Reversible cardiac disease features in an inducible CUG repeat RNA-expressing mouse model of myotonic dystrophy.

Ashish N Rao,Tarah A Word,Hannah M Campbell,Zheng Xia,Xander H.T Wehrens,Thomas A Cooper,Xiangnan Guan

doi:10.1172/jci.insight.143465

Abstract

Myotonic dystrophy type 1 (DM1) is caused by a CTG repeat expansion in the DMPK gene. Expression of pathogenic expanded CUG repeat (CUGexp) RNA causes multisystemic disease by perturbing the functions of RNA-binding proteins, resulting in expression of fetal protein isoforms in adult tissues. Cardiac involvement affects 50% of individuals with DM1 and causes 25% of disease-related deaths. We developed a transgenic mouse model for tetracycline-inducible and heart-specific expression of human DMPK mRNA containing 960 CUG repeats. CUGexp RNA is expressed in atria and ventricles and induced mice exhibit electrophysiological and molecular features of DM1 disease, including cardiac conduction delays, supraventricular arrhythmias, nuclear RNA foci with Muscleblind protein colocalization, and alternative splicing defects. Importantly, these phenotypes were rescued upon loss of CUGexp RNA expression. Transcriptome analysis revealed gene expression and alternative splicing changes in ion transport genes that are associated with inherited cardiac conduction diseases, including a subset of genes involved in calcium handling. Consistent with RNA-Seq results, calcium-handling defects were identified in atrial cardiomyocytes isolated from mice expressing CUGexp RNA. These results identify potential tissue-specific mechanisms contributing to cardiac pathogenesis in DM1 and demonstrate the utility of reversible phenotypes in our model to facilitate development of targeted therapeutic approaches.

Highlights

Myotonic dystrophy type 1 (DM1) is the most common form of adult-onset muscular dystrophy characterized by multisystemic manifestations affecting skeletal muscle, cardiac, central nervous system, and gastrointestinal tissues [1]
We developed a mouse model that uses a bitransgenic system for tetracycline-inducible and cardiomyocyte-specific expression of CUGexp RNA
To make the expression of CUGexp RNA heart-specific, TREDT960I mice were crossed with a MHCrtTA line, in which the expression of a modified reverse tetracycline transactivator is regulated by an α myosin heavy chain promoter [39]

Summary

Introduction

Myotonic dystrophy type 1 (DM1) is the most common form of adult-onset muscular dystrophy characterized by multisystemic manifestations affecting skeletal muscle, cardiac, central nervous system, and gastrointestinal tissues [1]. The cardiac manifestations in DM1 are multifaceted and primarily consist of conduction delays and both supraventricular and ventricular arrhythmias. Individuals with DM1 exhibit a variety of arrhythmias, the more common of which are those of supraventricular origin, consisting of sinus node dysfunction, atrial flutter, atrial fibrillation, and supraventricular tachycardia [17, 22, 25]. Apart from the more common effects on cardiac conduction, a small proportion of affected individuals exhibit left ventricular hypertrophy, dilatation, and systolic dysfunction [29, 30]

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Results

Conclusion