Reduced cardiomyocyte Na+ current in the age-dependent murine Pgc-1β-/- model of ventricular arrhythmia.
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Authors
Ahmad, Shiraz
Valli, Haseeb
Jiang, Anita Y
Matthews, Hugh R
Publication Date
2019-04Journal Title
J Cell Physiol
ISSN
0021-9541
Publisher
Wiley
Volume
234
Issue
4
Pages
3921-3932
Language
eng
Type
Article
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
Ahmad, S., Valli, H., Smyth, R., Jiang, A. Y., Jeevaratnam, K., Matthews, H. R., & Huang, C. L. (2019). Reduced cardiomyocyte Na+ current in the age-dependent murine Pgc-1β-/- model of ventricular arrhythmia.. J Cell Physiol, 234 (4), 3921-3932. https://doi.org/10.1002/jcp.27183
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/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 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.
Keywords
K+ currents, Na+ currents, Pgc-1β, age-dependent arrhythmia, energetic deficiency, murine hearts, ventricles, Action Potentials, Age Factors, Animals, Arrhythmias, Cardiac, Disease Models, Animal, Female, Heart Rate, Kinetics, Male, Mice, Inbred C57BL, Mice, Knockout, Myocytes, Cardiac, Nuclear Proteins, Potassium, Sodium, Transcription Factors
Sponsorship
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.
Funder references
Medical Research Council (MR/M001288/1)
British Heart Foundation (None)
Wellcome Trust (105727/Z/14/Z)
British Heart Foundation (PG/15/12/31280)
Identifiers
External DOI: https://doi.org/10.1002/jcp.27183
This record's URL: https://www.repository.cam.ac.uk/handle/1810/284595
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