The treatment of muscle disease is hindered by limited knowledge of the basic cell biology that governs muscle development and muscle function. This is true even of Duchenne muscular dystrophy despite the gene locus and the protein product of that gene locus, dystrophin, being identified over 20 years ago. During the last 20 years, numerous functions for dystrophin have been identified, yet the specific contribution of each function makes with regards to muscle development and muscle function have not been determined. To close this gap, the coPIs of this research proposal have established a collaboration. The goal of this collaboration is to design and execute experiments in divergent systems to fully evaluate muscle development and function in a variety of contexts including muscular dystrophy and muscle aging. In the proposed research we will combine the genetic and cell biological strengths of the model organism Drosophila melanogaster with the physiological relevance of mouse models to identify the mechanisms of dystrophin-dependent nuclear positioning and dystrophin-dependent microtubule organization. Furthermore, we will determine the mechanistic connection between these two dystrophin-dependent functions. This mechanistic connection will be determined relative to both the genetic networks that regulate the process and the temporal dependence for dystrophin. Finally, we will evaluate the contribution of each process to muscle function. These experiments necessitate that that we use emergent techniques that have been developed by the coPIs for this research proposal, and those recently developed by other researchers who will advise our adaptations of their technology. Successful completion of the proposed research will delineate two specific dystrophin functions and provide a framework by which additional functions for dystrophin, and factors linked to other muscle disorders, can be evaluated.
Impaired muscle function that is associated with muscle disease imposes a large burden, both as an economic effect on society and as a quality of life effect on the individual. Progress in treatment of impaired muscle function is limited in part by relatively poor understanding of the specialized cells that compose skeletal muscle. The proposed research will identify the mechanisms of dystrophin-dependent muscle functions with a focus on the cytoskeleton, nucleus, and their integration for mechanotransduction.
