The central hypothesis of the application is that insulin is the major regulator of skeletal muscle protein metabolism in humans, acting directly to regulate tissue proteolysis and indirectly to modulate the action of hormones, mechanical factors and amino acids. This action of insulin is important both for the maintenance of muscle mass per se and for the regulation of the mobilization of amino acids used to fuel hepatic glucose production. The effects of insulin deficiency and excess in the action of a) branched chain amino acids; b) epinephrine; and c) exercise on muscle protein will be addressed. We will also address whether lysosomes in human skeletal muscle mediate significant rates of proteolysis and whether the antiproteolytic action of BCAA and EPI will also be evaluated. Finally, the effect of chronic insulin resistance, as encountered in type II diabetes, on skeletal muscle sensitivity to insulin's antiproteolytic action will be assessed and compared with insulin's effects on muscle glucose metabolism. Conduct of these studies rests entirely on the use of a combined forearm catheterization-radioisotope tracer method developed in our laboratory. This method is unique in allowing the simultaneous measurement of forearm protein synthesis, degradation and balance. In addition, hormones be infused locally into the brachial artery and exercise isolated to a small group of muscles. In this manner the effects of hormone infusions can be evaluated isolated from the systemic changes that accompany systemic administration of hormones like insulin and epinephrine. Likewise, this model will allow isolation of the effect of exercise per se on muscle protein dynamics in man.
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