Regulation of Skeletal Muscle Metabolism

骨骼肌代谢的调节

• 批准号: 8006688
• 负责人: LEONARD S JEFFERSON
• 金额: $ 10.65万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-31 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8006688
• 关键词: Aging; Amino Acids; Area; Catecholamines; Cell Size; Cloning; Cyclic AMP; DUSP1 gene; Development; Disease; Eukaryotic Initiation Factors; Exercise; Fiber; GTPase-Activating Proteins; Genetic Translation; Glucocorticoids; Goals; Grant; Hormonal; Hormones; Indium; Insulin; Insulin-Like Growth Factor I; Leucine; Mediating; Messenger RNA; Modification; Molecular Target; Muscle; Nutrient; Pathway interactions; Pattern; Peptide Initiation Factors; Phosphorylation; Physiological; Positioning Attribute; Principal Investigator; Process; Productivity; Protein Biosynthesis; Proteins; Raptors; Records; Regulation; Research; Research Personnel; Resistance; Role; STK11 gene; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Sirolimus; Site; Skeletal Muscle; Somatomedins; Testing; Therapeutic; Translation Initiation; Translations; Work; base; cell growth; design; experience; genetic manipulation; genetic regulatory protein; human TSC1 protein; human TSC2 protein; insight; mTOR protein; muscle form; muscle metabolism; novel; programs; protein expression; research study; response; therapeutic development

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.

描述（申请人提供）：许多重要的与健康相关的病症，包括但不限于衰老、身体活动不足、营养不平衡或不足、激素不平衡或不足以及许多疾病状态，与骨骼肌质量的急剧损失相关，这主要是由于蛋白质合成和降解速率之间的不平衡的发展，特别是在那些由高比例的快速收缩纤维组成的肌肉中。为了更好地理解这些病症中的每一种的不平衡的原因，并开始开发用于消除或逆转肌肉质量损失的治疗策略，在该竞争性更新申请中描述的项目的长期目标是鉴定和表征骨骼肌中mRNA翻译的起始通过其调节的信号传导途径和效应器机制。为下一个赠款期提出的研究旨在检验以下假设：氨基酸对骨骼肌蛋白质表达模式和蛋白质合成总体速率的影响（例如亮氨酸）、激素（如胰岛素、糖皮质激素和儿茶酚胺），和/或抗阻运动部分由通过哺乳动物雷帕霉素靶蛋白（mTOR）起作用的调节输入的动态相互作用控制信号传导途径介导参与选择mRNA进行翻译的效应子机制的控制。该项目的具体目标是：（1）鉴定亮氨酸如何起作用以刺激mTOR介导的信号传导至参与选择用于翻译的mRNAs的效应器机制;（2）鉴定诸如糖皮质激素和儿茶酚胺的试剂如何起作用以抑制mTOR介导的信号传导至参与选择用于翻译的mRNAs的效应器机制;（3）鉴定mTOR介导的信号通路中选定的分子靶点，所述分子靶点在被激活时对通路的其他组分的输入产生显性效应;以及（4）鉴定mTOR介导的信号通路如何起作用以刺激eIF 2B的翻译。mRNA，定位赋予调节的e-亚基信息中的功能元件，并分析增加的eIF 2Be表达对蛋白质合成和细胞生长的功能影响。总的来说，拟议的研究应该提供新的见解，通过营养素，激素和抗阻力运动的信号通路和效应机制，以调节蛋白质表达模式和蛋白质合成的全球速率在骨骼肌。