Testosterone Effects on Muscle in Burn Injury

描述（由申请人提供）：在过去几年的支持， 我们已经证明了睾丸激素、皮质醇和胰岛素的作用 骨骼肌蛋白质。我们已经证明， 正常受试者的睾酮是通过肌肉蛋白质的增加来实现的 合成，而在成人烧伤，主要影响是减少 蛋白质分解我们还发现，高皮质醇血症， 长时间不活动，加剧肌肉氮的损失， 加速蛋白质分解由于这两种激素的关系是 在烧伤后发生了巨大的变化，这种变化很可能是 影响骨骼肌此外，我们已经证明，外源性胰岛素 增加烧伤患者肌肉蛋白质的净合成。我们提出建设 根据我们最近在烧伤患者中的发现，通过改变睾酮和皮质醇， 浓度，以描绘对肌肉蛋白质的最终影响。我们 假设增加睾丸激素与皮质醇的比例 骨骼肌中的净蛋白质平衡。我们认为睾丸激素可以 通过两种不同的机制潜在地促进成人的肌肉强直 不耐烦。如果糖皮质激素对肌肉的影响没有改善， 睾酮主要作为抗分解代谢剂， 蛋白质分解的程度。然而，如果皮质醇的分解作用 减少，那么睾丸激素将通过增加 蛋白质合成我们进一步提出了胰岛素和 睾酮对蛋白质合成的影响，因为每一种都通过不同的途径促进蛋白质合成。 机制等 本提案的总体目标是将我们先前的观察扩展到 研究以下与激素对 烧伤后的骨骼肌：假设1。皮质醇减少 分泌将减少肌肉蛋白质分解，提高净蛋白质 骨骼肌的平衡假设2.睾酮正常化， 皮质醇的减少将以累加的方式改善净蛋白质平衡。我们 我认为这是通过减少净蛋白质分解和增加净蛋白质分解来实现的。 蛋白质合成假设3.睾酮和局部的合成代谢作用 高胰岛素血症在烧伤患者中将是附加的。假设4.的 高皮质醇血症和不活动的联合作用是主要的 严重损伤后肌肉痉挛的决定因素。 所有研究将使用稳定同位素方法进行， 通过肌肉活检进行腿部动静脉取样。假设1和 3将在两种性别的成人和儿童烧伤患者中进行研究。 假设2将在成年男性烧伤患者中进行研究。假设4 将在卧床休息期间的健康男性和女性成年人中进行研究。的 这些研究的结果将有助于我们了解激素 严重损伤后骨骼肌蛋白质代谢的调节。在 此外，这些研究还将调查廉价药物的安全性和有效性。 减轻烧伤后肌肉损失的药物。

DESCRIPTION (provided by applicant): 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.