Reduced cardiomyocyte Na⁺ current in the age‐dependent murine Pgc‐1β^−/− model of ventricular arrhythmia

Abstract

Peroxisome proliferator-activated receptor-γ coactivator-1 deficient (Pgc-1β ) murine hearts model the increased, age-dependent, ventricular arrhythmic risks attributed to clinical conditions associated with mitochondrial energetic dysfunction. These were accompanied by compromised action potential (AP) upstroke rates and impaired conduction velocities potentially producing arrhythmic substrate. We tested a hypothesis implicating compromised Na current in these electrophysiological phenotypes by applying loose patch-clamp techniques in intact young and aged, wild-type (WT) and Pgc-1β , ventricular cardiomyocyte preparations for the first time. This allowed conservation of their in vivo extracellular and intracellular conditions. Depolarising steps elicited typical voltage-dependent activating and inactivating inward Na currents with peak amplitudes increasing or decreasing with their respective activating or preceding inactivating voltage steps. Two-way analysis of variance associated Pgc-1β genotype with independent reductions in maximum peak ventricular Na currents from -36.63 ± 2.14 (n = 20) and -35.43 ± 1.96 (n = 18; young and aged WT, respectively), to -29.06 ± 1.65 (n = 23) and -27.93 ± 1.63 (n = 20; young and aged Pgc-1β , respectively) pA/μm (p < 0.0001), without independent effects of, or interactions with age. Voltages at half-maximal current V*, and steepness factors k in plots of voltage dependences of both Na current activation and inactivation, and time constants for its postrepolarisation recovery from inactivation, remained indistinguishable through all experimental groups. So were the activation and rectification properties of delayed outward (K ) currents, demonstrated from tail currents reflecting current recoveries from respective varying or constant voltage steps. These current-voltage properties directly implicate decreases specifically in maximum available Na current with unchanged voltage dependences and unaltered K current properties, in proarrhythmic reductions in AP conduction velocity in Pgc-1β ventricles.

Ageing in Pgc-1β−/− mice modelling mitochondrial dysfunction induces differential expression of a range of genes regulating ventricular electrophysiology

“…At single gene level we have found a handful genes to be differentially expressed to a significance level P <0.05 as presented in Figures 1 and 2. To further explore the changes in gene expression pattern and potentially correlate these changes with the functional changes seen on the electrophysiological level [14,15,22] we have subgrouped the genes into ten groups according to their functions as indicated in Table 1 and discussed in the introduction.…”

“…The Pgc-1β −/ − mouse model has proven to be a relevant model to study ‘metabolism induced’ arrhythmia [10,30]. Several previous studies [15,22,31,32] have explored the effects that this mitochondrial dysfunction has on the ventricular heart and it is now well established that mice deficient in Pgc-1β present with an age-dependent pro-arrhythmic phenotype. In the present study our aim was to investigate the molecular mechanisms causing this phenotype.…”

“…We found that unprovoked young and aged Pgc-1β −/− hearts subject to a pacing protocol showed increased incidences of alternans in both AP activation (upshoot velocity and latency), recovery duration and resting membrane potential (RMP) compared with WT hearts, and aged Pgc-1β −/− hearts displayed increased incidence of actual arrhythmia. In conclusion Pgc-1β −/− hearts show pro-arrhythmic instabilities attributable to altered AP conduction and activation [14] and Pgc-1β −/− ventricular preparations showed consistently smaller Na + currants independent of age even though other factors such as Na + channel inactivation and K + current activation were unchanged [15]. Moreover, morphometric assessments of the cardiac tissue indicated significantly increased fibrotic tissue with age and Pgc-1β −/− genotype [15].…”

“…In conclusion Pgc-1β −/− hearts show pro-arrhythmic instabilities attributable to altered AP conduction and activation [14] and Pgc-1β −/− ventricular preparations showed consistently smaller Na + currants independent of age even though other factors such as Na + channel inactivation and K + current activation were unchanged [15]. Moreover, morphometric assessments of the cardiac tissue indicated significantly increased fibrotic tissue with age and Pgc-1β −/− genotype [15].…”

Mitochondrial Dysfunction Increases Arrhythmic Triggers and Substrates; Potential Anti-arrhythmic Pharmacological Targets

“…Detailed electrophysiological studies in peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Pgc-1α) and Pgc-1β knockout models of mitochondrial dysfunction yield similar overt arrhythmic phenotypes whilst also yielding information on the ionic basis of these arrhythmias. For example, Pgc-1β-/- mice show decreased atrial and ventricular conduction velocity, which may be attributed to reduced voltage gated inward Na + currents ( 53 – 60 ).…”