Abstract

Introduction: Ageing and chronic metabolic disorders are associated with mitochondrial dysfunction and cardiac pro-arrhythmic phenotypes which were recently attributed to slowed atrial and ventricular action potential (AP) conduction in peroxisome proliferator-activated receptor γ co-activator deficient (Pgc-1β−/−) mice. Methods: We compared expression levels of voltage-gated Na+ channel (NaV1.5) and gap junction channels, Connexins 40 and 43 (Cx40 and Cx43) in the hearts of young and old, and wild-type (WT) and Pgc-1β−/− mice. This employed Western blotting (WB) for NaV1.5, Cx40 and Cx43 in atrial/ventricular tissue lysates, and immunofluorescence (IF) from Cx43 was explored in tissue sections. Results were analysed using two-way analysis of variance (ANOVA) for independent/interacting effects of age and genotype. Results: In atria, increased age and Pgc-1β−/− genotype each independently decreased both Cx40 and Cx43 expression without interacting effects. In IF experiments, both age and Pgc-1β deletion independently reduced Cx43 expression. In ventricles, age and genotype exerted interacting effects in WB studies of NaV1.5 expression. Young Pgc-1β−/− then showed greater NaV1.5 expression than young WT ventricles. However, neither age nor Pgc-1β deletion affected Cx43 expression, independently or through interacting effects in both WB and IF studies. Conclusion: Similar pro-arrhythmic atrial/ventricular phenotypes arise in aged/Pgc-1β−/− from differing contributions of altered protein expression and functional effects that may arise from multiple acute mechanisms.

Highlights

  • Ageing and chronic metabolic disorders are associated with mitochondrial dysfunction and cardiac pro-arrhythmic phenotypes which were recently attributed to slowed atrial and ventricular action potential (AP) conduction in peroxisome proliferator-activated receptor γ co-activator deficient (Pgc-1β−/−) mice

  • We measured and compared expression levels of NaV1.5, connexin 40 (Cx40) and connexin 43 (Cx43) in atria and ventricles from four experimental, young and aged, WT and Pgc-1β−/− mouse groups in a 2 × 2 factorial design, matching ose adopted in the previous electrophysiological studies statistically testing for independent or interacting effects on these of increased age and Pgc-1β−/− genotype [36,37,38]

  • The experiments in the present study explored the extent to which altered molecular NaV1.5, Cx40 and Cx43 expression as opposed to functional effects might contribute to the observed pro-arrhythmic electrophysiological phenotypes in ageing and Pgc-1β−/−, atria and ventricles

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Summary

Introduction

Ageing and chronic metabolic disorders are associated with mitochondrial dysfunction and cardiac pro-arrhythmic phenotypes which were recently attributed to slowed atrial and ventricular action potential (AP) conduction in peroxisome proliferator-activated receptor γ co-activator deficient (Pgc-1β−/−) mice. Methods: We compared expression levels of voltage-gated Na+ channel (NaV1.5) and gap junction channels, Connexins 40 and 43 (Cx40 and Cx43) in the hearts of young and old, and wild-type (WT) and Pgc-1β−/− mice This employed Western blotting (WB) for NaV1.5, Cx40 and Cx43 in atrial/ventricular tissue lysates, and immunofluorescence (IF) from Cx43 was explored in tissue sections. Conclusion: Similar pro-arrhythmic atrial/ventricular phenotypes arise in aged/Pgc-1β−/− from differing contributions of altered protein expression and functional effects that may arise from multiple acute mechanisms. Both increased age and metabolic disorders, the latter themselves age-dependent, and associated with physical inactivity [1], obesity [2], diabetes mellitus [3] and metabolic syndrome [4] constitute cardiac health issues of increasing clinical importance. Experimental studies in the mouse-related genetic defects increasing levels of somatic mtDNA mutations to License 4.0 (CC BY)

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