RESUMEN

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High fat feeding impairs skeletal muscle metabolic flexibility and induces insulin resistance, whereas exercise training exerts positive effects on substrate handling and improves insulin sensitivity. To identify the genomic mechanisms by which exercise ameliorates some of the deleterious effects of high fat feeding, we investigated the transcriptional and epigenetic response of human skeletal muscle to 9 days of a high-fat diet (HFD) alone (Sed-HFD) or in combination with resistance exercise (Ex-HFD), using genome-wide profiling of gene expression and DNA methylation. HFD markedly induced expression of immune and inflammatory genes, which was not attenuated by Ex. Conversely, Ex markedly remodelled expression of genes associated with muscle growth and structure. We detected marked DNA methylation changes following HFD alone and in combination with Ex. Among the genes that showed a significant association between DNA methylation and gene expression changes were PYGM, which was epigenetically regulated in both groups, and ANGPTL4, which was regulated only following Ex. In conclusion, while short-term Ex did not prevent a HFD-induced inflammatory response, it provoked a genomic response that may protect skeletal muscle from atrophy. These epigenetic adaptations provide mechanistic insight into the gene-specific regulation of inflammatory and metabolic processes in human skeletal muscle.

Asunto(s)

Dieta Alta en Grasa , Ejercicio Físico , Regulación de la Expresión Génica , Adaptación Fisiológica , Metilación de ADN , Perfilación de la Expresión Génica , Humanos , Músculo Esquelético/fisiología

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AIMS: To investigate the effects of short-term, reduced-volume sprint interval training (SIT) compared to traditional exercise recommendations (TER) in sedentary obese men. METHODS: Sixteen subjects [37.8 ± 5.8 years; body mass index (BMI) 32.8 ± 4.7 kg/m(2)] were randomly allocated to 2 weeks of either SIT (6 sessions of 8-12 × 10 s sprints) or TER [10 sessions of 30 min at 65% peak oxygen consumption (VO(2peak))] cycle exercise. Fasting plasma glucose, insulin, non-esterified fatty acids (NEFA), homeostasis model assessment of insulin sensitivity (HOMA-IR), body composition and VO(2peak) were assessed at baseline and approximately 72 h after the final training bout. Skeletal muscle biopsy samples were also obtained before and 72 h after training and analysed for AS160 phosphorylation and COX II, COX IV, GLUT-4, Nur77 and SIRT1 protein expression. RESULTS: No changes in BMI, body composition, VO(2peak), glucose, insulin, NEFA and HOMA-IR were observed after training, either within or between groups. Skeletal muscle markers of glucose metabolism and mitochondrial function also remained unaltered after 2 weeks of exercise training. CONCLUSIONS: Our findings show that 2 weeks of reduced-volume SIT or TER did not elicit any measurable metabolic adaptations in sedentary obese men. Further work is needed to determine the minimal amount of exercise required for short-term adaptations in this population.

Asunto(s)

Terapia por Ejercicio/métodos , Obesidad/terapia , Conducta Sedentaria , Adulto , Índice de Masa Corporal , Metabolismo Energético/fisiología , Ácidos Grasos no Esterificados/metabolismo , Transportador de Glucosa de Tipo 4/metabolismo , Homeostasis , Humanos , Insulina/metabolismo , Masculino , Músculo Esquelético/metabolismo , Obesidad/metabolismo , Consumo de Oxígeno/fisiología , Fosforilación/fisiología

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Since the work of Eriksson and Lindgärde, published over two decades ago (Diabetologia 1991;34:891-898), we have known that type 2 diabetes can be prevented or delayed by supervised lifestyle interventions (physical exercise and diet modification) in persons at risk of the disease. Here we discuss a novel, time-efficient approach to physical exercise prescription, low-volume, high-intensity interval training (LVHIT), and its efficacy for inducing a range of health benefits in a variety of populations at risk of inactivity-related diseases. We look to the future and suggest that current guidelines for exercise may need to be revised to include different training techniques to deliver the optimum exercise prescription. Indeed, we predict that subsequent exercise guidelines will include LVHIT as part of a comprehensive 'fitness menu' that allows individuals to select the exercise regimen that best fulfils their medical needs, is suited to their lifestyle and daily time restraints, and meets their personal goals.

