Role of plakophilin-2 expression on exercise-related progression of arrhythmogenic right ventricular cardiomyopathy: a translational study

Abstract

Aims Exercise increases arrhythmia risk and cardiomyopathy progression in arrhythmogenic right ventricular cardiomyopathy (ARVC) patients, but the mechanisms remain unknown. We investigated transcriptomic changes caused by endurance training in mice deficient in plakophilin-2 (PKP2cKO), a desmosomal protein important for intercalated disc formation, commonly mutated in ARVC and controls. Methods and results Exercise alone caused transcriptional downregulation of genes coding intercalated disk proteins. The changes converged with those in sedentary and in exercised PKP2cKO mice. PKP2 loss caused cardiac contractile deficit, decreased muscle mass and increased functional/transcriptomic signatures of apoptosis, despite increased fractional shortening and calcium transient amplitude in single myocytes. Exercise accelerated cardiac dysfunction, an effect dampened by pre-training animals prior to PKP2-KO. Consistent with PKP2-dependent muscle mass deficit, cardiac dimensions in human athletes carrying PKP2 mutations were reduced, compared to matched controls. Conclusions We speculate that exercise challenges a cardiomyocyte “desmosomal reserve” which, if impaired genetically (e.g., PKP2 loss), accelerates progression of cardiomyopathy.

Loss of Nuclear Envelope Integrity and Increased Oxidant Production Cause DNA Damage in Adult Hearts Deficient in PKP2: A Molecular Substrate of ARVC

“…This increase occurred despite the fact that desmin clusters, measured throughout the cell, were larger and more elongated in PKP2cKO cardiomyocytes than in controls and that desmin protein abundance was increased in PKP2cKO hearts (Figure S8B and S8C), as was also the case in hearts of patients with ARVC (Figure 3B). Consistent with data showing that altered nuclear morphology is a consequence of reduced desmin attachment, 22 we observed that nuclei of PKP2cKO myocytes were more circular than those of controls (Figure 4C).…”

Sex‐Related Differences in Genetic Cardiomyopathies

“…In mice, plakophilin‐2 loss and training synergically worsened cardiac function because of a reduced reserve of desmosomal proteins. 72 Although in a limited sample, when adjusted for exercise, odds of proband status and ventricular arrhythmias did not differ between sexes, and, after introduction of exercise restrictions, disease progression did not differ between sexes. 69 …”

Arrhythmogenic right-ventricular cardiomyopathy with plakophilin-2 genetic variant concomitant with early manifestation of ventricular tachyarrhythmia: a case series

“…A recent experimental model revealed that endurance training in PKP2 knockout mice decreased cardiac muscle mass and increased cardiac myocyte apoptosis, despite enhanced arrhythmogenicity such as increased fractional shortening and calcium transient amplitude. 9 Based on these findings, most ARVC patients with a PKP2 genetic variant might need to severely restrict daily exercise. The three siblings were heterozygous for the previously reported pathogenic splice site variation c.2489 + 1G > A in Intron 12 of the PKP2.…”

“… 7 , 8 Plakophilin-2 (PKP2) genetic variants has been shown to enhance progression of pathogenesis in ARVC in terms of systolic cardiac function and lethal arrhythmia. 9 A recent study using genetically PKP2 knockout mice showed that loss of the PKP2 function reduced ventricular systolic function and enhanced vulnerability to ventricular arrhythmia. The current study presents a case series of three siblings (sports athletes) with PKP2 genetic variants, where intensive training potentially promoted the pathogenesis of ARVC through early manifestation of ventricular tachyarrhythmia.…”