Mentored Patient-Oriented Research Career Development Aw

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DESCRIPTION (Adapted from the applicant's abstract): Many disease states, including glucocorticoid excess and hyperthyroidism, are associated with accelerated protein catabolism, causing chronic muscle wasting and increasing morbidity and mortality. The exact cellular mechanisms responsible remain elusive. One of the possible mechanisms is glucocorticoid- or thyroid hormone-induced resistance to the anabolic agents in skeletal muscle. Insulin, branched chain amino acids (BCAA), balanced amino acid (AA) mixtures and insulin-like growth factor 1 (IGF-1) all have been demonstrated to retard proteolysis and/or enhance protein synthesis. The investigators propose to study the muscle's response to these four anabolic agents in the setting of acute and chronic glucocorticoid and thyroid hormone excess. The studies will be conducted in healthy human subjects with or without dexamethasone or triiodothyronine ingestion and patients with Cushing's syndrome or hyperthyroidism by examining: a) protein turnover in forearm muscle; b) the phosphorylation status of two key regulatory proteins involved in signaling mRNA translation (PHAS-I and p70 S6 kinase); and c) the activity, protein content and expression of several components in the ubiquitin-proteasome proteolytic pathway. The results should help to define the mechanisms of accelerated proteolysis associated with glucocorticoid or thyroid hormone excess. They will define: l) whether insulin, BCAA, AA mixtures and IGF-1 increase protein synthesis by stimulating phosphorylation of two key regulatory proteins involved in the protein translation initiation (PHAS-I and p70 S6 kinase); 2) whether insulin, BCAA, AA mixtures and IGF-1 retard proteolysis via blocking the ubiquitin-proteasome proteolytic pathway; and 3) whether glucocorticoid or thyroid hormone excess activates the ubiquitin- proteasome pathway and antagonizes the anabolic actions of insulin, BCAA, AA mixtures and IGF-1. By understanding the cellular mechanisms underlying the accelerated muscle catabolism and the actions of four anabolic agents in muscle, it may be possible to correct the protein wasting and to decrease the associated morbidity and mortality.