Abstract
BACKGROUND: Deficiencies in the transcriptional co-activator, peroxisome proliferative activated receptor, gamma, coactivator-1β are implicated in deficient mitochondrial function. The latter accompanies clinical conditions including aging, physical inactivity, obesity, and diabetes. Recent electrophysiological studies reported that Pgc-1β(-/-) mice recapitulate clinical age-dependent atrial pro-arrhythmic phenotypes. They implicated impaired chronotropic responses to adrenergic challenge, compromised action potential (AP) generation and conduction despite normal AP recovery timecourses and background resting potentials, altered intracellular Ca(2+) homeostasis, and fibrotic change in the observed arrhythmogenicity. OBJECTIVE: We explored the extent to which these age-dependent physiological changes correlated with alterations in gene transcription in murine Pgc-1β(-/-) atria. METHODS AND RESULTS: RNA isolated from murine atrial tissue samples from young (12-16 weeks) and aged (>52 weeks of age), wild type (WT) and Pgc-1β(-/-) mice were studied by pre-probed quantitative PCR array cards. We examined genes encoding sixty ion channels and other strategic atrial electrophysiological proteins. Pgc-1β(-/-) genotype independently reduced gene transcription underlying Na(+)-K(+)-ATPase, sarcoplasmic reticular Ca(2+)-ATPase, background K(+) channel and cholinergic receptor function. Age independently decreased Na(+)-K(+)-ATPase and fibrotic markers. Both factors interacted to alter Hcn4 channel activity underlying atrial automaticity. However, neither factor, whether independently or interactively, affected transcription of cardiac Na(+), voltage-dependent K(+) channels, surface or intracellular Ca(2+) channels. Nor were gap junction channels, β-adrenergic receptors or transforming growth factor-β affected. CONCLUSION: These findings limit the possible roles of gene transcriptional changes in previously reported age-dependent pro-arrhythmic electrophysiologial changes observed in Pgc-1β(-/-) atria to an altered Ca(2+)-ATPase (Atp2a2) expression. This directly parallels previously reported arrhythmic mechanism associated with p21-activated kinase type 1 deficiency. This could add to contributions from the direct physiological outcomes of mitochondrial dysfunction, whether through reactive oxygen species (ROS) production or altered Ca(2+) homeostasis.