Impact of aging on catecholaminergic ventricular arrhythmia and cardiac transcriptome of cardiac calsequestrin null...

Catecholamine-induced polymorphic ventricular tachycardia (CPVT) is associated typically with mutations in Ryanodine Receptor type 2 (RYR2) and cardiac Calsequestrin (CASQ2) genes. RyR2 and CASQ2 along with membrane proteins, junctin and triadin, constitute the Ca2+ release unit in the junctional sarcoplasmic reticulum in mammalian cardiomyocytes. Mouse models lacking Casq2 gene phenocopy CPVT and have been used to study CPVT pathophysiology and to identify novel therapies. Here, we analyze roles of normal aging for the development of cardiac dysfunctions of Casq2-null mice. We show that aging intensifies the disease phenotype. Age-dependent changes in triadin but not in RyR2 or junctin correlate with a more severe CPVT phenotype. We also examine transcriptomes at 1 month and 2 years of age. We identify 583 genes whose expression is dependent on Casq2 genotype with enrichment for genes associated with calcium handling and transport, sarcomere structures, extracellular matrix, and natriuretic peptide signaling. Age-stratified analyses identified 76 genes that were dysregulated only in aged mice and 22 genes that were dysregulated only in young animals.