Myocardial dysfunction remains a major cause of morbidity and mortality in patients after thermal injury. Our preliminary data provide evidence that the burn-induced decrease in intrinsic mechanical function is associated with an impairment in myocardial protein synthesis and translational efficiency. The working hypothesis to be tested is that the burn-induced decrease in myocardial protein synthesis is mediated by defects in translational efficiency resulting from an impairment in both peptide-chain initiation and elongation, and that these changes are mediated by the overproduction of tumor necrosis factor (TNF)a which alters the responsiveness of the heart to insulin-like growth (IGF)-l and growth hormone (GH), To address the questions implicit in this hypothesis, the proposed research has the following specific aims: (1) to determine the temporal progression of burn-induced changes in protein synthesis, indices of peptide-chain initiation and myocardial function, and to determine whether these changes are mediated by TNFa; (2) to determine the mechanism by which thermal injury decreases activity of eIF2B in heart, by assessing the phosphorylation of elF2Be, content of p67, and the importance of alterations in kinase and phosphatase activities directed towards eIF2a and eIF2Be; (3) to determine the mechanism by which burn alters elF4E availability, by assessing the phosphorylation status of the various 4E-binding proteins and p7OS6 kinase, and quantitating the degradation of eIF4G; (4) to determine the mechanism by which burn impairs peptide-chain elongation in heart, by quantitating the rate of elongation under in vivo conditions and by determining the myocardial content and phosphorylation state of elongation factors EFI and EF2; and (5) to determine the signaling mechanisms by which burn injury impairs GH and IGF-I action in heart. Our data suggest that the bum-induced changes in cardiac protein synthesis and translation initiation are relatively unique, and do not occur in skeletal muscle in response to burn or in heart in response to other traumatic conditions. Overall, the research will elucidate the mechanisms by which myocardial protein synthesis is reduced after thermal injury, leading to the better understanding and treatment of the resulting cardiomyopathy. -
