Cardiomyocyte ionic currents in intact young and aged murine Pgc-1β−/− atrial preparations

Haseeb Valli,Shiraz Ahmad,Anita Y Jiang,Robert Smyth,Kamalan Jeevaratnam,Hugh R Matthews,Christopher L.-H Huang

doi:10.1016/j.mad.2017.11.016

Abstract

IntroductionRecent studies reported that energetically deficient murine Pgc-1β−/− hearts replicate age-dependent atrial arrhythmic phenotypes associated with their corresponding clinical conditions, implicating action potential (AP) conduction slowing consequent upon reduced AP upstroke rates. Materials and methodsWe tested a hypothesis implicating Na+ current alterations as a mechanism underlying these electrophysiological phenotypes. We applied loose patch-clamp techniques to intact young and aged, WT and Pgc-1β−/−, atrial cardiomyocyte preparations preserving their in vivo extracellular and intracellular conditions. Results and discussionDepolarising steps activated typical voltage-dependent activating and inactivating inward (Na+) currents whose amplitude increased or decreased with the amplitudes of the activating, or preceding inactivating, steps. Maximum values of peak Na+ current were independently influenced by genotype but not age or interacting effects of genotype and age on two-way ANOVA. Neither genotype, nor age, whether independently or interactively, influenced voltages at half-maximal current, or steepness factors, for current activation and inactivation, or time constants for recovery from inactivation following repolarisation. In contrast, delayed outward (K+) currents showed similar activation and rectification properties through all experimental groups. These findings directly demonstrate and implicate reduced Na+ in contrast to unchanged K+ current, as a mechanism for slowed conduction causing atrial arrhythmogenicity in Pgc-1β−/− hearts.

Highlights

Recent studies reported that energetically deficient murine Pgc-1β−/− hearts replicate age-dependent atrial arrhythmic phenotypes associated with their corresponding clinical conditions, implicating action potential (AP) conduction slowing consequent upon reduced AP upstroke rates
As adopted in previous reports utilizing this technique, membrane potentials are expressed as voltage excursions relative to the resting membrane potential (RMP) in the protocols illustrated in Figs. 1–5 (Almers et al, 1983a, 1983b)
Positive and negative voltage steps applied through the pipette respectively hyperpolarise and depolarise the membrane potential from its RMP

Summary

Introduction

Recent studies reported that energetically deficient murine Pgc-1β−/− hearts replicate age-dependent atrial arrhythmic phenotypes associated with their corresponding clinical conditions, implicating action potential (AP) conduction slowing consequent upon reduced AP upstroke rates. Delayed outward (K+) currents showed similar activation and rectification properties through all experimental groups These findings directly demonstrate and implicate reduced Na+ in contrast to unchanged K+ current, as a mechanism for slowed conduction causing atrial arrhythmogenicity in Pgc-1β−/− hearts. Implicated in long term arrhythmic substrate (Park et al, 2009; Miyamoto et al, 2009) have been reported in early clinical AF (Zheng et al, 2017) Murine models, those deficient in peroxisome proliferator activated receptor-γ coactivator-1 (PGC-1) transcriptional coactivators proved useful in biochemical studies of metabolic conditions. PGC-1α and PGC-1β are highly expressed in cardiac, brain and skeletal muscle, tissues with high oxidative capacity

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Results

Conclusion