This application is a competitive renewal which originally hypothesized that hypermetabolic responses to a thermal injury greater than 40% total body surface area burned, persisted throughout the first year post burn, and was partially mediated by an increase in the production of cortisol and catecholamines leading to muscle wasting, weakness, immunosuppression, chronic bone loss, decreased growth, and increases in metabolic, hemodynamic, inflammatory and scar responses. We have shown that the hypermetabolic response to a severe burn is associated with increased resting energy expenditure, insulin resistance, immunodeficiency, and whole body catabolism that persists for months after injury. Furthermore, bone mineral content, lean body mass, and muscle strength is decreased at 6 and 9 months after severe burn. We have also shown that these responses can be positively affected by a high carbohydrate diet, exercise and growth hormone. The strong benefits of exercise have led us to propose three research projects and three core units. Project 1 will test the hypothesis that diet and exercise in conjunction with daily administration of propranolol, oxandrolone, or a cortisol-blocking agent (ketoconazole) will improve clinical outcomes and promote functional recovery in burned children. Project 2, tests the hypothesis that glucocorticoid antagonism is integral to the restoration of muscle anabolism in burned children. Project 3, will test the hypothesis that accumulation of intracellular triglycerides in liver and muscle directly causes insulin resistance in those tissues, or indicates intracellular accumulation of active fatty acid products, thereby disrupting insulin action. These projects, the Analytic Core, the Mass Spectrometry Core, and the Human Subjects Core, allow us to study mechanisms by which exercise and anabolic/anticatabolic agents affect muscle protein metabolism (Project 2), fat metabolism, and its interaction with protein metabolism in muscle and liver (Project 3), and how these mechanisms translate to clinical outcomes and the rehabilitation of burned children (Project 1).
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