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Abstract
BackgroundDeficiencies 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 Ca2+ homeostasis, and fibrotic change in the observed arrhythmogenicity.ObjectiveWe explored the extent to which these age-dependent physiological changes correlated with alterations in gene transcription in murine Pgc-1β-/- atria.Methods and ResultsRNA 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 Ca2+-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 Ca2+ channels. Nor were gap junction channels, β-adrenergic receptors or transforming growth factor-β affected.ConclusionThese 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 Ca2+-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 Ca2+ homeostasis.
Highlights
Atrial arrhythmias constitute a major public health problem
The studies explored transcription profiles in atria of young and aged, Wild Type (WT) and Pgc-1β−/− murine hearts previously demonstrated to recapitulate cardiac pro-arrhythmic phenotypes associated with energetic deficiency
Genes were selected and grouped according to the component physiological processes underlying excitable activity leading to arrhythmia (Huang, 2017), adapting approaches introduced in rat hearts (Atkinson et al, 2013)
Summary
Atrial arrhythmias constitute a major public health problem. Atrial fibrillation (AF), affects 1–3% of the developed world population. Are metabolic factors, arising from physical inactivity, obesity, diabetes mellitus, and metabolic syndrome Themselves agedependent, these account for ∼60% of current upward trends in AF incidence (Miyasaka et al, 2006). 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 Ca2+ homeostasis, and fibrotic change in the observed arrhythmogenicity
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