Muscle wasting remains a major cause of morbidity and mortality in patients after injury and infection. The working hypothesis to be tested by the proposed research is that Components of the insulin-like growth factor (IGF) system, regulated by the overproduction of endogenous cytokines, are capable of impairing muscle protein synthesis in response to a septic challenge. To address this hypothesis, the research has the following specific aims: (1) to determine the role of sepsis and TNFalpha in modulating in vivo gene expression of myostatin, a negative regulator of muscle mass, and to assess whether changes in myostatin are associated with alterations in the systemic and local IGF system; (2) to determine the mechanism by which TNFalpha alters IGF and myostatin mRNA in cultured myocytes by assessing gene transcription and stability as well as elucidating the signaling pathways responsible for the changes in IGF and myostatin; (3) to determine the mechanism by which sepsis impairs in vivo growth hormone signaling in skeletal muscle by measuring activation of the JAK/STAT pathway and modulation of the suppressors of cytokine signaling (SOCS) protein family; (4) to determine whether the sepsis- induced change in IGF-l influences muscle protein synthesis via an endocrine or autocrine/paracrine (muscle) mechanism, using transgenic mice with a liver-specific deletion of the igf 1 gene but normal IGF-l expression in muscle; (5) to determine the mechanism by which the sepsis- induced increase in IGF binding protein-1 impairs muscle protein synthesis; and (6) to determine whether sepsis alters nontraditional components of the IGF system, such as the number of insulin.IGF-l hybrid receptors and the expression of IGF binding protein-related protein-1, which can potentially regulate muscle protein synthesis by modulating insulin action. This proposed research is unique because it integrates both in vivo and in vitro studies designed to elucidate the cellular basis for the changes in IGF-l during sepsis, and also because it directly assesses the interaction between TNF, the IGF system, and known regulators of protein synthesis. The data obtained will provide a more complete understanding of the factors influencing the IGF system and cellular metabolism, which is needed to realize the full potential and to avoid possible pitfalls of anabolic agents used in the management of the critically ill patient.
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