In the past years of support of this project we have demonstrated the effects of testosterone, cortisol, and insulin on skeletal muscle protein. We have demonstrated that the anabolic effects of testosterone in normal subjects is realized by an increase in muscle protein synthesis, whereas in adult burns, the primary effect is on the reduction of protein breakdown. We have also shown that hypercortisolemia, when combined with prolonged inactivity, exacerbates the loss of muscle nitrogen by accelerating protein breakdown. As the relationship of these two hormones is dramatically altered after burn injury, it is likely that this alteration affects skeletal muscle. Further, we have demonstrated that exogenous insulin increases net muscle protein synthesis in burn patients. We propose to build upon our recent findings in burn patients by altering testosterone and cortisol concentrations to delineate the resultant affects on muscle protein. We hypothesize that increasing the ratio of testosterone to cortisol will improve net protein balance in skeletal muscle. We propose that testosterone can potentially promote muscle anabolism by two different mechanisms in the adult bumpatient. If the glucocorticoid effects on muscle are not ameliorated, then testosterone acts primarily as an anti-catabolic agent by reducing the magnitude of protein breakdown. However, if the catabolic effects of cortisol are diminished, then testosterone will promote muscle anabolism by increasing protein synthesis. We further propose an additive effect between insulin and testosterone on protein synthesis, since each promotes synthesis via different mechanisms. The general goal of this proposal is to extend our previous observations to investigate the following hypotheses relating to the hormonal influence on skeletal muscle after burn injury: Hypothesis 1. Reduction of cortisol secretion will diminish muscle protein breakdown and improve net protein balance in skeletal muscle. Hypothesis 2. Normalization of testosterone with reduced cortisol will improve net protein balance in an additive manner. We propose this occurs by decreasing net protein breakdown and increasing net protein synthesis. Hypothesis 3. The anabolic effects of testosterone and local hyperinsulinemia will be additive in the burned patient. Hypothesis 4. The combined effects of hypercortisolemia and inactivity are the primary determinants of muscle catabolism after severe injury. All studies will be performed using stable isotope methodology and arterial-venous sampling across the leg with muscle biopsies. Hypotheses 1 and 3 will be investigated in adult and pediatric burn patients of both genders. Hypothesis 2 will be investigated in adult male burn patients. Hypothesis 4 will be investigated in healthy male and female adults during bed rest. The results of these studies will contribute to our understanding of hormonal regulation of skeletal muscle protein metabolism after severe injury. In addition, these studies will investigate the safety and efficacy of inexpensive agents in ameliorating muscle loss after burn injury.
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