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Diabetes Mellitus Tipo 2/prevención & control , Dieta , Ejercicio Físico , Promoción de la Salud , Adolescente , Adulto , Diabetes Mellitus Tipo 2/dietoterapia , Diabetes Mellitus Tipo 2/terapia , Trastornos del Metabolismo de la Glucosa/dietoterapia , Trastornos del Metabolismo de la Glucosa/prevención & control , Trastornos del Metabolismo de la Glucosa/terapia , Guías como Asunto , Humanos , Estilo de Vida , Actividad Motora , Educación y Entrenamiento Físico/tendencias

Asunto(s)

Insulina/farmacología , Ciclismo , Glucemia/efectos de los fármacos , Glucemia/metabolismo , LDL-Colesterol/sangre , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/fisiopatología , Tolerancia al Ejercicio , Salud Global , Prueba de Tolerancia a la Glucosa , Estado de Salud , Humanos , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Persona de Mediana Edad , Prevalencia , Esquí , Caminata

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Efforts to identify exercise-induced signaling events in skeletal muscle have been influenced by ground-breaking discoveries in the insulin action field. Initial discoveries demonstrating that exercise enhances insulin sensitivity raised the possibility that contraction directly modulates insulin receptor signaling events. Although the acute effects of exercise on glucose metabolism are clearly insulin-independent, the canonical insulin signaling cascade has been used as a framework by investigators in an attempt to resolve the mechanisms by which muscle contraction governs glucose metabolism. This review focuses on recent advances in our understanding of exercise-induced signaling pathways governing glucose metabolism in skeletal muscle. Particular emphasis will be placed on the characterization of AS160, a novel Akt substrate that plays a role in the regulation of glucose transport.

Asunto(s)

Ejercicio Físico/fisiología , Proteínas Activadoras de GTPasa/fisiología , Contracción Muscular/fisiología , Músculo Esquelético/fisiología , Proteínas Quinasas/fisiología , Proteínas Proto-Oncogénicas c-akt/fisiología , Quinasas de la Proteína-Quinasa Activada por el AMP , Animales , Glucosa/metabolismo , Humanos , Ratones , Músculo Esquelético/metabolismo , Transducción de Señal/fisiología

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Individuals with insulin resistance are characterized by impaired insulin action on whole-body glucose uptake, in part due to impaired insulin-stimulated glucose uptake into skeletal muscle. A single bout of exercise increases skeletal muscle glucose uptake via an insulin-independent mechanism that bypasses the typical insulin signalling defects associated with these conditions. However, this 'insulin sensitizing' effect is short-lived and disappears after approximately 48 h. In contrast, repeated physical activity (i.e. exercise training) results in a persistent increase in insulin action in skeletal muscle from obese and insulin-resistant individuals. The molecular mechanism(s) for the enhanced glucose uptake with exercise training have been attributed to the increased expression and/or activity of key signalling proteins involved in the regulation of glucose uptake and metabolism in skeletal muscle. Evidence now suggests that the improvements in insulin sensitivity associated with exercise training are also related to changes in the expression and/or activity of proteins involved in insulin signal transduction in skeletal muscle such as the AMP-activated protein kinase (AMPK) and the protein kinase B (Akt) substrate AS160. In addition, increased lipid oxidation and/or turnover is likely to be another mechanism by which exercise improves insulin sensitivity: exercise training results in an increase in the oxidative capacity of skeletal muscle by up-regulating lipid oxidation and the expression of proteins involved in mitochondrial biogenesis. Determination of the underlying biological mechanisms that result from exercise training is essential in order to define the precise variations in physical activity that result in the most desired effects on targeted risk factors, and to aid in the development of such interventions.

Asunto(s)

Ejercicio Físico/fisiología , Resistencia a la Insulina/fisiología , Proteínas Quinasas Activadas por AMP , Proteínas Adaptadoras Transductoras de Señales/fisiología , Diabetes Mellitus Tipo 2/fisiopatología , Humanos , Insulina/fisiología , Metabolismo de los Lípidos/fisiología , Complejos Multienzimáticos/fisiología , Músculo Esquelético/metabolismo , Fosfatidilinositol 3-Quinasas/fisiología , Proteínas Serina-Treonina Quinasas/fisiología , Transducción de Señal/fisiología

