Phosphoinositide metabolism and its role in skeletal myogenesis

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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.