Myotonic dystrophy (DM) is the most common cause of adult onset muscular dystrophy and the second most common cause of muscular dystrophy overall. At least 50% of individuals affected by DM type 1 (DM1) have cardiac involvement, primarily conduction abnormalities and life threatening arrhythmias. Cardiac involvement is the second leading cause of mortality in DM1 responsible for 25% of disease-related deaths. The pathogenic cause of DM1 is well established to be toxicity of the expanded CUG repeat- containing (CUGexp) RNA expressed from the expanded DMPK allele. The CUGexp RNA disrupts RNA processing, signaling pathways and microRNA regulation. However the specific molecular mechanisms by which expression of CUGexp RNA in heart tissue causes conduction abnormalities, arrhythmias and ventricular dysfunction are unknown. Therapeutic approaches applied to DM1 have focused on skeletal muscle and heart presents a separate set of issues with regard to both the details of disease mechanisms and therapeutic approaches. We developed a mouse model for tetracycline (tet)-inducible expression of CUGexp RNA specifically in cardiomyocytes. The tet-inducible transgene expresses 960 interrupted CUG repeats in the context of a human DMPK genomic segment containing exons 11-15. Expression of CUG960 RNA produces most of the cardiac conduction abnormalities and propensity for the arrhythmias that are likely to be responsible for cardiac sudden death in DM1. The mice also show robust splicing changes as observed in DM1 heart tissue. Importantly molecular and electrophysiological abnormalities are reversible upon shutting off expression of CUG960 RNA. In this project we will use the mouse model to identify and test hypotheses for the molecular basis for heart pathogenesis in DM1 and apply novel therapeutic approaches. The goal of the first aim is to use in vivo and ex vivo electrophysiological analyses in combination with detailed analyses of intracellular structure, transcriptome and signaling changes to identify the basis for the cardiac manifestations induced by CUG960 RNA. The key results will be tested in DM1 tissue samples for validation.
The second aim i s to use genetic rescue of the cardiac features to test hypothesized disease mechanisms, and with the expectation that multiple mechanisms contribute to pathogenesis, to determine the contributions of different mechanisms.
The third aim i s to apply approaches using deactivated Cas9 to target CUG960 RNA for transcriptional or post-transcriptional downregulation. Upon completion of this project we anticipate having an understanding of the molecular and physiological pathways linking CUGexp RNA to cardiac dysfunction and to have optimized a therapeutic approach to reverse DM1 cardiac features.

Public Health Relevance

Myotonic dystrophy (DM) is the most common cause of adult onset muscular dystrophy. This proposal studies the mechanisms responsible for the heart manifestations in myotonic dystrophy type 1 (DM1) in which more than 50% of affected individuals have heart involvement and one quarter of mortality is due to cardiac features. The three goals of this proposal are to use a newly established mouse model determine the molecular mechanisms responsible for arrhythmias, establish the contributions of different mechanisms and apply approaches to down regulate the toxic RNA from the mutated allele that is the primary cause of pathogenesis.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Therapeutic Approaches to Genetic Diseases Study Section (TAG)
Program Officer
Li, Huiqing
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Baylor College of Medicine
Schools of Medicine
United States
Zip Code