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The Na+ -K+ -ATPase enzyme is vital in skeletal muscle function. We investigated the effects of acute high-intensity interval exercise, before and following high-intensity training (HIT), on muscle Na+ -K+ -ATPase maximal activity, content, and isoform mRNA expression and protein abundance. Twelve endurance-trained athletes were tested at baseline, pretrain, and after 3 wk of HIT (posttrain), which comprised seven sessions of 8 x 5-min interval cycling at 80% peak power output. Vastus lateralis muscle was biopsied at rest (baseline) and both at rest and immediately postexercise during the first (pretrain) and seventh (posttrain) training sessions. Muscle was analyzed for Na+ -K+ -ATPase maximal activity (3-O-MFPase), content ([3H]ouabain binding), isoform mRNA expression (RT-PCR), and protein abundance (Western blotting). All baseline-to-pretrain measures were stable. Pretrain, acute exercise decreased 3-O-MFPase activity [12.7% (SD 5.1), P < 0.05], increased alpha1, alpha2, and alpha3 mRNA expression (1.4-, 2.8-, and 3.4-fold, respectively, P < 0.05) with unchanged beta-isoform mRNA or protein abundance of any isoform. In resting muscle, HIT increased (P < 0.05) 3-O-MFPase activity by 5.5% (SD 2.9), and alpha3 and beta3 mRNA expression by 3.0- and 0.5-fold, respectively, with unchanged Na+ -K+ -ATPase content or isoform protein abundance. Posttrain, the acute exercise induced decline in 3-O-MFPase activity and increase in alpha1 and alpha3 mRNA each persisted (P < 0.05); the postexercise 3-O-MFPase activity was also higher after HIT (P < 0.05). Thus HIT augmented Na+ -K+ -ATPase maximal activity despite unchanged total content and isoform protein abundance. Elevated Na+ -K+ -ATPase activity postexercise may contribute to reduced fatigue after training. The Na+ -K+ -ATPase mRNA response to interval exercise of increased alpha- but not beta-mRNA was largely preserved posttrain, suggesting a functional role of alpha mRNA upregulation.

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Adaptación Fisiológica , Ejercicio Físico/fisiología , Fatiga Muscular , Resistencia Física/fisiología , Músculo Cuádriceps/enzimología , ATPasa Intercambiadora de Sodio-Potasio/biosíntesis , Adaptación Fisiológica/genética , Inducción Enzimática , Fluoresceínas/metabolismo , Humanos , Isoenzimas/metabolismo , Masculino , Fatiga Muscular/genética , Ouabaína/metabolismo , Resistencia Física/genética , Unión Proteica , ARN Mensajero/biosíntesis , ATPasa Intercambiadora de Sodio-Potasio/genética

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Diabetes Mellitus Tipo 2/terapia , Mitocondrias/metabolismo , Mitocondrias/fisiología , Animales , Humanos , Resistencia a la Insulina , Modelos Biológicos , Contracción Muscular , Músculo Esquelético/metabolismo , Oxígeno/metabolismo , Consumo de Oxígeno , Fosforilación

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AIM: This study investigated the effects of endurance training status and sex differences on skeletal muscle Na+,K+-pump mRNA expression, content and activity. METHODS: Forty-five endurance-trained males (ETM), 11 recreationally active males (RAM), and nine recreationally active females (RAF) underwent a vastus lateralis muscle biopsy. Muscle was analysed for Na+,K+-pump alpha1, alpha2, alpha3, beta1, beta2 and beta3 isoform mRNA expression (real-time reverse transcription-polymerase chain reaction), content ([3H]-ouabain-binding site) and maximal activity (3-O-methylfluorescein phosphatase, 3-O-MFPase). RESULTS: ETM demonstrated lower alpha1, alpha3, beta2 and beta3 mRNA expression by 74%, 62%, 70% and 82%, respectively, than RAM (P<0.04). In contrast, [3H]-ouabain binding and 3-O-MFPase activity were each higher in ETM than in RAM, by 16% (P<0.03). RAM demonstrated a 230% and 364% higher alpha3 and beta3 mRNA expression than RAF, respectively (P<0.05), but no significant sex differences were found for alpha1, alpha2, beta1 or beta2 mRNA, [3H]-ouabain binding or 3-O-MFPase activity. No significant correlation was found between years of endurance training and either [3H]-ouabain binding or 3-O-MFPase activity. Significant but weak correlations were found between the number of training hours per week and 3-O-MFPase activity (r=0.31, P<0.02) and between incremental exercise VO2(peak)) and both [3H]-ouabain binding (r=0.33, P<0.01) and 3-O-MFPase activity (r=0.28, P<0.03). CONCLUSIONS: Isoform-specific differences in Na+,K+-pump mRNA expression were found with both training status and sex differences, but only training status influenced Na+,K+-pump content and maximal activity in human skeletal muscle.

Asunto(s)

Regulación de la Expresión Génica , Músculo Esquelético/enzimología , Resistencia Física , Isoformas de Proteínas/genética , ARN Mensajero/metabolismo , ATPasa Intercambiadora de Sodio-Potasio/genética , Adulto , Análisis de Varianza , Sitios de Unión , Biopsia , Estudios Transversales , Ciclofilinas/genética , Activación Enzimática , Femenino , Humanos , Masculino , Ouabaína/metabolismo , Educación y Entrenamiento Físico , ARN Mensajero/análisis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores Sexuales , ATPasa Intercambiadora de Sodio-Potasio/análisis , Factores de Tiempo

