Key result
Pgc-1β deficiency independently reduced gene transcription for Na+-K+-ATPase, sarcoplasmic reticular Ca2+-ATPase, background K+ channels, and cholinergic receptors, limiting transcriptional roles in pro-arrhythmic changes to altered Atp2a2 expression.
Why the study?
Pgc-1β-/- mice recapitulate clinical age-dependent atrial pro-arrhythmic phenotypes, but the extent to which these physiological changes correlate with transcriptional alterations was unknown.
Transcriptional changes in Pgc-1β-/- atria are limited primarily to altered Ca2+-ATPase (Atp2a2) expression, suggesting arrhythmias may stem more from direct physiological outcomes of mitochondrial dysfunction than broad transcriptional remodeling.
Answers are grounded in this paper and cite their sources.
Animal data on Pgc-1β ion channel transcription warrant no practice change; leaves open human relevance beyond Atp2a2.
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 ageing, 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. Objective. We explored the extent to which these age-dependent physiological changes correlated with alterations in gene transcription in murine Pgc-1β-/- atria. Methods & 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 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. 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 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.
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Edling et al. (2019) studied Atrial pro-arrhythmic phenotypes (Pgc-1β deficiency and aging) (n=12). Pgc-1β deficiency and aging vs. Wild-type and young mice was evaluated on Atrial gene transcription profiles (fold changes) of electrophysiological targets. Pgc-1β deficiency independently reduced gene transcription for Na+-K+-ATPase, sarcoplasmic reticular Ca2+-ATPase, background K+ channels, and cholinergic receptors, limiting transcriptional roles in pro-arrhythmic changes to altered Atp2a2 expression.
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