Abstract 114: Myocardin-Related Transcription Factors Are Required for Compensatory Signaling in Maladaptive Cardiac Remodeling

Abstract

Intercellular communication is essential for coordinating the contraction of cardiomyocytes. This synchrony is established by coupling electrical activity and force transmission at specialized junctions called intercalated discs (ICDs). We have recently found that myocardin-related transcription factor A (MRTF-A) and –B (MRTFs) accumulate at ICDs of healthy mouse and human hearts, but are redistributed in cardiac pathology. MRTFs are mechanosensitive transcriptional co-activators of serum response factor (SRF) that regulate the actin cytoskeleton; however, the role of MRTFs in cardiomyocyte homeostasis remains unclear. We conditionally deleted Mrtfb in cardiomyocytes of mice harboring a homozygous null allele of Mrtfa (called MRTF cmdKO ). MRTF cmdKO mice exhibit no changes in cardiac function for up to a year; however, MRTF depletion results in conspicuous gap junction remodeling at ICDs and reduced cardiomyocyte communication. This phenotype stems from a significant reduction in genes important for trafficking gap junction proteins, including RP/EB family member 1 ( Mapre1 ), which we show is a direct transcriptional target of SRF/MRTFs. The absence of a functional phenotype amid gap junction displacement prompted us to model heart failure and mechanical stress at ICDs by subjecting MRTF cmdKO mice to transaortic constriction (TAC) surgery. Unexpectedly, MRTF cmdKO mice display partially penetrant sudden cardiac death within 2 weeks post-TAC surgery. MRTF cmdKO survivors undergo accelerated heart failure with a reduced adaptive gene response compared to controls. Future investigations are underway to determine the mechanisms governing accentuated heart failure in MRTF cmdKO mice. Taken together, the subcellular localization of MRTFs to ICDs creates a paradigm in which potent transcription factors are anchored to regions of electromechanical stress, which may represent a signaling circuit for ICD maintenance and remodeling in disease.