We propose to characterize the mechanisms that regulate the development and maintenance of pattern in mammalian muscle. Muscle tissues are characterized by complex patterns of diverse interspersed muscle fibers specialized for different rates of contraction. The pattern of muscle fibers differs among muscles, a difference that is stably maintained in the course of tissue development and repair. The studies in this proposal will focus on these two fundamental developmental processes. Muscle is advantageous for this type of analysis, because the biochemical and contractile properties of muscle fibers have been extensively studied by others. Moreover the pattern of fiber types that is present during development and aging, altered in response to activity and innervation, and degenerates in disease states is well documented. Two related but distinct questions central to muscle regulatory biology will be addressed: (1) How is muscle fiber pattern established during development? The relative roles of cell autonomous behavior (lineage) and cell-cell interactions (environment) in establishing muscle fiber diversity will be examined during embryogenesis. Specifically, the cellular basis for the temporal pattern of primary and secondary fiber development and the spatial pattern of fast and slow fiber development will be elucidated. (2) How is myoblast migration controlled during fiber regeneration? Chemotactic signals that trigger myoblast proliferation and migration to sites of damage will be elucidated. Adhesive signals that promote myoblast binding and incorporation into fibers to sites of damage will be characterized. These studies will take advantage of properties unique to muscle: progeny of a single myoblast (clone) can be genetically marked with retroviral vectors and monitored in vivo, isolated and extensively characterized in vitro, and reimplanted into muscle tissues. Thus, findings in the simple milieu of tissue culture can be tested in the complex environment of the organism. These studies should contribute to a basic understanding of muscle development and regeneration and have direct application to therapeutic approaches to inherited and acquired diseases using myoblasts as vehicles for gene delivery.
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