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ResearchIn-Press PreviewCardiologyCell biology Open Access | 10.1172/jci.insight.143465

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

Ashish N. Rao,1 Hannah M. Campbell,2 Xiangnan Guan,3 Tarah A. Word,2 Xander H.T. Wehrens,2 Zheng Xia,3 and Thomas A. Cooper1

1Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States of America

2Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, United States of America

3Computational Biology Program, Oregon Health & Science University, Portland, United States of America

Find articles by Rao, A. in: JCI | PubMed | Google Scholar

1Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States of America

2Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, United States of America

3Computational Biology Program, Oregon Health & Science University, Portland, United States of America

Find articles by Campbell, H. in: JCI | PubMed | Google Scholar |

1Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States of America

2Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, United States of America

3Computational Biology Program, Oregon Health & Science University, Portland, United States of America

Find articles by Guan, X. in: JCI | PubMed | Google Scholar

1Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States of America

2Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, United States of America

3Computational Biology Program, Oregon Health & Science University, Portland, United States of America

Find articles by Word, T. in: JCI | PubMed | Google Scholar

1Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States of America

2Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, United States of America

3Computational Biology Program, Oregon Health & Science University, Portland, United States of America

Find articles by Wehrens, X. in: JCI | PubMed | Google Scholar |

1Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States of America

2Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, United States of America

3Computational Biology Program, Oregon Health & Science University, Portland, United States of America

Find articles by Xia, Z. in: JCI | PubMed | Google Scholar |

1Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States of America

2Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, United States of America

3Computational Biology Program, Oregon Health & Science University, Portland, United States of America

Find articles by Cooper, T. in: JCI | PubMed | Google Scholar |

Published January 26, 2021 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.143465.
Copyright © 2021, Rao et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published January 26, 2021 - Version history
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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.

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