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"Molecular Mechanisms of Compensation in Mouse Models of Muscular Dystrophy"

Joel Schneider
Cell Biology and Molecular Medicine Program
B.A. 2006, Brandeis University, Waltham, MA

Thesis Advisor: Diego Fraidenraich, Ph.D.
Assistant Professor
Department of Cell Biology and Molecular Medicine

Thursday, December 13, 2012
12:00 P.M., MSB Room G-609


Duchenne Muscular Dystrophy (DMD) is an incurable disease, characterized by the absence of the dystrophin protein, which leads to progressive muscular degeneration in both skeletal and cardiac muscle. DMD is recapitulated in mouse models, like mdx mice which lack dystrophin and mdx:utrophin double knockout mice (mdx:utr). The nitric oxide (NO) pathway plays a key role in DMD and its associated cardiomyopathy. We have identified a requirement for dystrophin in the production of nitric oxide via the neuronal nitric oxide synthase (nNOS) isoform in cardiac musculature. We have also observed that the levels and the function of the Cationic Amino Acid Transporter (CAT) were upregulated. As CAT mediates the membrane transport of the nNOS substrate, L-arginine, its activity is an obligate process for NO synthesis. This enhancement may represent a potential compensatory mechanism in response to decreased nitric oxide production.
Calcium homeostasis, which is affected by nitric oxide, was dysregulated in DMD mouse skeletal muscle, as well. Sarcolipin, an atrial inhibitor of the cardiac calcium pump localized to the sarcoplasmic reticulum, was ectopically observed in the DMD mouse skeletal muscle, particularly in the absence of both dystrophin and utrophin. Thus, dystrophin/utrophin differentially regulate the nitric oxide pathway, which in turn exerts a broad range of effects, both in cardiac and skeletal muscle.
To model DMD-cardiomyopathy in the Petri dish, we have utilized DMD cardiac myocytes from mouse and human induced pluripotent stem cells (iPSCs). In these cells, key members of the nitric oxide pathway were detected. Our analysis, on both murine and human iPSC populations suggest that, despite the fact that the iPSC-derived cardiac myocytes are not fully mature, they can be used as a model to study the nitric oxide pathway in vitro.

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