This application proposes to study respiratory insufficiency associated with progressive muscle degenerative disorders. Lethality in muscle degenerative disorders arises from a combination respiratory and cardiac dysfunction. The dystrophin complex is essential for providing stability to skeletal myofibers and cardiomyocytes, and mutations in the genes encoding dystrophin and its associated proteins are the most common and most severe causes of muscular dystrophy. In Duchenne Muscular dystrophy, respiratory muscle function is lost by the age of 20 necessitating pulmonary support. Respiratory dysfunction in the muscular dystrophies is clinically important and largely understudied. We propose to investigate the pathological mechanisms of cardiopulmonary dysfunction and its response to therapy. Furthermore, data from in vitro and in vivo techniques will be integrated in order to fully investigate the mechanisms of respiratory disease progression and therapeutic benefits. Preliminary studies have been conducted in mice lacking the dystrophin-associated protein, 3-sarcoglycan (Sgcg null) since these mice display a severe phenotype, most similar to what is seen in human patients. The diaphragm muscle is severely diseased in this model. We previously described that Sgcg null mice display a less severe or protected phenotype when placed in the 129Sv/J background. These mice are designated "129-Sgcg". The Sgcg null allele has a more severe or enhanced phenotype when in the DBA2J background (D2-Sgcg). The D2-Sgcg mouse strain has a hyper- activated TGF2 signaling cascade leading to the heightened fibrosis observed in these mice. Genomic mapping of diaphragm fibrosis as a quantitative trait has yielded four chromosomal loci that modulate diaphragm fibrosis in an F2 cohort of animals between the D2-Sgcg and 129-Sgcg strains. Notably, these genetic loci are different between limb based muscle and the diaphragm muscle highlighting the unique pathology of the respiratory system. We also introduced the Sgcg null allele into the "super-healing" MRL background and find that the MRL contribution reduces disease progression in diaphragm and cardiac muscles. We hypothesize that modifier genes regulate fibrosis differentially in diaphragm muscle compared to other skeletal muscles. We also hypothesize that TGF2-mediated fibrosis and resultant scar tissue functionally impedes diaphragm muscle function in muscular dystrophy and other pulmonary diseases.
We propose to identify genes responsible for diaphragm scarring and to functionally test therapies to reduce diaphragm fibrosis in mouse models of muscular dystrophy. The importance of this work arises from the devastating morbidity and mortality as a consequence of diaphragm fibrosis in muscular dystrophy. Furthermore, other diseases with respiratory muscle scarring and weakness components will also be better treated with the knowledge gained from this work.
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