Regulation of Skeletal Muscle Metabolism

描述(申请人提供)：许多与健康相关的重要疾病，包括但不限于衰老、体力活动不足、营养失衡或不足、荷尔蒙失衡或不足，以及一些疾病状态与骨骼肌块的急剧减少有关，这主要是由于蛋白质合成和降解速率之间的失衡，特别是在那些由高比例快速抽动纤维组成的肌肉中。为了更好地了解每种情况下失衡的原因，并开始开发消除或逆转肌肉质量损失的治疗策略，本竞争性更新申请中描述的项目的长期目标是识别和表征在骨骼肌中启动mRNA翻译的信号通路和效应器机制。建议在下一个授权期进行的研究旨在检验以下假设：氨基酸(例如亮氨酸)、激素(例如胰岛素、糖皮质激素和儿茶酚胺)和/或抵抗运动导致骨骼肌蛋白质表达模式和全球蛋白质合成速率的变化部分是由调控输入的动态相互作用控制的，这些调控输入通过哺乳动物雷帕霉素靶标(MTOR)信号通路介导对参与选择翻译的mRNAs的效应机制的控制。该项目的具体目标是：(1)确定亮氨酸如何刺激mTOR介导的信号传递给参与选择翻译的mRNAs的效应器机制；(2)确定糖皮质激素和儿茶酚胺等药物如何作用于抑制mTOR介导的信号传递到参与mRNAs选择的效应器机制；(3)为选定的药物确定mTOR介导的信号通路中的分子靶点，这些靶点在激活时产生主导作用，而不是对该途径的其他成分的输入；以及(4)确定mTOR介导的信号如何刺激elF2B？mRNA的翻译，定位e-亚基消息中提供调控的功能元件，并分析elF2Be表达增加对蛋白质合成和细胞生长的功能影响。总体而言，拟议的研究应该为营养物质、激素和耐力运动调节骨骼肌蛋白质表达模式和整体蛋白质合成速率的信号通路和效应器机制提供新的见解。

DESCRIPTION (provided by applicant): A number of important health-related conditions including, but not limited to, aging, physical inactivity, nutrient imbalance or insufficiency, hormonal imbalance or insufficiency, and a number of disease states are associated with a dramatic loss of skeletal muscle mass due largely to development of an imbalance between rates of protein synthesis and degradation, particularly in those muscles composed of a high proportion of fast-twitch fibers. In order to better understand the causes of the imbalance for each of these conditions and to begin to develop therapeutic strategies for abrogating or reversing the loss of muscle mass, the long-term objectives of the project described in this competitive renewal application are to identify and characterize the signaling pathways and effector mechanisms through which the initiation of mRNA translation is regulated in skeletal muscle. The studies proposed for the next grant period are designed to test the following hypothesis: alterations in protein expression patterns and global rates of protein synthesis in skeletal muscle in response to amino acids (e.g. leucine), hormones (e.g. insulin, glucocorticoids, and catecholamines), and/or resistance exercise are governed in part by a dynamic interplay of regulatory inputs acting through the mammalian target of rapamycin (mTOR) signaling pathway to mediate control of effector mechanisms involved in the selection of mRNAs for translation. The specific aims of the project are: (1) to identify how leucine acts to stimulate mTOR-mediated signaling to effector mechanisms involved in the selection of mRNAs for translation; (2) to identify how agents such as glucocorticoids and catecholamines act to repress mTOR-mediated signaling to effector mechanisms involved in the selection of mRNAs for translation; (3) to identify for selected agents molecular targets within the mTOR-mediated signaling pathway that when activated produce a dominant effect over inputs to other components of the pathway; and (4) identify how mTOR-mediated signaling acts to stimulate translation of elF2B¿ mRNA, locate the functional elements in the e-subunit message that confer regulation, and analyze the functional effects of increased elF2Be expression on protein synthesis and cell growth. Overall, the proposed studies should provide new insights into the signaling pathways and effector mechanisms through which nutrients, hormones, and resistant exercise act to modulate protein expression patterns and global rates of protein synthesis in skeletal muscle.