Reversible cardiac disease features in an inducible CUG repeat RNA–expressing mouse model of myotonic dystrophy
Year: 2021
Type: article
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.
Source: JCI Insight
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,100
Funders: Myotonic Dystrophy Foundation, Cancer Prevention and Research Institute of Texas, Muscular Dystrophy Association, John S. Dunn Gulf Coast Consortium for Chemical Genomics, Agence Nationale de la Recherche, National Institutes of Health, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases, U.S. National Library of Medicine
Awards: G1081826082, G1099493753, G1147702603, G1246071610, Mechanisms underlying atrial fibrillation associated with chronic kidney disease, G2006895178, G2035409072, G274084553, G3016977689, G3154728698, G3455007010, G4222846132, Determining the Role of Junctophilin-2 in Cardiac Disease, The Combinatorial Drug Discovery Program (CDDP), G4819929959, G518420523, G529149866, G5313339769, G539326793, G5424208343, G5465708471, G6785102785, High Throughput Genomic Sequencer at BCM Core Facility, The Role of Striated Muscle Preferentially Expressed Protein Kinase in the Regulation of Ryanodine Receptor Type-2., G7182425300, GCC Center for Advanced Microscopy and Image Informatics, Transcriptome processing networks in skeletal muscle: mechanisms and functions, G7711948935, G7719408726, G7837447426, G8076540680, G8413015676, G9000013585, G9000023230, G9000032895, G9000051474, G9000134607, G9000150432, G9000191673, G9000213352, G9000240210, G9000355867, Baylor College of Medicine Cancer Center - Cancer Center Support Grant, Research Training Program in Cardiovascular Surgery
OpenAlex ID: W3125817652