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Sedentary and trained men respond differently to the same intensity of exercise, this is probably related to their platelet reactivity and antioxidant capacity. There is growing interest in the utilization of antioxidant-rich plant extracts as dietary food supplements. The aim of this study was to investigate the effect of an acute bout of sub maximal exercise on platelet count and differential response of platelet activation in trained and sedentary subjects and to observe if cocoa polyphenols reverse the effect of exercise on platelet function. The practical significance of this study was that many sedentary people engage in occasional strenuous exercise that may predispose them to risk of heart disease. Fasting blood samples were collected from 16 male subjects, pre and post 1-h cycling exercise at 70% of maximal aerobic power (VO2max) before and after consumption of cocoa or placebo. Agonist stimulated citrated whole blood was utilized for measuring platelet aggregation, adenosine triphosphate (ATP) release and platelet activation. Baseline platelet count (221 +/- 33 x 10(9)/L) and ATP release (1.4 +/- 0.6 nmol) increased significantly (P < 0.05) after exercise in all subjects. Baseline platelet numbers in the trained were higher (P < 0.05) than in the sedentary (235 +/- 37 vs. 208 +/- 34 x 10(9)/L), where as platelet activation in trained was lower (P < 0.05) than sedentary (51 +/- 6 vs. 59 +/- 5%). Seven days of cocoa polyphenol supplementation had little effect on any of the parameters measured. We conclude that trained subjects show decreased activation of stimulated platelets when compared to the sedentary subjects and short-term cocoa polyphenol supplementation did not decrease platelet activity in response to exercise independent of prior training status.

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Cacao , Ejercicio Físico/fisiología , Flavonoles/farmacología , Activación Plaquetaria/efectos de los fármacos , Activación Plaquetaria/fisiología , Adolescente , Adulto , Análisis de Varianza , Antioxidantes/análisis , Antioxidantes/farmacología , Plaquetas/efectos de los fármacos , Plaquetas/fisiología , Estudios Cruzados , Suplementos Dietéticos , Método Doble Ciego , Flavonoides/farmacología , Humanos , Masculino , Fenoles/farmacología , Aptitud Física , Extractos Vegetales/farmacología , Recuento de Plaquetas , Polifenoles

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Hypoxia and exercise each modulate muscle Na(+), K(+)ATPase activity. We investigated the effects on muscle Na(+), K(+)ATPase activity of only 5 nights of live high, train low hypoxia (LHTL), 20 nights consecutive (LHTLc) versus intermittent LHTL (LHTLi), and acute sprint exercise. Thirty-three athletes were assigned to control (CON, n = 11), 20-nights LHTLc (n = 12) or 20-nights LHTLi (4 x 5-nights LHTL interspersed with 2-nights CON, n = 10) groups. LHTLc and LHTLi slept at a simulated altitude of 2,650 m (F(I)O(2) 0.1627) and lived and trained by day under normoxic conditions; CON lived, trained, and slept in normoxia. A quadriceps muscle biopsy was taken at rest and immediately after standardised sprint exercise, before (Pre) and after 5-nights (d5) and 20-nights (Post) LHTL interventions and analysed for Na(+), K(+)ATPase maximal activity (3-O-MFPase) and content ([(3)H]-ouabain binding). After only 5-nights LHTLc, muscle 3-O-MFPase activity declined by 2% (P < 0.05). In LHTLc, 3-O-MFPase activity remained below Pre after 20 nights. In contrast, in LHTLi, this small initial decrease was reversed after 20 nights, with restoration of 3-O-MFPase activity to Pre-intervention levels. Plasma [K(+)] was unaltered by any LHTL. After acute sprint exercise 3-O-MFPase activity was reduced (12.9 +/- 4.0%, P < 0.05), but [(3)H]-ouabain binding was unchanged. In conclusion, maximal Na(+), K(+)ATPase activity declined after only 5-nights LHTL, but the inclusion of additional interspersed normoxic nights reversed this effect, despite athletes receiving the same amount of hypoxic exposure. There were no effects of consecutive or intermittent nightly LHTL on the acute decrease in Na(+), K(+)ATPase activity with sprint exercise effects or on plasma [K(+)] during exercise.

