The original specific aims of this project were to:

1. Identify the roles of dystrophin-based pathway as a signaling pathway for muscle plasticity most active in Type II fibers. The mdx null mouse line which is dystrophin-negative will be studied.
2. Delineate the roles of the myotonic protein kinase (DMPK)-based system which appears to represent a signaling pathway for muscle plasticity most active in Type I fibers. Knockout and transgenic mouse lines which are either DMPK-negative or overexpressing DMPK will be studied.
3. Characterize the roles of focal adhesion kinase and associated molecules as a general myogenic signaling pathway in muscle plasticity. Transgenic mouse lines with inducible knockout and mutant constructs will be studied.
4. Analyze genetically the interactions between dystrophin, focal adhesion kinase, and DMPK pathways in specific double mutant combinations, and further characterizing the mechanisms by which those pathways regulate muscle plasticity.

The central molecule of interest has been DMPK. The interactions of DMPK with Rac-1 that we have studied are related in vivo to the actions of focal adhesion kinase. Rac-1 is a downstream effector of focal adhesion kinase, which is an integral component of the integrin/actin cytoskeleton-signaling pathway that is adhesion-sensitive. The interactions of DMPK with Raf-1 kinase of the chemical signaling pathway and Rac-1 represent an important further characterization of the signaling pathways that regulate muscle plasticity.

In the last year, our work on the UNC-45 myosin assemblase has become relevant to this project because we broadened our focus there from genetic and biochemical experiments in C. elegans to the identification and characterization of UNC-45 homologues in humans and mice.

NASA Task Book Entry