Our laboratory has described in healthy humans the acute regulatory effects of both hormones and amino acids on skeletal muscle protein synthesis (growth hormone, IGF-I, amino acid mixtures (AA)) and degradation (insulin, branched-chain amino acids(BCAA)), each thereby having a net protein anabolic action. We propose to define how muscle protein metabolism is altered in three clinically important states that promote muscle protein catabolism namely, insulin-withdrawn type I diabetes, glucocorticoid excess, and burn injury. The mechanisms leading to muscle protein loss have not been well defined in these states. Using a tracer kinetic method developed for this purpose, we will define whether altered rates of proteolysis, of synthesis or of both processes are responsible. In addition, in insulin withdrawn IDDM, we will test a series of hypotheses relating to the insulin's direct antiproteolytic action as well as its indirect or permissive effects on the expression of the anabolic actions of BCAA, IGF-I and balanced AA infusions. Likewise, we will determine whether antagonism of insulin's antiproteolytic action causes muscle wasting that contributes to morbidity of glucocorticoid excess and whether glucocorticoids effect the action of other anabolic agents on muscle. Finally, the effect of insulin and IGF-I on forearm muscle in Post-burn patients will also be defined and the changes in muscle protein metabolism induced by IDDM or glucocorticoid excess compared with those following burn. In all studies, we will use steady-state tracer infusions and bilateral forearm catherization methods that have allowed us to clarify the actions of anabolic hormones and substrates in healthy humans. As recent evidence implicates the ATP-ubiquitin-proteosome system as a major proteolytic pathway in muscle, we will test whether changes in the expression of key components of this system are involved in the accelerated net protein catabolism in each of the three patient groups. Information gained from these mechanistic studies of human muscle protein metabolism should be directly relevant to the rational use of anabolic agents in the treatment or prevention of muscle wasting.
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