Asunto(s)

Altitud , Ejercicio Físico/fisiología , Hipoxia/fisiopatología , Resistencia Física , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Adulto , Regulación Enzimológica de la Expresión Génica , Humanos , Hipoxia/metabolismo , Masculino , Músculo Esquelético/enzimología , Músculo Esquelético/metabolismo , Ouabaína/metabolismo , Potasio/sangre , Tritio/metabolismo

RESUMEN

AIMS/HYPOTHESIS: We compared metabolic gene expression in adipose tissue and skeletal muscle from patients with type 2 diabetes and from well-matched healthy control subjects. We hypothesised that gene expression would be discordantly regulated when comparing the two groups. Our secondary aim was to determine the effect of Interleukin-6 (IL6) infusion on circulating adipokines and on gene expression in human adipose tissue. To do this we used real-time RT-PCR. METHODS: Both diabetic and control subjects underwent basal skeletal muscle and subcutaneous adipose tissue biopsies. A subset of these individuals underwent a 3-h infusion of recombinant human IL6 and had adipose tissue samples taken before and after infusion. RESULTS: The mRNA gene expression of suppressor of cytokine signalling (SOCS) 3, peroxisome proliferative activated receptor (PPAR) alpha/delta, PPAR gamma, coactivator 1, alpha (PPARGC1A), carnitine palmitoyltransferase 1B and solute carrier family 2 (facilitated glucose transporter), member 4 (formerly known as glucose transporter 4/GLUT4), was higher in adipose tissue, but lower in skeletal muscle of diabetic patients than in that of control subjects. In addition, uncoupling protein 1 (UCP1) gene was detected in the adipose tissue of some of the diabetic patients, but not in the control subjects. The following genes were increased by infusion of recombinant human IL6 in both groups: SOCS1/3, resistin, adiponectin, AMP-activated protein kinase-alpha-1 and PPARA. Plasma tumour necrosis factor alpha, adiponectin and resistin were all unaffected by IL6 infusion, but plasma resistin was lower in the diabetic subjects than in control subjects. CONCLUSIONS/INTERPRETATION: The observation that PPARGC1A and the PPARs were upregulated in the adipose tissue of type 2 diabetic patients, along with the finding that adipose tissue from some patients with type 2 diabetes can express UCP1 mRNA, suggests that in these patients white adipose tissue may move towards a brown adipose tissue phenotype.

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Tejido Adiposo/fisiopatología , Diabetes Mellitus Tipo 2/genética , Regulación de la Expresión Génica , Interleucina-6/farmacología , Músculo Esquelético/fisiopatología , Adiponectina/genética , Biopsia , Diabetes Mellitus Tipo 2/patología , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Infusiones Intravenosas , Hormonas de Insectos/genética , Interleucina-6/administración & dosificación , Masculino , Persona de Mediana Edad , Oligopéptidos/genética , Ácido Pirrolidona Carboxílico/análogos & derivados , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Necrosis Tumoral alfa/genética

RESUMEN

A popular method to attempt to enhance performance is for athletes to sleep at natural or simulated moderate altitude (SMA) when training daily near sea level. Based on our previous observation of periodic breathing in athletes sleeping at SMA, we hypothesised that athletes' sleep quality would also suffer with hypoxia. Using two typical protocols of nocturnal SMA (2650 m), we examined the effect on the sleep physiology of 14 male endurance-trained athletes. The selected protocols were Consecutive (15 successive exposure nights) and Intermittent (3x 5 successive exposure nights, interspersed with 2 normoxic nights) and athletes were randomly assigned to follow either one. We monitored sleep for two successive nights under baseline conditions (B; normoxia, 600 m) and then at weekly intervals (nights 1, 8 and 15 (N1, N8 and N15, respectively)) of the protocols. Since there was no significant difference in response between the protocols being followed (based on n=7, for each group) we are unable to support a preference for either one, although the likelihood of a Type II error must be acknowledged. For all athletes (n=14), respiratory disturbance and arousal responses between B and N1, although large in magnitude, were highly individual and not statistically significant. However, SpO2 decreased at N1 versus B (p<0.001) and remained lower on N8 (p<0.001) and N15 (p<0.001), not returning to baseline level. Compared to B, arousals were more frequent on N8 (p=0.02) and N15 (p=0.01). The percent of rapid eye movement sleep (REM) increased from N1 to N8 (p=0.03) and N15 (p=0.01). Overall, sleeping at 2650 m causes sleep disturbance in susceptible athletes, yet there was some improvement in REM sleep over the study duration.

Asunto(s)

Altitud , Sueño/fisiología , Deportes , Adulto , Cámaras de Exposición Atmosférica , Humanos , Hipoxia/etiología , Masculino , Oximetría , Oxígeno/sangre , Polisomnografía , Fases del Sueño

