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.