Testosterone Effects on Muscle in Burn Injury

描述(由申请人提供)：在过去的几年中支持此 我们已经证明了睾丸激素、皮质醇和胰岛素的作用。 关于骨骼肌蛋白质。我们已经证明了合成代谢的作用 正常人体内的睾丸素是通过增加肌肉蛋白质来实现的 合成，而在成人烧伤中，主要作用是减少 蛋白质分解。我们还表明，当高皮质醇血症合并使用时 由于长期不活动，会加剧肌肉氮的损失 加速蛋白质分解。因为这两种荷尔蒙的关系是 烧伤后发生了巨大的变化，很可能是这种变化 影响骨骼肌。此外，我们还证明了外源性胰岛素 增加烧伤患者肌肉蛋白质的净合成。我们计划建造一座 根据我们最近在烧伤患者中通过改变睾酮和皮质醇的发现 浓度来描述对肌肉蛋白质的综合影响。我们 假设增加睾酮与皮质醇的比率将会改善 骨骼肌中的净蛋白质平衡。我们认为，睾丸激素可以 可能通过两种不同的机制促进成人肌肉合成代谢 自暴自弃。如果糖皮质激素对肌肉的影响没有改善，那么 睾丸素主要作为一种抗分解新陈代谢药物，通过减少 蛋白质分解的程度。然而，如果皮质醇的分解代谢作用 减少，那么睾丸素将通过增加 蛋白质合成。我们进一步提出了胰岛素和胰岛素之间的相加效应。 睾酮对蛋白质合成的影响，因为每种激素都通过不同的途径促进合成 机械装置。 这项建议的总体目标是将我们之前的观察结果扩展到 调查以下与荷尔蒙对 烧伤后骨骼肌：假设1皮质醇减少 分泌会减少肌肉蛋白质的分解，提高净蛋白质 骨骼肌的平衡。假设2：睾酮的正常化和皮质醇的减少将以一种相加的方式改善净蛋白质平衡。我们 认为这是通过减少净蛋白质分解和增加净蛋白质来实现的 蛋白质合成。假设3：烧伤患者体内睾酮和局部高胰岛素血症的合成代谢作用是相加的。假设4. 高皮质醇血症和缺乏活动的综合影响是主要的 严重创伤后肌肉分解代谢的决定因素。 所有研究都将使用稳定同位素方法和 对腿部的动静脉进行肌肉活组织检查。假设1和 3将在成人和儿童烧伤患者中进行调查，无论男女。 假设2将在成年男性烧伤患者中进行研究。假设4 将在卧床休息期间对健康的男性和女性成年人进行调查。这个 这些研究的结果将有助于我们理解荷尔蒙 严重创伤后骨骼肌蛋白质代谢的调节。在……里面 此外，这些研究将调查廉价的安全性和有效性 用于改善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.