Chronic sepsis is associated with profound wasting of skeletal muscle. Development of rational and specific therapies to attenuate the loss of protein from skeletal muscle sepsis requires knowledge of which steps in the pathway of protein turnover are altered in sepsis. Preliminary studies have demonstrated a 50% reduction in the rate of protein synthesis in skeletal muscle of an animal model of chronic sepsis. Therefore, the overall goal of this project is to provide fundamental information regarding the mechanism by which sepsis alters specific events in the protein synthetic pathway in skeletal muscle.
The specific aims of the proposal are: (1) to further establish the effects of chronic sepsis and sterile inflammation on the in vivo rate of protein synthesis in various skeletal muscles using the specific radioactivity of tRNA-bound phenylalanine as the precursor for estimating protein synthesis; (2) to define the biochemical mechanisms responsible for the sepsis-induced inhibition of translational efficiency of protein synthesis in skeletal muscle by investigating the regulation of peptide-chain initiation and elongation and by examining the formation of 43S initiation complexes, the activity and concentration of individual initiation (eIF-2, GEF) and elongation factors (EF-2), and the covalent modification eIF-2 and EF-2; (3) to characterize the sensitivity of protein synthesis in skeletal muscle from septic animals to the stimulatory effects of insulin and branched-chain amino acids; and (4) to evaluate the role of monokines in mediating this reduction in protein synthesis in skeletal muscle of septic animals.
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