Muscle myopathies and dystrophies cause debilitating disease in children and are associated with premature death in nearly all patients affected. Many muscle disorders, such as Duchenne, Becker, and Merosin-deficient muscular dystrophies, are caused by mutations in adhesion complexes that anchor muscle cells to their surrounding basement membrane (BM). Despite great strides in identifying the genetic basis of many myopathies, mechanisms that mediate BM assembly and adhesion are not well understood. In particular, there is a need for small molecule therapeutics and discovery of new targets for drug development. We have shown that NAD+ biosynthesis is necessary for muscle development and sufficient to correct dystrophic phenotypes in zebrafish. Nicotinamide Riboside Kinase 2b (Nrk2b)-mediated NAD+ biosynthesis ameliorates muscle degeneration by increasing BM organization and promoting the subcellular localization of an intracellular Integrin-binding protein, Paxillin. Paxillin is an essential signaling nexus that regulates cell adhesion, morphology, and migration. Preliminary data indicate that Paxillin overexpression dramatically improves muscle structure and decreases degeneration in dystrophic zebrafish, but the mechanisms are not known. The rationale of the proposed research is that because mechanical failure in cell adhesion between muscle fibers and their surrounding BM underlies the etiology of many myopathies, the Nrk2b pathway may have therapeutic utility for multiple congenital muscular dystrophies (CMDs). The objectives of this application are to elucidate the molecular underpinnings of Paxillin function in this pathway. Our central hypothesis is that Nrk2b-mediated NAD+ biosynthesis regulates subcellular localization of Paxillin;resulting in downstream signaling events that increase organization and structure of the BM microenvironment. The contribution of the proposed research is expected to be the elucidation of molecular mechanisms underlying a novel pathway that restores muscle structure/function in dystrophic zebrafish. This contribution is significant because this is a new paradigm in the effort to eradicate myopathies. The approach is innovative because it represents a shift in thinking. Instead of focusing on "canonical" muscle adhesion proteins, the focus is on the compensatory response of adhesion proteins that are traditionally understudied in muscle. Thus, this unique approach focuses on improving muscle structure by strengthening existing machinery. The long-term goal of this work is to capitalize on elucidation of a novel pathway that ameliorates dystrophy to identify new drug targets for the treatment of muscle degenerative disorders.
Childhood muscular dystrophies are currently incurable and lack effective treatment options. These diseases result from the disruption of cellular machinery that regulates muscle fiber integrity. The proposed research is relevant to public health because the outlined experiments focus on new pathways that enhance existing machinery and can be manipulated to alleviate myopathies. This research is fundamentally relevant to the part of NICHD's mission that aims to reduce the impact of childhood diseases.
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|Goody, Michelle F; Sher, Roger B; Henry, Clarissa A (2015) Hanging on for the ride: adhesion to the extracellular matrix mediates cellular responses in skeletal muscle morphogenesis and disease. Dev Biol 401:75-91|