Reduced cardiomyocyte Na+ current in the age-dependent murine Pgc-1β-/- model of ventricular arrhythmia.
Jiang, Anita Y
Journal of cellular physiology
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Ahmad, S., Valli, H., Smyth, R., Jiang, A. Y., Jeevaratnam, K., Matthews, H., & Huang, C. (2019). Reduced cardiomyocyte Na+ current in the age-dependent murine Pgc-1β-/- model of ventricular arrhythmia.. Journal of cellular physiology, 234 (4), 3921-3932. https://doi.org/10.1002/jcp.27183
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) depolarisation 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, 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 ANOVA 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/μm2 (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 post-repolarisation 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 pro-arrhythmic reductions in AP conduction velocity in Pgc-1β-/- ventricles.
Myocytes, Cardiac, Animals, Mice, Inbred C57BL, Mice, Knockout, Disease Models, Animal, Potassium, Sodium, Nuclear Proteins, Transcription Factors, Age Factors, Action Potentials, Heart Rate, Kinetics, Female, Male, Arrhythmias, Cardiac
Medical Research Council (MR/M001288/1) Wellcome Trust (105727/Z/14/Z) British Heart Foundation (PG/14/79/31102 and PG/15/12/31280) Fundamental Research Grant Scheme (FRGS/2/2014/SKK01/PERDANA/02/1), Ministry of Education, Malaysia Sudden Arrhythmic Death Syndrome SADS UK.
British Heart Foundation (PG/14/79/31102)
WELLCOME TRUST (105727/Z/14/Z)
British Heart Foundation (PG/15/12/31280)
External DOI: https://doi.org/10.1002/jcp.27183
This record's URL: https://www.repository.cam.ac.uk/handle/1810/284595
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/