RESUMEN

AIMS/HYPOTHESIS: Our aim was to examine the possible direct relationship of interleukin-6 and TNFalpha with insulin sensitivity in humans. METHODS: We carried out two series of euglycaemic-hyperinsulinaemic clamp experiments. In the first (CLAMP1), skeletal muscle mRNA expression and plasma concentrations of IL-6 and TNFalpha were examined in patients with Type 2 diabetes ( n=6), subjects matched for age (n=6), and young healthy (n=11) control subjects during a 120-min supra-physiological hyperinsulinaemic (40 mU.m(-2).min(-1)) euglycaemic clamp. In the second series of experiments (CLAMP2), patients with Type 2 diabetes (n=6) and subjects matched for age (n=7) were studied during a 240-min high-physiological hyperinsulinaemic (7 mU.m(-2).min(-1)) euglycaemic clamp, during which arterial and venous (femoral and subclavian) blood samples were measured for IL-6 and TNFalpha flux. RESULTS: In both experiments the glucose infusion rate in the patients was markedly lower than that in the other groups. In CLAMP1, basal skeletal muscle IL-6 and TNFalpha mRNA were the same in all groups. They were not affected by insulin and they were not related to the glucose infusion rate. In CLAMP2, neither cytokine was released from the arm or leg during insulin stimulation in either group. In both experiments plasma concentrations of these cytokines were similar in the patients and in the control subjects, although in CLAMP1 the young healthy control group had lower (p<0.05) plasma IL-6 concentrations. Using data from all subjects, a strong positive correlation (r=0.85; p<0.00001) was observed between basal plasma IL-6 and BMI. Conversely, a negative relationship (r=-0.345; p<0.05) was found between basal plasma TNFalpha and BMI, although this was not significant when corrected for BMI. When corrected for BMI, no relationship was observed between either basal plasma IL-6 or TNFalpha and GIR. CONCLUSIONS/INTERPRETATION: These data show that the increased circulating IL-6 concentrations seen in patients with Type 2 diabetes are strongly related to fat mass and not insulin responsiveness, and suggest that neither IL-6 nor TNFalpha are indicative of insulin resistance.

Asunto(s)

Tejido Adiposo/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Resistencia a la Insulina/fisiología , Insulina/fisiología , Interleucina-6/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Tejido Adiposo/química , Animales , Australia , Índice de Masa Corporal , Interpretación Estadística de Datos , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/complicaciones , Glucosa/administración & dosificación , Técnica de Clampeo de la Glucosa/instrumentación , Técnica de Clampeo de la Glucosa/métodos , Humanos , Hiperinsulinismo/sangre , Hiperinsulinismo/complicaciones , Infusiones Intravenosas , Interleucina-6/química , Interleucina-6/genética , Masculino , Músculo Esquelético/química , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Factor de Necrosis Tumoral alfa/química , Factor de Necrosis Tumoral alfa/genética

RESUMEN

AIMS/HYPOTHESIS: Recruitment of the protein c-Cbl to the insulin receptor (IR) and its tyrosine phosphorylation via a pathway that is independent from phosphatidylinositol 3'-kinase is necessary for insulin-stimulated GLUT4 translocation in 3T3-L1 adipocytes. The activation of this pathway by insulin or exercise has yet to be reported in skeletal muscle. METHODS: Lean and obese Zucker rats were randomly assigned to one of three treatment groups: (i). control, (ii). insulin-stimulated or (iii). acute, exhaustive exercise. Hind limb skeletal muscle was removed and the phosphorylation state of IR, Akt and c-Cbl measured. RESULTS: Insulin receptor phosphorylation was increased 12-fold after insulin stimulation ( p<0.0001) in lean rats and threefold in obese rats. Acute exercise had no effect on IR tyrosine phosphorylation. Similar results were found for serine phosphorylation of Akt. Exercise did not alter c-Cbl tyrosine phosphorylation in skeletal muscle of lean or obese rats. However, in contrast to previous studies in adipocytes, c-Cbl tyrosine phosphorylation was reduced after insulin treatment ( p<0.001). CONCLUSIONS/INTERPRETATION: We also found that c-Cbl associating protein expression is relatively low in skeletal muscle of Zucker rats compared to 3T3-L1 adipocytes and this could account for the reduced c-Cbl tyrosine phosphorylation after insulin treatment. Interestingly, basal levels of c-Cbl tyrosine phosphorylation were higher in skeletal muscle from insulin-resistant Zucker rats ( p<0.05), but the physiological relevance is not clear. We conclude that the regulation of c-Cbl phosphorylation in skeletal muscle differs from that previously reported in adipocytes.

