Molecular basis of ventricular arrhythmogenicity in a Pgc-1α deficient murine model

Mitochondrial dysfunction underlying metabolic disorders such as obesity and diabetes mellitus is strongly associated with cardiac arrhythmias. Murine Pgc-1α(−/−) hearts replicate disrupted mitochondrial function and model the associated pro-arrhythmic electrophysiological abnormalities. Quantitative PCR, western blotting and histological analysis were used to investigate the molecular basis of the electrophysiological changes associated with mitochondrial dysfunction. qPCR analysis implicated downregulation of genes related to Na(+)-K(+) ATPase activity (Atp1b1), surface Ca(2+) entry (Cacna1c), action potential repolarisation (Kcnn1), autonomic function (Adra1d, Adcy4, Pde4d, Prkar2a), and morphological properties (Myh6, Tbx3) in murine Pgc-1α(−/−) ventricles. Western blotting revealed reduced Na(V)1.5 but normal Cx43 expression. Histological analysis revealed increased tissue fibrosis in the Pgc-1α(−/−) ventricles. These present findings identify altered transcription amongst a strategically selected set of genes established as encoding proteins involved in cardiac electrophysiological activation and therefore potentially involved in alterations in ventricular activation and Ca(2+) homeostasis in arrhythmic substrate associated with Pgc-1α deficiency. They complement and complete previous studies examining such expression characteristics in the atria and ventricles of Pgc-1 deficient murine hearts.