Accelerated muscle protein catabolism following injury can persist for months and is a major component of the overall catabolic response. Amelioration of the catabolism of muscle protein after trauma has been difficult because of the failure to identify a mediator of the response. Therefore, the general goal of this project is to determine the factors regulating muscle protein synthesis and breakdown in severely burned or septic patients and the best approach to reversing net catabolism. We will investigate the general hypothesis that a defect in amino acid transmembrane transport is central in mediating the changes in muscle protein metabolism. we will perform the following specific experiments: (1) We will compare the amino acid transmembrane transport rates of representative essential and nonessential amino acids and the rates of muscle protein synthesis and breakdown in burned or septic patients with the same rates in normal volunteers. The responses of those parameters to amino acid infusion will also be tested. (2) The role and mechanism of action on muscle amino acid and protein kinetics of important anabolic factors (testosterone, IGF-1, insulin, beta2 adrenergic agonism) will be determined in normal volunteers. (3) The effectiveness of the most appropriate anabolic treatment, ascertained from the volunteer studies, will be tested in patients. The assessment of muscle amino acid and protein kinetics will involve a new model we have recently developed based on the systemic continuous infusion of stable isotopic tracers of several amino acids that use different transporters, and the measurement of enrichment and concentration in the arterial and femoral vein plasma and the intracellular free water in muscle. In addition, the rate of incorporation of tracer into muscle protein is measured. These results will provide novel basic information about the normal regulation of muscle amino acid and protein metabolism, and provide insight into both the mechanism responsible for muscle catabolism in patients, and also the most effective therapeutic approach.
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