: KE intake did not affect muscle glycogen resynthesis, but more rapidly lowered post-exercise AMPK phosphorylation and resulted in higher mTORC1 activation, as evidenced by the higher phosphorylation of its main downstream targets S6K1 and 4E-BP1. As enhanced mTORC1 activation following KE suggests higher protein synthesis rates, we used myogenic C2C12 cells to further confirm that ketone bodies increase both leucine-mediated mTORC1 activation and protein synthesis in muscle cells. Conclusion: Our results indicate that adding KE to a standard post-exercise recovery beverage enhances the post-exercise activation of mTORC1 but does not affect muscle glycogen resynthesis in young healthy volunteers. In vitro, we confirmed that ketone bodies potentiate the increase in mTORC1 activation and protein synthesis in leucine-stimulated myotubes. Whether, chronic oral KE intake during recovery from exercise can facilitate training-induced muscular adaptation and remodeling need to be further investigated.
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In the setting of "living high," it is unclear whether high-intensity interval training (HIIT) should be performed "low" or "high" to stimulate muscular and performance adaptations. Therefore, 10 physically active males participated in a 5-week "live high-train low or high" program (TR), whilst eight subjects were not engaged in any altitude or training intervention (CON). Five days per week (~15.5 h per day), TR was exposed to normobaric hypoxia simulating progressively increasing altitude of ~2,000-3,250 m. Three times per week, TR performed HIIT, administered as unilateral knee-extension training, with one leg in normobaric hypoxia (~4,300 m; TRHYP) and with the other leg in normoxia (TRNOR). "Living high" elicited a consistent elevation in serum erythropoietin concentrations which adequately predicted the increase in hemoglobin mass (r = 0.78, P < 0.05; TR: +2.6%, P < 0.05; CON: -0.7%, P > 0.05). Muscle oxygenation during training was lower in TRHYP vs. TRNOR (P < 0.05). Muscle homogenate buffering capacity and pH-regulating protein abundance were similar between pretest and posttest. Oscillations in muscle blood volume during repeated sprints, as estimated by oscillations in NIRS-derived tHb, increased from pretest to posttest in TRHYP (~80%, P < 0.01) but not in TRNOR (~50%, P = 0.08). Muscle capillarity (~15%) as well as repeated-sprint ability (~8%) and 3-min maximal performance (~10-15%) increased similarly in both legs (P < 0.05). Maximal isometric strength increased in TRHYP (~8%, P < 0.05) but not in TRNOR (~4%, P > 0.05). In conclusion, muscular and performance adaptations were largely similar following normoxic vs. hypoxic HIIT. However, hypoxic HIIT stimulated adaptations in isometric strength and muscle perfusion during intermittent sprinting.
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High rate of muscular oxygen utilization facilitates the development of hypoxemia during exercise at altitude. Because endurance training stimulates oxygen extraction capacity, we investigated whether endurance athletes are at higher risk to developing hypoxemia and thereby acute mountain sickness symptoms during exercise at simulated high altitude. Elite athletes (ATL; n = 8) and fit controls (CON; n = 7) cycled for 20 min at 100 W (EX100W), as well as performed an incremental maximal oxygen consumption test (EXMAX) in normobaric hypoxia (0.107 inspired O2 fraction) or normoxia (0.209 inspired O2 fraction). Cardiorespiratory responses, arterial Po2 (PaO2), and oxygenation status in m. vastus lateralis [tissue oxygenation index (TOIM)] and frontal cortex (TOIC) by near-infrared spectroscopy, were measured. Muscle O2 uptake rate was estimated from change in oxyhemoglobin concentration during a 10-min arterial occlusion in m. gastrocnemius. Maximal oxygen consumption in normoxia was 70 ± 2 ml·min(-1·)kg(-1) in ATL vs. 43 ± 2 ml·min(-1·)kg(-1) in CON, and in hypoxia decreased more in ATL (-41%) than in CON (-25%, P < 0.05). Both in normoxia at PaO2 of â¼95 Torr, and in hypoxia at PaO2 of â¼35 Torr, muscle O2 uptake was twofold higher in ATL than in CON (0.12 vs. 0.06 ml·min(-1)·100 g(-1); P < 0.05). During EX100W in hypoxia, PaO2 dropped to lower (P < 0.05) values in ATL (27.6 ± 0.7 Torr) than in CON (33.5 ± 1.0 Torr). During EXMAX, but not during EX100W, TOIM was â¼15% lower in ATL than in CON (P < 0.05). TOIC was similar between the groups at any time. This study shows that maintenance of high muscular oxygen extraction rate at very low circulating PaO2 stimulates the development of hypoxemia during submaximal exercise in hypoxia in endurance-trained individuals. This effect may predispose to premature development of acute mountain sickness symptoms during exercise at altitude.
