Atrial Transcriptional Profiles of Molecular Targets Mediating Electrophysiological Function in Aging and β Deficient Murine Hearts.

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 β 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 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 β 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 mice were studied by pre-probed quantitative PCR array cards. We examined genes encoding sixty ion channels and other strategic atrial electrophysiological proteins. genotype independently reduced gene transcription underlying Na-K-ATPase, sarcoplasmic reticular Ca-ATPase, background K channel and cholinergic receptor function. Age independently decreased Na-K-ATPase and fibrotic markers. Both factors interacted to alter 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 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 β atria to an altered Ca-ATPase () 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 homeostasis.