Atrial and ventricular transcriptomic alterations in a cardiac mouse model of myotonic dystrophy expressing 960 CUG repeats

Purpose: The goal of this study was to characterize the atrial and ventricular transcriptomic changes in a cardiac mouse model of myotonic dystrophy. The mouse model utilizes a bitransgenic system for doxycycline (dox) inducible and cardiomyocyte specific expression of pathogenic RNA containing 960 CUG repeats. Bitransgenic animals (called CUG960 mice) homozygous for the TREDT960I transgene (containing 960 interrupted CTG repeats) and hemizygous for reverse transactivator (rtTA) transgene containing a cardiomyocyte-specific alpha myosin heavy chain promoter are given dox food for expression of CUG repeat RNA. Mice hemizygous for rtTA transgene (MHCrtTA) given dox food were used as controls. Methods:We performed RNA-seq for high-resolution analysis of transcriptomic alterations in atria and ventricles of CUG960 experimental and MHCrtTA control mice given dox chow since postnatal day 1 (PN1) for a period of 10 weeks. Results: We identified pathogenic CUG repeat RNA induced 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. Conclusions: We identified potential tissue-specific mechanisms contributing to the cardiac disease relevant phenotypes in an animal model of DM1. Overall design: Mouse atrial and ventricular cardiac muscle mRNA profiles of CUG960 experimental and MHCrtTA control mice were generated by deep sequencing using Illumina Novaseq 6000.