HORMONAL REGULATION OF SKELETAL MUSCLE METABOLISM

激素对肌肉蛋白质代谢的调节是一个动态过程 反映了在任何特定时间内几种激素的作用。 其中研究得最好的是胰岛素，它能抑制前臂两侧的蛋白水解 肌肉和全身蛋白质。 与胰岛素不同，生长激素的作用 (GH)在调节正常人的蛋白质代谢方面， 很好的描述。 由于胰岛素和生长激素都需要正常的 生长在人，生长激素，本身或通过IGF-1，将影响 肌肉蛋白质代谢 初步数据显示， 局部输注GH刺激蛋白质的急性（6小时内）效应 合成由前臂骨骼肌组织在人。基于这些结果 和本申请中引用的其他实验，所述实验试图 分析GH、胰岛素和IGF-1在调节胰岛素分泌中的作用， 骨骼肌和全身蛋白质代谢的影响。 描述了四组实验。 第一个检查是否GH 以连续或脉动方式全身输注产生 整个身体和前臂肌肉蛋白质合成的急性变化， 在局部动脉灌注期间见于前臂肌肉。 第二组研究检查胰岛素和GH之间的相互作用 在调节蛋白质代谢方面。 内源性GH和胰岛素的抑制 生长抑素的分泌使我们能够建立GH缺乏或 I型糖尿病的发病率 选择性再给予GH或 这些模型中的胰岛素使我们能够探测对这些 激素在不同病理生理环境中的作用。 第三组实验旨在比较IGF-1的作用 与生长激素和胰岛素有关。 在大鼠中，IGF-1抑制肌肉蛋白水解 像胰岛素，不刺激蛋白质合成，因为生长激素似乎这样做。 拟议的研究旨在帮助阐明作用机制 胰岛素-生长激素-胰岛素样生长因子三联体对人体蛋白质代谢的影响。 最后，最后一组实验着眼于 细胞内信使cAMP和cGMP介导的反应， 生长激素胰岛素和IGF-1 GH在体外可阻止细胞内 cGMP。 GH的这种抑制作用与刺激 体外蛋白质合成。 拟议中的实验试图与 体内激素给药，测量cGMP和cAMP水平。

The hormonal regulation of muscle protein metabolism is a dynamic process that reflects, at any given time, the effects of several hormones. Insulin, the best studied of these, suppresses proteolysis in both forearm muscle and whole body protein. Unlike insulin, the role of growth hormone (GH) in the regulation of protein metabolism in normal man has not been well characterized. Since both insulin and GH are required for normal growth in man, GH, by itself or via IGF-1, would be expected to affect muscle protein metabolism. Preliminary data in presented demonstrating an acute (within 6 hours) effect of locally infused GH to stimulate protein synthesis by forearm skeletal muscle tissue in man. Based on these results and others cited in the application, the experiments described attempt to dissect apart the contributions of GH, insulin and IGF-1 to the regulation of skeletal muscle and whole body protein metabolism in man. Four sets of experiments are described. The first examines whether GH infused systemically in either a continuous or pulsatile fashion produces acute changes in whole body and forearm muscle protein synthesis like those seen in forearm muscle during local arterial infusion. The second set of studies examines the interaction between insulin and GH in regulating protein metabolism. Suppression of endogenous GH and insulin secretion with somatostatin allows us to develop models of GH deficiency or type I diabetes in normal subjects. Selected readministration of GH or insulin in these models then allows us to probe the responses to these hormones in different pathophysiological settings. The third group of experiments in intended to compare the effects of IGF-1 with those of GH and insulin. In rats, IGF-1 suppresses muscle proteolysis like insulin and does not stimulate protein synthesis, as GH appears to do. The proposed studies are designed to help clarify the mechanisms of action of the insulin-GH-IGF triad on protein metabolism in man. Finally, the last group of experiments looks at the role of the intracellular messengers cAMP and cGMP in the mediation of the responses to GH, insulin, and IGF-1. GH in vitro prevents the intracellular rise of cGMP. This suppressive effect of GH is associated with stimulation of protein synthesis in vitro. The proposed experiments attempt to relate in vivo hormone administration with measured levels of cGMP and cAMP.