The goal of this proposal is to investigate the general hypothesis that glucocorticoid antagonism isintegral to the restoration of muscle anabolism in burned children. Children remain hypercortisolemic at least24 months post-injury, thus we propose that the amelioration of cortisors catabolic effects on muscle is key tothe restoration of muscle anabolism and the accumulation of lean body mass (LBM). We have demonstratedthat administration of growth hormone (GH) exerts a differential anabolic effect on skeletal muscle, dependingupon the duration of administration. Our data indicates that the testosterone analog, oxandrolone (Ox), exertssimilar effects. Ox stimulates muscle protein synthesis during acute hospitalization and wound closure;however, long-term administration throughout rehabilitation is expected to counter the glucocorticoid stimulusfor muscle protein breakdown. In other words, we propose that the long-term administration of oxandrolonewill exert an anabolic effect by decreasing muscle protein breakdown. Further, the effect on proteinbreakdown will be realized during amino acid intake, thus restoring the anabolic effect of feeding in burnedchildren. We will also directly assess the catabolic influence of cortisol by decreasing cortisol synthesis with acommon antimycotic agent, ketoconazole. We propose to examine the chronic effects of both Ox andketoconazole on skeletal muscle protein metabolism in bumed children. This proposal will determine the acuteeffects of each drug during amino acid intake, as well as the chronic effects of both agents after six months ofadministration. We will utilize stable isotope methodology and lean body mass determinations to address thehypotheses that, 1) chronic administration of Ox will improve skeletal muscle metabolism by suppressingprotein breakdown when combined with amino acid feeding; 2) amelioration of hypercortisolemia withketoconazole will decrease skeletal muscle protein breakdown and ameliorate the loss of muscle proteinduring acute hospitalization; and 3) prolonged administration of ketoconazole during rehabilitation willameliorate the hypercortosolemic effects on skeletal muscle protein breakdown and restore the anaboliceffects of feeding. The restoration of the anabolic effects of feeding will result in a more favorable muscle netbalance and accrual of lean body mass throughout 6 months of n-house treatment and rehabilitation.
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