Regulation of Skeletal Muscle Metabolism

描述（由申请人提供）：许多重要的健康相关状况，包括但不限于，衰老、缺乏身体活动、营养失衡或不足、激素失衡或不足，以及许多疾病状态，都与骨骼肌质量的急剧减少有关，这主要是由于蛋白质合成和降解速率之间的不平衡，特别是在那些由高比例的快肌纤维组成的肌肉中。为了更好地理解每种情况下失衡的原因，并开始制定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骨骼肌中mRNA翻译起始调控的信号通路和效应机制。为下一个赠款期提出的研究旨在检验下列假设：在氨基酸（如亮氨酸）、激素（如胰岛素、糖皮质激素和儿茶酚胺）和/或阻力运动的影响下，骨骼肌中蛋白质表达模式和整体蛋白质合成速率的改变，在一定程度上是由调节输入的动态相互作用决定的，这些调节输入通过哺乳动物雷帕霉素靶蛋白（mTOR）信号通路介导了参与mrna翻译选择的效应机制的控制。该项目的具体目标是：(1)确定亮氨酸如何刺激mtor介导的信号传导到参与mrna翻译选择的效应机制；(2)确定糖皮质激素和儿茶酚胺等药物如何抑制mtor介导的信号传导到参与mrna翻译选择的效应机制；(3)为选定的药物确定mtor介导的信号通路内的分子靶点，这些靶点在激活时对该通路的其他组分的输入产生主导作用；(4)确定mtor介导的信号传导如何刺激elF2B¿mRNA的翻译，定位e-亚基信息中赋予调控的功能元件，并分析elF2Be表达增加对蛋白质合成和细胞生长的功能影响。总的来说，拟议的研究应该为营养物质、激素和抵抗性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.