Key result
Pgc-1β deficiency in mice downregulates potassium channel genes while ageing upregulates calcium homeostasis pathways.
Why the study?
Mice deficient in Pgc-1β present with ventricular arrhythmia, but the molecular mechanisms underlying the arrhythmic substrate remain unclear.
Does Pgc-1β deficiency and ageing alter the expression of genes regulating ventricular electrophysiology in mice?
Does Pgc-1β deficiency and ageing alter the expression of genes regulating ventricular electrophysiology in mice?
Pgc-1β deficiency and ageing induce complex changes in the expression of genes regulating ventricular electrophysiology, providing a molecular basis for the arrhythmic substrate associated with mitochondrial dysfunction.
Highlights potential arrhythmic mechanisms in mitochondrial dysfunction; leaves open human translation and clinical relevance.
Mice deficient in mitochondrial promoter peroxisome proliferator activated receptor-γ co-activator-1β (Pgc-1β−/−) is a valuable model for metabolic diseases and has been found to present with several pathologies including ventricular arrhythmia. In the present study, our aim was to shed light on the molecular mechanisms behind the observed arrhythmic substrate by studying how the expression of selected genes critical for cardiac function differs in wild-type (WT) compared with Pgc-1β knockout mice and young compared with aged mice. We found that a clear majority of genes are down-regulated in the Pgc-1β−/− ventricular tissue compared with the WT. Although most individual genes are not significantly differentially expressed, a pattern is apparent when the genes are grouped according to their functional properties. Genes encoding proteins relating to ATPase activity, potassium ion channels relating to repolarisation and resting membrane potential, and genes encoding proteins in the cAMP pathway are found to be significantly down-regulated in the Pgc-1β deficient mice. On the contrary, the pacemaker channel genes Hcn3 and Hcn4 are up-regulated in subsets of the Pgc-1β deficient tissue. Furthermore, we found that with age, especially in the Pgc-1β−/− genotype, most genes are up-regulated including genes relating to the resting membrane potential, calcium homeostasis, the cAMP pathway, and most of the tested adrenoceptors. In conclusion, we here demonstrate how a complex pattern of many modest changes at gene level may explain major functional differences of the action potential related to ageing and mitochondrial dysfunction.
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Edling et al. (2019) studied Mitochondrial dysfunction and ventricular arrhythmia. Pgc-1β knockout and ageing vs. Wild-type and young mice was evaluated on Differential expression of genes regulating ventricular electrophysiology. Pgc-1β deficiency in mice down-regulates genes related to ATPase activity and potassium channels, while ageing up-regulates genes related to resting membrane potential and calcium homeostasis.
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