Physical exercise acutely increases skeletal muscle glucose uptake, and in the period following exercise there are increases in the rates of both glucose uptake and glycogen synthesis. A single bout of exercise also induces transient changes in gene transcription and alters rates of protein metabolism, both of which are important for the chronic adaptations observed after repeated bouts of exercise. These adaptations in skeletal muscle lead to some of the most important health benefits of exercise, perhaps including the ability of regular physical exercise to reduce the risk of developing type 2 diabetes. A central issue in exercise biology is to elucidate the molecular signaling mechanisms that regulate these important metabolic and transcriptional events in skeletal muscle. We have established that exercise regulates Akt and GSK3 signaling in skeletal muscle, two critical serine/threonine (Ser/Thr) protein kinases that have been implicated in the regulation of a host of cellular metabolic and transcriptional events. To understand the physiological function of these proteins in contracting skeletal muscle 4 specific aims have been proposed: 1) to elucidate the signaling mechanism that leads to Akt activation with exercise, and to determine the biological consequences of exercise-induced activation of Akt in skeletal muscle; 2) to elucidate the mechanisms through which exercise decreases GSK3 activity in skeletal muscle; 3) to determine the biological consequences of exercise-induced deactivation of GSK3 in skeletal muscle; and 4) to determine the effects of exercise training on GSK3 expression and activity in skeletal muscle. This work should lead to a better understanding of the molecular signaling mechanisms responsible for the beneficial effects of physical exercise in skeletal muscle.