Phosphoinositide metabolism and its role in skeletal myogenesis

骨骼肌的主要功能是产生力量，使运动成为可能。肌肉有几个独特的结构来帮助它执行这一功能，包括神经肌肉连接、三联体和肌节。人们对肌肉发育(称为肌肉发生)有很多非常笼统的了解。然而，指导和控制肌肉独特的力生成结构的创建和维护的关键分子却知之甚少。我们研究的首要目标是定义管理这些结构的生物发生的分子事件。我们团队和其他人最近的工作发现，磷脂酰肌醇(PIP)和调节它们的酶可能是骨骼肌发育的关键角色。PIP是具有共同骨架的脂类，但基于磷酸基团含量和位置的不同而不同。有7个独立的PIP，每个都有独特的定位、调节和生物功能。虽然已经有大量关于PIP在单个细胞中的功能的知识，但它们在骨骼肌中的作用(S)尚未得到系统的研究。因此，这项建议的具体目的是了解PIP与肌肉发育之间的关系，目的是确定PIP在使肌肉执行其专门功能的独特细胞亚结构形成中所起的作用(S)。我们将通过以下方式实现这一目标：(1)建立在肌肉发生过程中关键肌肉亚结构的单个PIP的空间和时间定位；(2)确定肌肉亚结构形成和维持对PIP的总体需求；(3)了解单个PIP在肌肉发生特别是神经肌肉连接和三联体形成中的特定作用。为此，我们将利用斑马鱼模型系统，并利用我们开发的许多工具来研究其中的肌肉结构和功能。这项拟议研究的成功完成将极大地促进对肌肉发育的了解。特别是，它将首次定义肌肉发生过程中对PIP的要求(S)，特别是定义骨骼肌的独特亚细胞结构的形成。我们的发现将对肌肉生物界具有重要的相关性和重要性，并将对PIP和器官生物发生的研究产生重大影响。

Skeletal muscle’s main function is to generate force to enable movement. Muscle has several unique structures that help it to perform this function, including the neuromuscular junction, the triad, and the sarcomere. Much is known about muscle development (called myogenesis) in very general terms. However, the key molecules that guide and control the creation and maintenance of muscle’s unique force generating structures are poorly understood. The overarching goal of our research is to define the molecular events that govern the biogenesis of these structures. Recent work from our group and others has identified phosphoinositides (PIPs) and the enzymes that regulate them as potentially key players for skeletal muscle development. PIPs are lipids that share a common backbone but differ based on phosphate group content and position. There are seven individual PIPs, each with unique localization, regulation, and biologic function. While there is an extensive body of knowledge related to function of PIPs in individual cells, their role(s) in skeletal muscle has yet to be systematically examined. The specific purpose of this proposal, therefore, is to understand the relationship between PIPs and muscle development with the goal of defining the role of PIPs in the formation of the unique cellular substructures that enable muscle to perform its specialized function(s). We will accomplish this goal by (1) establishing the spatial and temporal localization of individual PIPs at the key muscle substructures during myogenesis, (2) determining the overall requirement for PIPs for muscle substructure formation and maintenance, and (3) understanding the specific role of individual PIPs in myogenesis and particularly for neuromuscular junction and triad formation. To do this, we will utilize the zebrafish model system, and take advantage of the many tools we have developed for studying muscle structure and function in it. Successful completion of the proposed research will significantly advance the understanding of muscle development. In particular, it will define for the first time the requirement(s) for PIPs in myogenesis and specifically for the formation of the unique subcellular structures that define skeletal muscle. Our findings will be of great relevance and importance to the muscle biology community, and will also significantly impact the study of PIPs and organ biogenesis.