Mechanistic Insights into Duchenne Muscular Dystrophy-Associated Cardiomyopathy

By Pradeep P.A. Mammen, M.D., Associate Professor of Internal Medicine, and Tara C. Tassin, Ph.D., Assistant Instructor of Internal Medicine

Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disorder resulting from a mutation within the dystrophin gene. Loss of dystrophin leads to progressive skeletal muscle wasting and cardiomyopathy. Currently, advanced cardiomyopathy is the primary mode of death in DMD patients, despite the application of standard-of-care cardiac heart failure therapies. Recently, our group at UT Southwestern demon­strated that young adult DMD patients have small hearts with very low left ventricular (LV) mass as compared to age- and weight-matched patients with non-ischemic cardiomyopathy. During the 2018 AHA Scientific Sessions, our group presented novel data from the mdx murine model of DMD regarding mechanistic insights into our recent clinical observation in DMD patients.

Specifically, we observed that from birth mdx mice have smaller heart-to-body-weight (HBW) ratios compared to non-transgenic control (NTg) mice. While NTg and mdx cardio­myocyte cross-sectional areas are similar, there are fewer cardiomyocytes in mdx hearts as assessed by FACS analysis. Transcriptome profiling and immunohistological analyses identify a reduction in neonatal proliferation as a significant contributor to the reduced mdx-HBW ratio. Furthermore, YAP, a critical co-transcriptional regulator of proliferation and organ size, is reduced in the mdx cardiomyocyte nucleus, according to subcellular fractionation and immunohistological experiments. Moreover, RNA-Seq and quantitative RT-PCR analyses demonstrate YAP targets are downregulated in mdx hearts. 

Collectively, these data suggest that the mdx mouse is born with fewer cardiomyocytes due to a reduction in YAP-mediated proliferation. This study is innovative because it proposes a mechanism by which proliferative defects in early development contribute to progressive DMD-associated cardiomyopa­thy. The study sets the stage for investigation into potential novel therapeutic targets for the amelioration of DMD-associated cardiomyopathy.