Mechanisms of regulation of skeletal muscle mass and growth

骨骼肌质量和生长的调节机制

• 批准号: RGPIN-2015-05165
• 负责人: Adegoke, Olasunkanmi
• 金额: $ 1.75万
• 依托单位: York University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=679838
• 关键词: Mechanisms; regulation; skeletal; muscle; mass

Apart from their commonly appreciated roles in helping us to move, our skeletal muscles also play significant roles in the way our bodies use food nutrients. Therefore optimal muscle mass and metabolism are critical to normal body functions. The focus of my research program is the basic understanding of the regulation of skeletal muscle mass and growth. In the past few years, we have been studying the roles and regulation of a protein complex called the mammalian target of rapamycin complex 1 (mTORC1). This complex regulates muscle mass and protein metabolism in part by regulating a crucial phase in the protein synthetic pathway called mRNA translation. We have shown that disruption of muscle protein metabolism seen when animals or muscle cells are deprived of nutrients can be traced to reduced functions of this pathway. Muscle mass can be regulated by controlling the growth of each muscle cell and/or the number of cells. Crucially, there is little information on the regulation of mTORC1 and its substrates during myogenesis, a process required not only during development but also during muscle repair. It is also not known if specific amino acids (derived from our diets) called branched-chain amino acids, play a role in myogenesis. These amino acids are potent regulators of muscle protein synthesis and mass. Recently, we observed increased abundance of a number of mTORC1 substrates during the transition from myoblast (proliferating muscle cells) to myotubes (non proliferating muscle cells). To gain a deeper understanding of the roles, mechanisms of actions and regulation of mTORC1 in regulating muscle cell differentiation, the short-term objectives of my research program in the next 5 years are: ***1. Examine the regulation of mTORC1 and its substrates during the differentiation of muscle cells.****2. Study the requirement of these substrates by creating cells depleted of them and examining the ability of such cells to differentiate.***3. Examine amino acid  regulation of mTORC1 during differentiation. ***4. My long-term objective is to study the abundance and regulation of mTORC1 substrates during muscle regeneration after trauma, and the effects of amino acids on such a regulation. We will also study muscle specific knock-outs of mTORC1 substrates and of enzymes that regulate amino acid metabolism. We will examine whether muscles from such animals are defective in their ability to regenerate following injury.****These studies will increase our understanding of the basic processes involved in regulating muscle growth and may help in the design of approaches that can improve/enhance muscle functions. My research program also facilitates the training of high quality personnel: in the last 6 years, I have trained/am training 23 such individuals. My research program in the next 5 years will facilitate the training of at least 15 high quality personnel that will contribute to the continuing dominance of Canada in basic research.**

除了它们在帮助我们移动方面的普遍作用外，我们的骨骼肌在我们身体利用食物营养的方式中也起着重要作用。因此，最佳的肌肉质量和新陈代谢对正常的身体功能至关重要。我的研究计划的重点是对骨骼肌质量和生长调节的基本理解。在过去的几年里，我们一直在研究一种称为雷帕霉素复合物哺乳动物靶点1（mTORC 1）的蛋白质复合物的作用和调节。这种复合物通过调节蛋白质合成途径中称为mRNA翻译的关键阶段来调节肌肉质量和蛋白质代谢。我们已经证明，当动物或肌肉细胞缺乏营养时，肌肉蛋白质代谢的中断可以追溯到这一途径功能的降低。肌肉质量可以通过控制每个肌肉细胞的生长和/或细胞的数量来调节。至关重要的是，几乎没有关于mTORC 1及其底物在肌肉发生过程中的调节的信息，这一过程不仅在发育过程中需要，而且在肌肉修复过程中也需要。也不知道特定的氨基酸（来自我们的饮食）称为支链氨基酸，在肌生成中发挥作用。这些氨基酸是肌肉蛋白质合成和质量的有效调节剂。最近，我们观察到从成肌细胞（增殖肌细胞）到肌管（非增殖肌细胞）的过渡过程中，大量mTORC 1底物的丰度增加。为了更深入地了解mTORC 1在调节肌细胞分化中的作用、作用机制和调控，我在未来5年的研究计划的短期目标是：*1.研究mTORC 1及其底物在肌细胞分化过程中的调节作用。* 2.通过创建耗尽这些底物的细胞并检查这些细胞的分化能力来研究这些底物的需求。* 3.检查mTORC 1在分化过程中的氨基酸调节。*4.我的长期目标是研究创伤后肌肉再生过程中mTORC 1底物的丰度和调节，以及氨基酸对这种调节的影响。我们还将研究肌肉特异性敲除mTORC 1底物和调节氨基酸代谢的酶。我们将检查这些动物的肌肉是否在受伤后再生能力方面有缺陷。这些研究将增加我们对调节肌肉生长的基本过程的理解，并可能有助于设计可以改善/增强肌肉功能的方法。我的研究计划也促进了高素质人才的培训：在过去的6年里，我已经培训/正在培训23名这样的人。我在未来5年的研究计划将促进至少15名高素质人才的培训，这将有助于加拿大在基础研究中的持续主导地位。