HORMONAL REGULATION OF SKELETAL MUSCLE METABOLISM

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The hormonal regulation of muscle protein metabolism is a dynamic process that reflects, at any given time, the effects of several hormones. Insulin, the best studied of these, suppresses proteolysis in both forearm muscle and whole body protein. Unlike insulin, the role of growth hormone (GH) in the regulation of protein metabolism in normal man has not been well characterized. Since both insulin and GH are required for normal growth in man, GH, by itself or via IGF-1, would be expected to affect muscle protein metabolism. Preliminary data in presented demonstrating an acute (within 6 hours) effect of locally infused GH to stimulate protein synthesis by forearm skeletal muscle tissue in man. Based on these results and others cited in the application, the experiments described attempt to dissect apart the contributions of GH, insulin and IGF-1 to the regulation of skeletal muscle and whole body protein metabolism in man. Four sets of experiments are described. The first examines whether GH infused systemically in either a continuous or pulsatile fashion produces acute changes in whole body and forearm muscle protein synthesis like those seen in forearm muscle during local arterial infusion. The second set of studies examines the interaction between insulin and GH in regulating protein metabolism. Suppression of endogenous GH and insulin secretion with somatostatin allows us to develop models of GH deficiency or type I diabetes in normal subjects. Selected readministration of GH or insulin in these models then allows us to probe the responses to these hormones in different pathophysiological settings. The third group of experiments in intended to compare the effects of IGF-1 with those of GH and insulin. In rats, IGF-1 suppresses muscle proteolysis like insulin and does not stimulate protein synthesis, as GH appears to do. The proposed studies are designed to help clarify the mechanisms of action of the insulin-GH-IGF triad on protein metabolism in man. Finally, the last group of experiments looks at the role of the intracellular messengers cAMP and cGMP in the mediation of the responses to GH, insulin, and IGF-1. GH in vitro prevents the intracellular rise of cGMP. This suppressive effect of GH is associated with stimulation of protein synthesis in vitro. The proposed experiments attempt to relate in vivo hormone administration with measured levels of cGMP and cAMP.