REGULATION OF PROTEIN TURNOVER IN DIABETIC HEART

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The goal of this project is to examine the hypothesis that the balance between rates of protein synthesis and degradation in diabetic hearts is partially restored by accelerated uptake of non-carbohydrate substrates such as fatty acids, ketone bodies and branched-chain amino acids. Restoration of protein synthesis involves acceleration of peptide-chain initiation. Mechanisms to restore normal rates of degradation appear to be less effective. Provision of both fatty acids and amino acids restrains degradation, but not as effectively as insulin. More rapid degradation, together with a restriction in the number of ribosomes available for synthesis, would lead to a reduction in the levels of some heart proteins and may impair function of the tissue. This hypothesis will be examined by identifying the factors regulating peptide-chain initiation in hearts of normal and diabetic rats and by evaluating the contribution of these factors to maintenance of initiation in insulin-dificient tissue. Protein degradation will be assessed by measuring release of phenylalanine in the presence and absence of cycloheximide. Rates of release will be correlated with latency of lysosomal enzymes. Rates of synthesis and degradation will be measured in the isolated perfused rat heart. These rates will be varied by changing perfusate levels of free fatty acids, ketone bodies, amino acids and insulin. These studies should suggest new approaches to maintaining heart function in diabetic animals.