Abstract
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.
Highlights
Cardiac arrhythmias result when the normal sequence of electrical activation and recovery in the heart is disrupted
Metabolic conditions themselves are associated with mitochondrial dysfunction which in turn is strongly linked to cardiac arrhythmias suggesting that impaired mitochondrial capacity constitute a further link between metabolic disorders and cardiac arrhythmias [6]
In this study we examine fibrotic markers including the cytokine transforming growth factor β1 (TGF-β1; Tgfb1) [24], the gap junction forming protein δ 3, known as Connexin 30.2 in mouse, encoded by Gjd3, the collagen precursor Col3a1 encoding the collagen type III α1 chain and Col1a1 encoding the major component of type I collagen, the fibrillar collagen found in most connective tissues [25]
Summary
Cardiac arrhythmias result when the normal sequence of electrical activation and recovery in the heart is disrupted. Of the many arrhythmic variants the ventricular arrhythmias, ventricular tachycardia and ventricular fibrillation, constitute the primary cause of sudden cardiac death, a common cause of mortality and a significant public health burden especially in the ageing population [1,2]. Major risk factors for ventricular arrhythmia and sudden cardiac death include age [3] and metabolic disorders [4,5] such as obesity, diabetes and metabolic syndrome. PPARγ and Pgc-1β are highly expressed in white and brown adipose tissues and in other oxidative tissues including cardiac and skeletal muscles [8] where it is a key regulator of basal mitochondrial function maintenance [9]. Pgc-1’s pivotal involvement in the cellular energy balance means that modifications of these actors has been proven to serve as useful experimental models for the analysis of pathological changes associated with energetic deficiencies such as metabolic disorders [10]
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