Asunto(s)

Glucemia/metabolismo , Insulina/farmacología , Músculo Esquelético/metabolismo , Condicionamiento Físico Animal , Proteínas Proto-Oncogénicas/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Animales , Glucemia/efectos de los fármacos , Femenino , Transportador de Glucosa de Tipo 4 , Resistencia a la Insulina/fisiología , Proteínas de Transporte de Monosacáridos/metabolismo , Proteínas Musculares/metabolismo , Músculo Esquelético/efectos de los fármacos , Obesidad/genética , Obesidad/fisiopatología , Fosforilación , Proteínas Proto-Oncogénicas/efectos de los fármacos , Proteínas Proto-Oncogénicas c-cbl , Ratas , Ratas Zucker , Delgadez/fisiopatología , Ubiquitina-Proteína Ligasas/efectos de los fármacos

RESUMEN

AIM/HYPOTHESIS: We determined the effect of exercise training on insulin sensitivity and muscle lipids (triglyceride [TG(m)] and long-chain fatty acyl CoA [LCACoA] concentration) in patients with Type 2 diabetes. METHODS: Seven patients with Type 2 diabetes and six healthy control subjects who were matched for age, BMI, % body fat and VO(2)peak participated in a 3 days per week training program for 8 weeks. Insulin sensitivity was determined pre- and post-training during a 120 min euglycaemic-hyperinsulinaemic clamp and muscle biopsies were obtained before and after each clamp. Oxidative enzyme activities [citrate synthase (CS), beta-hydroxy-acyl-CoA (beta-HAD)] and TG(m) were determined from basal muscle samples pre- and post training, while total LCACoA content was measured in samples obtained before and after insulin-stimulation, pre- and post training. RESULTS: The training-induced increase in VO(2)peak (approximately 20%, p<0.01) was similar in both groups. Compared with control subjects, insulin sensitivity was lower in the diabetic patients before and after training (approximately 60%; p<0.05), but was increased to the same extent in both groups with training (approximately 30%; p<0.01). TG(m) was increased in patients with Type 2 diabetes (170%; p<0.05) before, but was normalized to levels observed in control subjects after training. Basal LCACoA content was similar between groups and was unaltered by training. Insulin-stimulation had no detectable effect on LCACoA content. CS and beta-HAD activity were increased to the same extent in both groups in response to training ( p<0.001). CONCLUSION/INTERPRETATION: We conclude that the enhanced insulin sensitivity observed after short-term exercise training was associated with a marked decrease in TG(m) content in patients with Type 2 diabetes. However, despite the normalization of TG(m )to levels observed in healthy individuals, insulin resistance was not completely reversed in the diabetic patients.

Asunto(s)

Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatología , Ejercicio Físico/fisiología , Insulina/farmacología , Músculo Esquelético/metabolismo , Triglicéridos/metabolismo , 3-Hidroxiacil-CoA Deshidrogenasas/metabolismo , Tejido Adiposo/anatomía & histología , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Índice de Masa Corporal , Citrato (si)-Sintasa/metabolismo , Técnica de Clampeo de la Glucosa , Humanos , Persona de Mediana Edad , Consumo de Oxígeno , Aptitud Física , Valores de Referencia

RESUMEN

The AMP-activated protein kinase (AMPK) cascade has been linked to many of the acute effects of exercise on skeletal muscle substrate metabolism, as well as to some of the chronic training-induced adaptations. We determined the effect of 3 wk of intensified training (HIT; 7 sessions of 8 x 5 min at 85% Vo2 peak) in skeletal muscle from well-trained athletes on AMPK responsiveness to exercise. Rates of whole body substrate oxidation were determined during a 90-min steady-state ride (SS) pre- and post-HIT. Muscle metabolites and AMPK signaling were determined from biopsies taken at rest and immediately after exercise during the first and seventh HIT sessions, performed at the same (absolute) pre-HIT work rate. HIT decreased rates of whole body carbohydrate oxidation (P < 0.05) and increased rates of fat oxidation (P < 0.05) during SS. Resting muscle glycogen and its utilization during intense exercise were unaffected by HIT. However, HIT induced a twofold decrease in muscle [lactate] (P < 0.05) and resulted in tighter metabolic regulation, i.e., attenuation of the decrease in the PCr/(PCr + Cr) ratio and of the increase in [AMPfree]/ATP. Resting activities of AMPKalpha1 and -alpha2 were similar post-HIT, with the magnitude of the rise in response to exercise similar pre- and post-HIT. AMPK phosphorylation at Thr172 on both the alpha1 and alpha2 subunits increased in response to exercise, with the magnitude of this rise being similar post-HIT. Acetyl-coenzyme A carboxylase-beta phosphorylation was similar at rest and, despite HIT-induced increases in whole body rates of fat oxidation, did not increase post-HIT. Our results indicate that, in well-trained individuals, short-term HIT improves metabolic control but does not blunt AMPK signaling in response to intense exercise.

