Muscle wasting remains a major cause of morbidity and mortality in patients after injury and infection. Although the sepsis-induced decrease in lean body mass is undoubtedly multifactorial, our previous work demonstrates a causal relationship between the insulin-like growth factor (IGF) system, tumor necrosis factor (TNF)-a, and translational control of muscle protein synthesis. Moreover, the sepsis-induced changes appear unique to skeletal muscle. The working hypothesis is tested by the proposed research is that the sepsis induced decrease in the local concentrations of IGF-1, regulated by the overproduction of inflammatory cytokines, impairs muscle protein synthesis via disruption of the mTOR (mammalian target of rapamycin} signaling complex. A tripartite strategy is used whereby studies are proposed to examine a) the novel mechanism by which sepsis produces growth hormone (GH) resistance in skeletal muscle and decreases synthesis of IGF-1: b) the mechanism by which sepsis and TNFa regulate translational control of muscle protein synthesis and thereby influence the anabolic effects of GH, IGF-1 and nutrient signaling; and c) the autocrine/paracrine role of inflammatory cytokines in regulating muscle IGF-I synthesis and protein synthesis. The proposed research has the following specific aims: (1) Elucidate the mechanism by which sepsis produces GH resistance in muscle by impairing Stat5 transcriptional activity, thus uncoupling Stat5 phosphorylation from IGF-I synthesis. (2)Determine whether inflammatory cytokines alter the regulation of IGF-I promoter activity by GH. (3) Delineate the mechanism by which sepsis and TNFa modulate mTOR-dependent signaling in muscle and thereby impair protein synthesis and translational initiation. (4) Determine whether the enhanced synthesis of TNFa impairs GH signaling and IGF-I expression in skeletal muscle in response to sepsis via a systemic and/or local cytokine network. (5) Determine whether sepsis alters mTOR signaling via a systemic and/or local muscle cytokine network. The ability to perform complementary studies using both rats and transgenic mice as well as cultured myocytes and isolated muscle cells places us in a unique position to delineate the molecular mechanisms responsible for the sepsis-induced impairment in muscle protein synthesis. These data will provide a better understanding of the numerous factors influencing the IGF system and cellular metabolism, which is needed to both realize the full potential and avoid possible pitfalls of anabolic agents used in the management of critically ill patients.
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