Cardiac complications of dystrophin deficiency in female carriers

About This Grant

PROJECT SUMMARY Female carriers of Duchenne muscular dystrophy (DMD) typically do not manifest symptoms; however, they are susceptible to dilated cardiomyopathy. DMD is caused by the lack of dystrophin expression. The gene encoding dystrophin is located on the X chromosome. Females have two X chromosomes, one of which is transcriptionally silenced during development. Mosaic expression of the wildtype copy prevents muscle degeneration, but in the heart, mosaic expression can result in premature cardiomyocyte loss and progression to dilated cardiomyopathy. Physical exertion or lifestyle risk factors, such as obesity and smoking, can lead to cardiac stress that exacerbates progression to heart failure. This proposed research will investigate how the lack of dystrophin affects cardiomyocytes differentiated from human induced pluripotent stem cells of female carriers. We will compare the functional characteristics of cardiomyocytes in dystrophin-expressing and dystrophin-deficient female cells. Specifically, we will test calcium handling and mechanical contraction in the context of chronic stress and acute stress. We will also measure cell viability in cells exposed to chronic stress as premature loss of cardiomyocytes is a hallmark of dilated cardiomyopathy. We will then examine the role of mosaic pattern of expression in 2D and 3D cardiac tissues. Collectively, the findings from this proposed research will elucidate how the mosaic pattern of dystrophin expression in the hearts of female carriers contributes to cardiomyocyte dysfunction and provide insight into therapeutic strategies to prevent heart failure.