Asunto(s)

Acidosis/enzimología , Ejercicio Físico/fisiología , Complejos Multienzimáticos/metabolismo , Músculo Esquelético/enzimología , Aptitud Física/fisiología , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Quinasas Activadas por AMP , Acetil-CoA Carboxilasa/metabolismo , Adulto , Análisis de Varianza , Glucógeno/metabolismo , Humanos , Ácido Láctico/metabolismo , Consumo de Oxígeno/fisiología , Fosforilación , Transducción de Señal/fisiología

RESUMEN

To investigate the effect of altitude exposure on running economy (RE), 22 elite distance runners [maximal O(2) consumption (Vo(2)) 72.8 +/- 4.4 ml x kg(-1) x min(-1); training volume 128 +/- 27 km/wk], who were homogenous for maximal Vo(2) and training, were assigned to one of three groups: live high (simulated altitude of 2,000-3,100 m)-train low (LHTL; natural altitude of 600 m), live moderate-train moderate (LMTM; natural altitude of 1,500-2,000 m), or live low-train low (LLTL; natural altitude of 600 m) for a period of 20 days. RE was assessed during three submaximal treadmill runs at 14, 16, and 18 km/h before and at the completion of each intervention. Vo(2), minute ventilation (Ve), respiratory exchange ratio, heart rate, and blood lactate concentration were determined during the final 60 s of each run, whereas hemoglobin mass (Hb(mass)) was measured on a separate occasion. All testing was performed under normoxic conditions at approximately 600 m. Vo(2) (l/min) averaged across the three submaximal running speeds was 3.3% lower (P = 0.005) after LHTL compared with either LMTM or LLTL. Ve, respiratory exchange ratio, heart rate, and Hb(mass) were not significantly different after the three interventions. There was no evidence of an increase in lactate concentration after the LHTL intervention, suggesting that the lower aerobic cost of running was not attributable to an increased anaerobic energy contribution. Furthermore, the improved RE could not be explained by a decrease in Ve or by preferential use of carbohydrate as a metabolic substrate, nor was it related to any change in Hb(mass). We conclude that 20 days of LHTL at simulated altitude improved the RE of elite distance runners.

Asunto(s)

Aclimatación/fisiología , Altitud , Consumo de Oxígeno/fisiología , Carrera/fisiología , Adulto , Distribución de Chi-Cuadrado , Frecuencia Cardíaca/fisiología , Humanos , Ácido Láctico/sangre , Modelos Lineales , Masculino , Factores de Tiempo

RESUMEN

We determined the interaction of exercise and diet on glucose transporter (GLUT-4) protein and mRNA expression in type I (soleus) and type II [extensor digitorum longus (EDL)] skeletal muscle. Forty-eight Sprague Dawley rats were randomly assigned to one of two dietary conditions: high-fat (FAT, n=24) or high-carbohydrate (CHO, n=24). Animals in each dietary condition were allocated to one of two groups: control (NT, n=8) or a group that performed 8 weeks of treadmill running (4 sessions week-1 of 1000 m @ 28 m min-1, RUN, n=16). Eight trained rats were killed after their final exercise bout for determination of GLUT-4 protein and mRNA expression: the remainder were killed 48 h after their last session for measurement of muscle glycogen and triacylglycerol concentration. GLUT-4 protein expression in NT rats was similar in both muscles after 8 weeks of either diet. However, there was a main effect of training such that GLUT-4 protein was increased in the soleus of rats fed with either diet (P < 0.05) and in the EDL in animals fed with CHO (P < 0.05). There was a significant diet-training interaction on GLUT-4 mRNA, such that expression was increased in both the soleus (100% upward arrowP < 0.05) and EDL (142% upward arrowP < 0.01) in CHO-fed animals. Trained rats fed with FAT decreased mRNA expression in the EDL ( downward arrow 45%, P < 0.05) but not the soleus ( downward arrow 14%, NS). We conclude that exercise training in CHO-fed rats increased both GLUT-4 protein and mRNA expression in type I and type II skeletal muscle. Despite lower GLUT-4 mRNA in muscles from fat-fed animals, exercise-induced increases in GLUT-4 protein were largely preserved, suggesting that control of GLUT-4 protein and gene expression are modified independently by exercise and diet.

Asunto(s)

Proteínas de Transporte de Monosacáridos/genética , Proteínas de Transporte de Monosacáridos/metabolismo , Proteínas Musculares , Músculo Esquelético/fisiología , Condicionamiento Físico Animal/fisiología , Animales , Peso Corporal , Dieta , Carbohidratos de la Dieta/farmacología , Grasas de la Dieta/farmacología , Femenino , Expresión Génica/fisiología , Glucosa/farmacocinética , Transportador de Glucosa de Tipo 4 , Glucógeno/metabolismo , Resistencia a la Insulina/fisiología , Fibras Musculares de Contracción Rápida/metabolismo , Fibras Musculares de Contracción Lenta/metabolismo , Músculo Esquelético/citología , ARN Mensajero/análisis , Ratas , Ratas Sprague-Dawley , Triglicéridos/farmacocinética