Straightjacket/α2δ3deregulation is associated with cardiac conduction defects in Myotonic Dystrophy type 1

Abstract

Cardiac conduction defects decrease life expectancy in myotonic dystrophy type 1 (DM1), a complex toxic CTG repeat disorder involving misbalance between two RNAbinding factors, MBNL1 and CELF1. How this pathogenic DM1 condition translates into cardiac conduction disorders remains poorly understood. Here, we simulated MBNL1 and CELF1 misbalance in the Drosophila heart and identified associated gene deregulations using TU-tagging based transcriptional profiling of cardiac cells. We detected deregulations of several genes controlling cellular calcium levels and among them increased expression of straightjacket/α2δ3 that encodes a regulatory subunit of a voltage-gated calcium channel.Straightjacket overexpression in the fly heart leads to asynchronous heart beating, a hallmark of affected conduction, whereas cardiac straightjacket knockdown improves these symptoms in DM1 fly models. We also show that ventricular α2δ3 expression is low in healthy mice and humans but significantly elevated in ventricular muscles from DM1 patients with conduction defects. Taken together, this suggests that reducing the straightjacket/α2δ3 transcript levels in ventricular cardiomyocytes could represent a strategy to prevent conduction defects and in particular intraventricular conduction delay associated with DM1 pathology.

Dissecting Pathogenetic Mechanisms and Therapeutic Strategies in Drosophila Models of Myotonic Dystrophy Type 1

“…The main cardiac dysfunctions associated with DM1 correspond to conduction defects [43] with potentially fatal ventricular and/or atrial arrhythmias [44] and mechanical diastolic and/or systolic dysfunction that can lead to combined systolic and diastolic heart failure [45]. Importantly, Drosophila DM1 models have reproduced all these cardiac disorders [46,47].…”

“…The data analysis revealed that the cardiac disorders observed in these DM1 models are the result of deregulation of genes involved in cellular calcium level and cardiac conduction. Among them are: inactivation no afterpotential D ( inaD ), syntrophin-like 1 ( syn1 ), Rad , Gem/Kir family member 2 ( Rgk2 ) and straightjacket ( stj ), all conserved in humans [47]. In particular, increased expression of stj , ortholog of CACNA2D3 in human, which encodes a regulatory subunit of a voltage-gated calcium channel CACNA1C/Cav1.2 was found to influence cardiac contractions.…”

“…Up-regulation of stj leads to increased Ca 2+ inward current, which induces asynchronous heart beating and mimics conduction defect phenotypes observed in DM1 contexts. Interestingly, reducing the expression of stj in cardiomyocytes of DM1 flies ameliorates asynchronous heart beating [47] strongly suggesting a novel pathogenic mechanism underlying conduction disturbances in DM1. This is supported by the overexpression of CACNA2D3 observed in human cardiac tissue from DM1 patients [47].…”

“…Bru3 stabilization also induces down-regulation of sarcomeric proteins associated with impaired motility and muscle morphology defects [59], whereas loss of MBNL1/Mbl blocks pre miR-1 processing [53] leading to up regulation of its target genes such as GJA1 and CACNA1C suggested as associated with conduction defects and arrhythmias/sudden death, respectively [45]. Both Bru3 stabilization and Mbl sequestration induce up regulation of Stj and down regulation of Rgk2 expression associated with conduction defects [47]. CTG repeats could be transcribed in both directions leading to CAGn–CUGn double stranded complexes and formation of siRNA duplex that interact with RISC complex to target the expression of genes containing CAG repeats, such as Ataxin-2 ( ATXN2 ) and TATA binding protein ( TBP ) [38].…”