mTOR Signaling in Skeletal Myogenesis

描述(申请人提供)：骨骼肌分化是一个精心安排的过程，由自分泌、旁分泌和内分泌因子通过信号转导通路的调节网络进行调节。近年来，哺乳动物靶标雷帕霉素(MTOR)已开始被认为是骨骼肌分化、生长和肥大的关键调节因子。我们实验室的工作有助于目前对mTOR对成肌细胞分化调控的理解，并揭示了mTOR通过组装不同的途径来调节肌肉发生的多个阶段，其中一些途径是意想不到的，尚未完全描述。结合生化、分子、细胞和遗传学方法，并利用体外和体内系统，我们的目标是通过解决以下三个主要问题来填补目前关于骨骼肌发生调控的分子通路知识的一个相当大的空白：(1)生长调节mTOR通路的已知组成部分如何参与肌肉发生，以及mTOR通路(S)是什么，它调节成肌细胞分化的启动以响应氨基酸可用信号？(2)mTOR通路是什么专门调节第二阶段肌细胞融合对肌管/肌纤维的生长和成熟至关重要，哪些分泌因子调节这一过程？(3)mTOR在肌肉再生中的作用是什么？其机制是什么？我们在信号转导机制的生化表征方面的专业知识、强大的初步数据以及我们创建的独特动物模型，使我们处于解决这些问题的理想位置。在这些研究中获得的知识将有助于从分子上理解骨骼肌的发育、修复、再生和肥大。公共卫生相关性：骨骼肌分化是一个精心安排的过程，由自分泌、旁分泌和内分泌因子通过多种信号转导途径调节。我们建议的研究旨在剖析调控骨骼肌分化和再生的分子机制，重点放在雷帕霉素信号网络的哺乳动物靶标上。在这些研究中获得的知识将有助于对骨骼肌生物学的分子理解，这可能对肌肉营养不良、衰老或疾病导致的肌肉萎缩、肌肉再生和运动诱导的肌肉肥大等与健康相关的问题产生重大影响。

DESCRIPTION (provided by applicant): Skeletal muscle differentiation is a well-orchestrated process regulated by autocrine, paracrine, and endocrine factors via a regulatory network of signal transduction pathways. In recent years the mammalian target of rapamycin (mTOR) has begun to be recognized as a critical regulator of skeletal muscle differentiation, growth and hypertrophy. Work from our laboratory has contributed to the current understanding of mTOR regulation of myoblast differentiation, and has led to the revelation that mTOR regulates multiple stages of myogenesis by assembling distinct pathways, some of which unexpected and yet to be fully delineated. With a combination of biochemical, molecular, cellular and genetic approaches, and utilizing both in vitro and in vivo systems, we aim to fill a sizable gap in the current knowledge of molecular pathways underlying the regulation of skeletal myogenesis by addressing these three major questions: (1) How are the known components of growth-regulating mTOR pathway involved in myogenesis, and what is the mTOR pathway(s) that regulates the initiation of myoblast differentiation in response to amino acids availability signals? (2) What is the mTOR pathway that specifically regulates the second-stage myocyte fusion critical for myotube/myofiber growth and maturation, and which secreted factors regulate this process? (3) What is mTOR's role in muscle regeneration and what are the mechanisms? Our expertise in biochemical characterization of signal transduction mechanisms, our strong preliminary data, and the unique animal models we have created, put us in an ideal position to tackle those questions. Knowledge gained in these studies will contribute to the molecular understanding of skeletal muscle development, repair, regeneration and hypertrophy. PUBLIC HEALTH RELEVANCE: Skeletal muscle differentiation is a well-orchestrated process regulated by autocrine, paracrine, and endocrine factors via multiple signal transduction pathways. Our proposed studies aim to dissect the molecular mechanisms underlying the regulation of skeletal muscle differentiation and regeneration, with a focus on the mammalian target of rapamycin signaling network. Knowledge gained in these studies will contribute to the molecular understanding of skeletal muscle biology, which may have significant impact on health-related issues such as muscular dystrophy, aging or disease-induced muscle atrophy, muscle regeneration, and exercise- induced muscle hypertrophy.