Molecular disturbance underlies to arrhythmogenic cardiomyopathy induced by transgene content, age and exercise in a truncated PKP2 mouse model

Abstract

Arrhythmogenic cardiomyopathy (ACM) is a disorder characterized by a progressive ventricular myocardial replacement by fat and fibrosis, which lead to ventricular arrhythmias and sudden cardiac death. Mutations in the desmosomal gene Plakophilin-2 (PKP2) accounts for >40% of all known mutations, generally causing a truncated protein. In a PKP2-truncated mouse model, we hypothesize that content of transgene, endurance training and aging will be determinant in disease progression. In addition, we investigated the molecular defects associated with the phenotype in this model. We developed a transgenic mouse model containing a truncated PKP2 (PKP2-Ser329) and generated three transgenic lines expressing increasing transgene content. The pathophysiological features of ACM in this model were assessed. While we did not observe fibro-fatty replacement, ultrastructural defects were exhibited. Moreover, we observed transgene content-dependent development of structural (ventricle dilatation and dysfunction) and electrophysiological anomalies in mice (PR interval and QRS prolongation and arrhythmia induction). In concordance with pathological defects, we detected a content reduction and remodeling of the structural proteins Desmocollin-2, Plakoglobin, native Plakophilin-2, Desmin and β-Catenin as well as the electrical coupling proteins Connexin 43 and cardiac sodium channel (Na1.5). Surprisingly, we observed structural but not electrophysiological abnormalities only in trained and old mice. We demonstrated that truncated PKP2 provokes ACM in the absence of fibro-fatty replacement in the mouse. Transgene dose is essential to reveal the pathology, whereas aging and endurance training trigger limited phenotype. Molecular abnormalities underlay the structural and electrophysiological defects.

Sudden Unexplained Nocturnal Death Syndrome: The Hundred Years' Enigma

“…Moreover, in cardiac‐myocyte‐specific VCL knock‐out mice, 2 stages of phenotype were observed: SCD caused by ventricular tachycardia attacked 49% mice younger than 3 months despite well‐preserved systolic cardiac function, while the surviving mice developed dilated cardiomyopathy and died of heart failure around 6 months of age . Similar effects were also observed in heterozygous JUP and truncated PKP2 mice, in which cardiac arrhythmia appeared preceding the structural abnormalities . Interestingly, reduced expression of Nav1.5 in cell membrane also appeared in these models .…”

“…101 Similar effects were also observed in heterozygous JUP and truncated PKP2 mice, in which cardiac arrhythmia appeared preceding the structural abnormalities. 102,103 Interestingly, reduced expression of Nav1.5 in cell membrane also appeared in these models. [101][102][103] These findings indicate that mutations in connexome can affect ion-channel functions or ID structures, thus disturbing propagation of electrical impulses and causing arrhythmia in the absence of structural abnormalities.…”

“…102,103 Interestingly, reduced expression of Nav1.5 in cell membrane also appeared in these models. [101][102][103] These findings indicate that mutations in connexome can affect ion-channel functions or ID structures, thus disturbing propagation of electrical impulses and causing arrhythmia in the absence of structural abnormalities. From Table 3, we can see that primary arrhythmia-associated or cardiomyopathy-associated genes seem to share equal proportions in SUNDS.…”

Transgenic mice overexpressing desmocollin-2 (DSC2) develop cardiomyopathy associated with myocardial inflammation and fibrotic remodeling

“…Several mouse models have been developed for Dsg2 [15, 20–22, 36], Jup [12, 23, 13, 37], Pkp2 [16, 24, 38], Dsp [17] and Des [39] showing either early embryonic lethality or different cardiac pathologies.…”

Dynamic Loading of Human Engineered Heart Tissue Enhances Contractile Function and Drives Desmosome-linked Disease Phenotype

“…As proof-of-concept, we chose to study ACM, where epidemiological data and animal models have indicated that enhanced mechanical loading, i.e. exercise, can accelerate disease progression in patients (5,(41)(42)(43)(44). To understand the impact of 2D versus 3D culture, we first investigated 2D monolayers of hiPSC-derived cardiomyocytes subjected to mechanical stretch.…”