Mechanisms of regulation of skeletal muscle mass and growth

我们的骨骼肌除了在帮助我们移动方面发挥着普遍的作用外，还在我们的身体利用食物营养的方式上扮演着重要的角色。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了解。在过去的几年里，我们一直在研究一种名为哺乳动物雷帕霉素复合体1靶蛋白(MTORC1)的蛋白质复合体的作用和调控。这种复合体调节肌肉质量和蛋白质代谢，部分是通过调节蛋白质合成途径中的一个关键阶段，称为信使核糖核酸翻译。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。关键的是，关于mTORC1及其底物在肌肉发生过程中的调控信息很少，这一过程不仅在发育过程中需要，在肌肉修复过程中也是如此。目前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)是否在肌肉发生中起作用。这些氨基酸是肌肉蛋白质合成和质量的有力调节器。最近，我们观察到在成肌细胞(增殖性肌细胞)向肌管(非增殖性肌细胞)的转变过程中，mTORC1底物的数量增加。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，我在未来5年的研究计划的短期目标是：*1.研究mTORC1及其底物在肌肉细胞分化过程中的调节。*2.通过建立去除这些底物的细胞并检测其分化能力来研究对这些底物的需求。*3.检测氨基酸对mTORC1在分化过程中的调节。*4.我的长期目标是研究mTORC1底物在肌肉创伤后再生过程中的丰度和调节以及氨基酸对这种代谢的影响。我们还将研究mTORC1底物和调节氨基酸新陈代谢的酶的肌肉特异性敲除。我们将检查这些动物的肌肉在受伤后是否有能力再生。*这些研究将增加我们对调节肌肉生长所涉及的基本过程的理解，并可能有助于设计能够改善/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训：在过去的6年里，我培训了/正在培训23名这样的人。我未来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领域继续占据主导地位。**

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.**