Regulation of Skeletal Muscle Metabolism

项目摘要/摘要 我们的长期目标是了解如何控制骨骼肌中的蛋白质合成 出于预防和治疗的目的而操纵。这里的目标是了解如何 预防和/或逆转因缺乏运动而导致的骨骼肌量减少。不活动包括许多 导致肌肉质量丧失的条件包括久坐不动的生活方式、慢性卧床休息、铸型、四肢 暂停和固定。这些不活动相关的情况中的每一种都被认为共享一个共同的特征， 即骨骼肌蛋白质合成对合成代谢的反应延迟和降低幅度 刺激，这一直被称为合成代谢抵抗。我们的中心假设是合成代谢抵抗 是由于营养物质，特别是氨基酸亮氨酸， 介导雷帕霉素复合体1(MTORC1)机制靶点的调节，导致细胞内存在缺陷 蛋白质合成的效率和能力以及蛋白酶体维持蛋白质稳定的功能 骨骼肌。我们的假设是基于我们过去在阐明 不同生理和生理状态下骨骼肌mTORC1信号和蛋白质合成的调节 病理生理条件。为了验证我们的假设，我们将使用一个包含模型的实验协议 从完整的老鼠到完整的组织再到细胞培养的系统，以及用于分析的尖端技术 信使核糖核酸翻译和蛋白质磷酸化位点。拟议的研究包括以下三个方面 具体目的：(1)鉴定亮氨酸选择性作用所需的分子成分。 MTORC1的激活；(2)Sestrin2磷酸化的调节及其在调节合成代谢中的作用 抵抗骨骼肌的废用性萎缩；以及(3)建立骨骼肌的激活状态与 MTORC1及其控制蛋白质合成效率和能力的靶标的反应，以及 蛋白酶体在骨骼肌中维持蛋白稳定的功能。总括而言，我们预期拟议的 研究揭示了可能被药理学操纵的分子靶点，从而产生新的和 预防和治疗肌肉萎缩状况的创新方法。

Project Summary/Abstract Our long-term goal is to understand how the control of protein synthesis in skeletal muscle can be manipulated for preventive and therapeutic purposes. The objective here is to gain an understanding of how to prevent and/or reverse inactivity-induced loss of skeletal muscle mass. Inactivity encompasses a number of conditions that lead to loss of muscle mass including sedentary lifestyles, chronic bed rest, casting, limb suspension, and immobilization. Each of these inactivity-related conditions is thought to share a common feature, i.e. a delayed and reduced magnitude in the response of skeletal muscle protein synthesis to an anabolic stimulus, which has been referred to as anabolic resistance. Our central hypothesis is that anabolic resistance is due to dysregulation of the molecular mechanisms through which nutrients, specifically the amino acid leucine, act to mediate regulation of the mechanistic target of rapamycin complex 1 (mTORC1) resulting in defects in the efficiency and capacity of protein synthesis as well as the function of the proteasome to maintain proteostasis in skeletal muscle. Our hypothesis has been formulated on the basis of our past accomplishments in elucidating the regulation of mTORC1 signaling and protein synthesis in skeletal muscle under a variety of physiological and pathophysiological conditions. To test our hypothesis, we will pursue an experimental protocol involving model systems ranging from intact rats to intact tissues to cell culture, as well as cutting-edge technologies for analyzing mRNA translation and protein phosphorylation sites. The proposed studies encompass the following three specific aims: (1) identify molecular components required for the selective action of leucine in mediating the activation of mTORC1; (2) delineate the regulation of Sestrin2 phosphorylation and its role in mediating anabolic resistance in disuse atrophy of skeletal muscle; and (3) establish the relationship between the activation state of mTORC1 and the response of its targets that control the efficiency and capacity of protein synthesis, as well as the function of the proteasome, in maintaining proteostasis in skeletal muscle. Overall, we expect the proposed research to reveal molecular targets that can likely be manipulated pharmacologically resulting in new and innovative approaches to the prevention and treatment of muscle wasting conditions.