mTOR Signaling in Skeletal Myogenesis

描述（由申请人提供）：骨骼肌分化是一个由自分泌、旁分泌和内分泌因素通过多种信号转导途径调控的精心安排的过程。细菌大环内酯类雷帕霉素抑制多种细胞功能，从增殖、生长到分化，它已被用作探测相关信号通路的有力工具。虽然在细胞生长和增殖的背景下，雷帕霉素敏感通路正在被深入研究，但它在骨骼肌发育中的重要性才刚刚开始被认识到。雷帕霉素的哺乳动物靶点mTOR是一种多功能蛋白，是雷帕霉素抑制的多种信号通路的中心成分。本实验室的初步研究揭示了mTOR在骨骼肌分化中的重要功能，以及mTOR信号传导的新机制的存在。本研究旨在验证一种假设，即mTOR通路不同于细胞生长和增殖，通过控制IGF-I和IGF-II的自分泌来调节骨骼肌卫星细胞分化。结合生化、分子、细胞和遗传等方法，在组织培养模型（C2C12）和小鼠原代卫星细胞系统中，本研究的具体目的是研究(1)mTOR对IGF自分泌的调控；(2)磷脂酶d-磷脂酸- mtor通路参与肌肉形成；(3) mTOR在分化中的结构-功能关系和新的信号伙伴。在这些研究中获得的知识不仅将为了解多功能性mTOR通路的信号机制提供宝贵的见解，而且还将对骨骼肌发育的分子理解做出重大贡献，骨骼肌发育与肌肉营养不良、运动诱导的肥大和衰老相关的萎缩等健康相关问题密切相关。

DESCRIPTION (provided by applicant): Skeletal muscle differentiation is a well-orchestrated process regulated by autocrine, paracrine, and endocrine factors via multiple signal transduction pathways. The bacterial macrolide rapamycin inhibits a wide spectrum of cellular functions, from proliferation, growth, to differentiation, and it has served as a powerful tool to probe relevant signaling pathways. While the rapamycin-sensitive pathway is under intensive investigation in the context of cell growth and proliferation, its importance in skeletal muscle development is only beginning to be recognized. The mammalian target of rapamycin - mTOR- is a multi-functional protein that serves as a central component of multiple signaling pathways that are inhibited by rapamycin. Preliminary studies from this investigator's laboratory have revealed an essential function of mTOR in skeletal muscle differentiation and the existence of novel mechanisms of mTOR signaling. The proposed studies are designed to test the hypothesis that an mTOR pathway distinct from that in cell growth and proliferation regulates skeletal muscle satellite cell differentiation by controlling the autocrine production of IGF-I and IGF-II. With a combination of biochemical, molecular, cellular and genetic approaches, and in the systems of a tissue culture model (C2C12) and mouse primary satellite cells, the specific aims of this proposal are to investigate (1) regulation of IGF autocrine production by mTOR; (2) involvement of a phospholipase D-phosphatidic acid-mTOR pathway in myogenesis; and (3) mTOR's structure-function relationship and novel signaling partners in differentiation. Knowledge gained in these studies will not only provide invaluable insights into the signaling mechanisms of the pleiotropic mTOR pathway, but also make significant contributions to the molecular understanding of skeletal muscle development, which is tightly coupled to health-related issues such as muscular dystrophy, exercise-induced hypertrophy, and aging-related atrophy.