Changes in mitogen-activated protein kinase phosphorylation and inorganic phosphate induced by skeletal muscle contraction

Abstract: Skeletal muscles adjust to the level of contractile activity by different biochemical alterations. Contraction is a multifactorial stimulus with short-term metabolic effects and long-term responses due to changes in protein synthesis. A central issue in exercise physiology is to elucidate the underlying signaling mechanisms behind adaptations to exercise. The mitogenactivated protein (MAP) kinase signaling pathway is suggested to be involved in exerciseinduced changes in gene expression in skeletal muscle. We studied short- and long-term adaptations to skeletal muscle contractions using both human and animal models, and by employing different exercise intensities and contraction regimens. An increased tetanic force production and reduced inorganic phosphate (Pi) concentration were observed within minutes after a brief bout of repeated contractions. Increases in ATP, phosphocreatine (PCr) or glucose-6-phosphate (G-6-P) could not account for the reduction in Pi. Intensity-dependent increases in the phosphorylation of two MAP kinases, MAPK erk 1/2 and MAPKK mek1/2, were identified in response to one-leg exercise in humans. In isolated rat muscle, isometric contractions induced a similar increase in phosphorylation of MAPKerk1/2 in slow- and fast-twitch muscles, while a significant increase in MAPK p38 phosphorylation was observed in fast- twitch skeletal muscles only. Since increased MAPK phoshporylation was observed in isolated muscles and in the exercised leg only in humans, the main stimulating factor(s) appears to be local. The total amount of MAPK erk 1/2 and MAPK p38 was higher in slow-twitch than in fast-twitch skeletal muscle. Mild passive stretches and concentric contrations induced phosphorylation of MAPK erk l/2 , but not MAPK p38. During concentric contractions, reactive oxygen species (ROS) was the key triggering factor behind the activation. Eccentric contractions resulted in an augmented phosphorylation of MAPKerk1/2 and MAPK p38 , whereas severe stretches mainly induced MAPKerk1/2 phosphorylation. Thus, mechanical perturbations, which are known to affect protein synthesis, stimulate phosphorylation of these kinases differently. In conclusion, repeated contractions result in marked adaptations in skeletal muscle: a reduced Pi may cause a transient increase in force production while increased MAP kinase signaling may induce long-term changes in protein expression.