Signaling mechanisms in skeletal muscle: acute responses and chronic adaptations to exercise.

Physical activity elicits physiological responses in skeletal muscle that result in a number of health benefits, in particular in disease states, such as type 2 diabetes. An acute bout of exercise/muscle contraction improves glucose homeostasis by increasing skeletal muscle glucose uptake, while chronic exercise training induces alterations in the expression of metabolic genes, such as those involved in muscle fiber type, mitochondrial biogenesis, or glucose transporter 4 (GLUT4) protein levels. A primary goal of exercise research is to elucidate the mechanisms that regulate these important metabolic and transcriptional events in skeletal muscle. In this review, we briefly summarize the current literature describing the molecular signals underlying skeletal muscle responses to acute and chronic exercise. The search for possible exercise/contraction-stimulated signaling proteins involved in glucose transport, muscle fiber type, and mitochondrial biogenesis is ongoing. Further research is needed because full elucidation of exercise-mediated signaling pathways would represent a significant step toward the development of new pharmacological targets for the treatment of metabolic diseases such as type 2 diabetes.

Diabetes, mitocondrias y ejercicio / Diabetes, mitochondria and exercise

El ejercicio produce efectos beneficiosos en la salud general de los individuos, y es indiscutible el papel que desempeña en el tratamiento y la prevención de la resistencia a la insulina y la diabetes tipo 2. Una sesión aguda de ejercicio o contracción muscular aumenta la captación de glucosa en el músculo esquelético a través de vías independientes de la insulina, y ello conduce a mejorías en la homeostasis corporal total de la glucosa. La actividad física regular induce cambios adaptativos en el músculo esquelético a través de modificaciones de la expresión de genes metabólicos. Estos cambios consisten en aumentos de las mitocondrias y modificaciones de la distribución de los tipos de fibras musculares. Un objetivo importante de la investigación sobre el ejercicio es el estudio de las señales moleculares que son inducidas por la actividad muscular y regulan los procesos metabólicos y transcripcionales clave en el músculo esquelético. En esta revisión, presentamos una breve panorámica general de la investigación sobre el ejercicio en el campo metabólico, describiendo diversas señales moleculares que subyacen en esos procesos. En este campo dinámico de investigación, se está realizando una búsqueda de otras proteínas de señalización estimuladas por el ejercicio. Los estudios que se realizan para aclarar en mayor medida las vías influidas por el ejercicio que intervienen en el transporte de glucosa, el tipo de fibra muscular y la biogénesis mitocondrial, permitirán comprender mejor cómo se producen los efectos favorables del ejercicio, mejorar nuestro conocimiento sobre los mecanismos patológicos de las enfermedades metabólicas como la diabetes tipo 2 e identificar nuevas dianas farmacológicas para el tratamiento (AU)

Exercise has beneficial effects on overall health, and its role in the treatment and prevention of insulin resistance and type 2 diabetes is undisputed. An acute bout of exercise or muscle contraction increases glucose uptake into skeletal muscle through insulin independent pathways, which leads to improvements in whole body glucose homeostasis. Regular physical activity induces adaptative changes in skeletal muscle through modification of metabolic gene expression. Such changes include increases in mitochondria and alteration of muscle fiber type distribution. An important goal of exercise research is to study molecular signals that are induced by muscle activity and that regulate key metabolic and transcriptional events in skeletal muscle. In this review, we give a brief overview of exercise research in the metabolic field, describing a number of molecular signals underlying these events. In this dynamic field of research the search for additional exercise-stimulated signalling proteins is ongoing. Studies to further elucidate exercise-mediated pathways involved in glucose transport, muscle fibre type and mitochondrial biogenesis will help to further understand the beneficial effects of exercise, to improve our knowledge about the pathological mechanisms of metabolic diseases such as type 2 diabetes, and to find new pharmacological targets for treatment (AU)

Skeletal muscle adaptation to exercise training: AMP-activated protein kinase mediates muscle fiber type shift.

Regular endurance exercise has profound benefits on overall health, including the prevention of obesity, cardiovascular disease, and diabetes. The objective of this study was to determine whether AMP-activated protein kinase (AMPK) mediates commonly observed adaptive responses to exercise training in skeletal muscle. Six weeks of voluntary wheel running induced a significant (P < 0.05) fiber type IIb to IIa/x shift in triceps muscle of wild-type mice. Despite similar wheel running capacities, this training-induced shift was reduced by approximately 40% in transgenic mice expressing a muscle-specific AMPKalpha2 inactive subunit. Sedentary mice carrying an AMPK-activating mutation (gamma1TG) showed a 2.6-fold increase in type IIa/x fibers but no further increase with training. To determine whether AMPK is involved in concomitant metabolic adaptations to training, we measured markers of mitochondria (citrate synthase and succinate dehydrogenase) and glucose uptake capacity (GLUT4 and hexokinase II). Mitochondrial markers increased similarly in wild-type and AMPKalpha2-inactive mice. Sedentary gamma1TG mice showed a approximately 25% increase in citrate synthase activity but no further increase with training. GLUT4 protein expression was not different in either line of transgenic mice compared with wild-type mice and tended to increase with training, although this increase was not statistically significant. Training induced a approximately 65% increase in hexokinase II protein in wild-type mice but not in AMPKalpha2-inactive mice. Hexokinase II was significantly elevated in sedentary gamma1TG mice, without an additional increase with training. AMPK is not necessary for exercise training-induced increases in mitochondrial markers, but it is essential for fiber type IIb to IIa/x transformation and increases in hexokinase II protein.

Human beta(3)-adrenoreceptors couple to KvLQT1/MinK potassium channels in Xenopus oocytes via protein kinase C phosphorylation of the KvLQT1 protein.

Modulation of the slow component of the delayed rectifier potassium current (IKs) in heart critically affects cardiac arrhythmogenesis. Its current amplitude is regulated by the sympathetic nervous system. However, the signal transduction from the beta-adrenergic system to the KvLQT1/MinK (KCNQ1/KCNE1) potassium channel, which is the molecular correlate of the IKs current in human cardiomyocytes, is not sufficiently understood. In the human heart, three subtypes of beta-adrenergic receptors (beta(1-3)-ARs) have been identified. Only beta(1)- and beta(3)-ARs have been shown so far to be involved in the regulation of IKs. Special interest has been paid to the regulation of IKs by the beta(3)-AR because of its potential importance in congestive heart failure. In heart failure beta(1)-ARs are known to be down regulated while the density of beta(3)-ARs is increased. Unfortunately, studies on the modulation of IKs by beta(3)-AR revealed conflicting results. We investigated the functional role of protein kinase C (PKC) in the signal transduction cascade between beta3-adrenergic receptors and IKs by expressing heterologously its molecular components, the KvLQT1/MinK potassium channel, together with human beta(3)-AR in Xenopus oocytes. Membrane currents were measured with the double electrode voltage-clamp technique. Using activators and inhibitors of PKC we demonstrated that PKC is involved in this regulatory process. Experiments in which the putative C-terminal PKC-phosphorylation sites in the KvLQT1 protein were destroyed by site directed mutagenesis reduced the isoproterenol-induced current to 27+/-3,5% compared to control. These results indicate that the amplitude of KvLQT1/MinK current is mainly increased by PKC activation. Our results suggest that the regulation of the KvLQT1/MinK potassium channel via beta(3)-AR is substantially mediated by PKC phosphorylation of the KvLQT1 protein at its four C-terminal PKC phosphorylation sites.