The goal of this proposal is to investigate the general hypothesis that glucocorticoid antagonism is integral to the restoration of muscle anabolism in burned children. Children remain hypercortisolemic at least 24 months post-injury, thus we propose that the amelioration of cortisors catabolic effects on muscle is key to the restoration of muscle anabolism and the accumulation of lean body mass (LBM). We have demonstrated that administration of growth hormone (GH) exerts a differential anabolic effect on skeletal muscle, depending upon the duration of administration. Our data indicates that the testosterone analog, oxandrolone (Ox), exerts similar effects. Ox stimulates muscle protein synthesis during acute hospitalization and wound closure; however, long-term administration throughout rehabilitation is expected to counter the glucocorticoid stimulus for muscle protein breakdown. In other words, we propose that the long-term administration of oxandrolone will exert an anabolic effect by decreasing muscle protein breakdown. Further, the effect on protein breakdown will be realized during amino acid intake, thus restoring the anabolic effect of feeding in burned children. We will also directly assess the catabolic influence of cortisol by decreasing cortisol synthesis with a common antimycotic agent, ketoconazole. We propose to examine the chronic effects of both Ox and ketoconazole on skeletal muscle protein metabolism in bumed children. This proposal will determine the acute effects of each drug during amino acid intake, as well as the chronic effects of both agents after six months of administration. We will utilize stable isotope methodology and lean body mass determinations to address the hypotheses that, 1) chronic administration of Ox will improve skeletal muscle metabolism by suppressing protein breakdown when combined with amino acid feeding;2) amelioration of hypercortisolemia with ketoconazole will decrease skeletal muscle protein breakdown and ameliorate the loss of muscle protein during acute hospitalization;and 3) prolonged administration of ketoconazole during rehabilitation will ameliorate the hypercortosolemic effects on skeletal muscle protein breakdown and restore the anabolic effects of feeding. The restoration of the anabolic effects of feeding will result in a more favorable muscle net balance and accrual of lean body mass throughout 6 months of n-house treatment and rehabilitation.
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