Mechanisms of regulation of skeletal muscle mass and growth

除了大家都知道的帮助我们运动的作用，我们的骨骼肌在我们身体利用食物营养的方式上也起着重要的作用。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的调节的基本了解。在过去的几年里，我们一直在研究一种叫做哺乳动物雷帕霉素靶蛋白1 （mTORC1）的蛋白质复合物的作用和调控。这种复合体部分通过调节蛋白质合成途径中一个叫做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，当动物或肌肉细胞被剥夺营养时，肌肉蛋白质代谢的破坏可以追溯到这一途径的功能降低。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，很少有关于mTORC1及其底物在肌肉发生过程中的调控的信息，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。我们也不知道被称为支链氨基酸的特定氨基酸（来源于我们的饮食）是否在肌肉形成中起作用。这些氨基酸是肌肉蛋白质合成和质量的有效调节剂。最近，我们观察到在成肌细胞（增殖肌细胞）向肌管细胞（非增殖肌细胞）的转变过程中，许多mTORC1底物的丰度增加。为了更深入地了解mTORC1在调节肌肉细胞分化中的作用、作用机制和调控，我未来5年的研究计划短期目标为：***1。研究肌肉细胞分化过程中mTORC1及其底物的调控。****通过制造缺乏这些底物的细胞并检查这些细胞的分化能力来研究对这些底物的需求。检测分化过程中mTORC1的氨基酸调控。* * * 4。我的长期目标是研究创伤后肌肉再生过程中mTORC1底物的丰度和调控，以及氨基酸对这种调控的影响。我们还将研究肌肉特异性敲除mTORC1底物和调节氨基酸代谢的酶。我们将检查这些动物的肌肉在受伤后再生能力是否有缺陷。****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。我的研究项目也促进了高素质人才的培养：在过去的6年里，我已经培训了23名这样的人才。我在未来5年的研究计划将培养至少15名高素质人才，为加拿大在基础研究领域的持续主导地位做出贡献

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.**