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Exercício Físico/fisiologia , Hipóxia/fisiopatologia , Oxigênio/metabolismo , Adulto , Altitude , Doença da Altitude/metabolismo , Doença da Altitude/fisiopatologia , Atletas , Gasometria/métodos , Humanos , Hipóxia/metabolismo , Masculino , Músculo Esquelético , Consumo de Oxigênio/fisiologia , Oxiemoglobinas/metabolismo , Resistência Física/fisiologia , Respiração , Adulto JovemRESUMO
Hypoxia-inducible factor-1 (HIF-1) is a master regulator of myocellular adaptation to exercise and hypoxia. However, the role of genetic factors in regulation of HIF-1 responses to exercise and hypoxia is unknown. We hypothesized that hypoxia at rest and during exercise stimulates the HIF-1 pathway and its downstream targets in energy metabolism regulation in a genotype-dependent manner. Eleven monozygotic twin (MZ) pairs performed an experimental trial in both normoxia and hypoxia (FiO2 10.7%). Biopsies were taken from m. vastus lateralis before and after a 20-min submaximal cycling bout @~30% of sea-level VO2max. Key-markers of the HIF-1 pathway and glycolytic and oxidative metabolism were analyzed using real-time PCR and Western Blot. Hypoxia increased HIF-1α protein expression by ~120% at rest vs. +150% during exercise (p < 0.05). Furthermore, hypoxia but not exercise increased muscle mRNA content of HIF-1α (+50%), PHD2 (+45%), pVHL (+45%; p < 0.05), PDK4 (+1200%), as well as PFK-M (+20%) and PPAR-γ1 (+60%; p < 0.05). Neither hypoxia nor exercise altered PHD1, LDH-A, PDH-A1, COX-4, and CS mRNA expressions. The hypoxic, but not normoxic exercise-induced increment of muscle HIF-1α mRNA content was about 10-fold more similar within MZ twins than between the twins (p < 0.05). Furthermore, in resting muscle the hypoxia-induced increments of muscle HIF-1α protein content, and HIF-1α and PDK4 mRNA content were about 3-4-fold more homogeneous within than between the twins pairs (p < 0.05). The present observations in monozygotic twins for the first time clearly indicate that the HIF-1α protein as well as mRNA responses to submaximal exercise in acute hypoxia are at least partly regulated by genetic factors.
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PURPOSE: We investigated the effect of sprint interval training (SIT) in normoxia, vs. SIT in hypoxia alone or in conjunction with oral nitrate intake, on buffering capacity of homogenized muscle (ßhm) and fiber type distribution, as well as on sprint and endurance performance. METHODS: Twenty-seven moderately-trained participants were allocated to one of three experimental groups: SIT in normoxia (20.9% FiO2) + placebo (N), SIT in hypoxia (15% FiO2) + placebo (H), or SIT in hypoxia + nitrate supplementation (HN). All participated in 5 weeks of SIT on a cycle ergometer (30-s sprints interspersed by 4.5 min recovery-intervals, 3 weekly sessions, 4-6 sprints per session). Nitrate (6.45 mmol NaNO3) or placebo capsules were administered 3 h before each session. Before and after SIT participants performed an incremental VO2max-test, a 30-min simulated cycling time-trial, as well as a 30-s cycling sprint test. Muscle biopsies were taken from m. vastus lateralis. RESULTS: SIT decreased the proportion of type IIx muscle fibers in all groups (P < 0.05). The relative number of type IIa fibers increased (P < 0.05) in HN (P < 0.05 vs. H), but not in the other groups. SIT had no significant effect on ßhm. Compared with H, SIT tended to enhance 30-s sprint performance more in HN than in H (P = 0.085). VO2max and 30-min time-trial performance increased in all groups to a similar extent. CONCLUSION: SIT in hypoxia combined with nitrate supplementation increases the proportion of type IIa fibers in muscle, which may be associated with enhanced performance in short maximal exercise. Compared with normoxic training, hypoxic SIT does not alter ßhm or endurance and sprinting exercise performance.
RESUMO
PURPOSE: To examine the effect of α-actinin-3 deficiency due to homozygosity for the ACTN3 577X-allele on contractile and morphological properties of fast muscle fibers in non-athletic young men. METHODS: A biopsy was taken from the vastus lateralis of 4 RR and 4 XX individuals to test for differences in morphologic and contractile properties of single muscle fibers. The cross-sectional area of the fiber and muscle fiber composition was determined using standard immunohistochemistry analyses. Skinned single muscle fibers were subjected to active tests to determine peak normalized force (P0), maximal unloading velocity (V0) and peak power. A passive stretch test was performed to calculate Young's Modulus and hysteresis to assess fiber visco-elasticity. RESULTS: No differences were found in muscle fiber composition. The cross-sectional area of type IIa and IIx fibers was larger in RR compared to XX individuals (P<0.001). P0 was similar in both groups over all fiber types. A higher V0 was observed in type IIa fibers of RR genotypes (P<0.001) but not in type I fibers. The visco-elasticity as determined by Young's Modulus and hysteresis was unaffected by fiber type or genotype. CONCLUSION: The greater V0 and the larger fast fiber CSA in RR compared to XX genotypes likely contribute to enhanced whole muscle performance during high velocity contractions.