Novel insights on the relationship between T-tubular defects and contractile dysfunction in a mouse model of hypertrophic cardiomyopathy

Year: 2016

Authors: Crocini C., Ferrantini C., Scardigli M., Coppini R., Mazzoni L., Lazzeri E., Pioner J.M., Scellini B., Guo A., Song L.S., Yan P., Loew L.M., Tarif J., Tesi C., Vanzi F., Cerbai E., Pavone F.S., Sacconi L., Poggesi C.

Autors Affiliation: European Laboratory for Non-Linear Spectroscopy, 50019 Florence, Italy;
Division of Physiology, Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy;
Division of Pharmacology, Department “NeuroFarBa,” University of Florence, 50139 Florence, Italy;
Division of Cardiovascular Medicine, Department of Internal Medicine and Francois M. Abboud Cardiovascular Research Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, U.S.A;
R. D. Berlin Center for Cell Analysis and Modeling, University of Connecticut Health Center, Farmington, CT 06030, U.S.A;
Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85721, U.S.A;
Department of Physics and Astronomy, University of Florence, 50019 Sesto Fiorentino, Italy;
National Institute of Optics, National Research Council, 50125 Florence, Italy

Abstract: Abnormalities of cardiomyocyte Ca2+ homeostasis and excitation-contraction (E-C) coupling are early events in the pathogenesis of hypertrophic cardiomyopathy (HCM) and concomitant determinants of the diastolic dysfunction and arrhythmias typical of the disease. T-tubule remodelling has been reported to occur in HCM but little is known about its role in the E-C coupling alterations of HCM. Here, the role of T-tubule remodelling in the electro-mechanical dysfunction associated to HCM is investigated in the Delta 160E cTnT mouse model that expresses a clinically-relevant HCM mutation. Contractile function of intact ventricular trabeculae is assessed in Delta 160E mice and wild-type siblings. As compared with wild-type, Delta 160E trabeculae show prolonged kinetics of force development and relaxation, blunted force-frequency response with reduced active tension at high stimulation frequency, and increased occurrence of spontaneous contractions. Consistently, prolonged Ca2+ transient in terms of rise and duration are also observed in Delta 160E trabeculae and isolated cardiomyocytes. Confocal imaging in cells isolated from Delta 160E mice reveals significant, though modest, remodelling of T-tubular architecture. A two-photon random access microscope is employed to dissect the spatio-temporal relationship between T-tubular electrical activity and local Ca2+ release in isolated cardiomyocytes. In Delta 160E cardiomyocytes, a significant number of T-tubules (>20%) fails to propagate action potentials, with consequent delay of local Ca2+ release. At variance with wild-type, we also observe significantly increased variability of local Ca2+ transient rise as well as higher Ca2+-spark frequency. Although T-tubule structural remodelling in Delta 160E myocytes is modest, T-tubule functional defects determine non-homogeneous Ca2+ release and delayed myofilament activation that significantly contribute to mechanical dysfunction. (C) 2015 The Authors. Published by Elsevier Ltd.


Volume: 91      Pages from: 42  to: 51

More Information: The research leading to these results received funding from the European Union Seventh Framework Programme (FP7/2007-2013) under Grant Agreements 241577, 241526, and 284464. This research project was also supported by National Institutes of Health (NIH Grant: R01 EB001963), by the Italian Ministry for Education, University and Research in the framework of the Flagship Project NANOMAX, by the Italian Ministry of Health (WFR GR-2011-02350583) and by Telethon-Italy (GGP13162).
KeyWords: Hypertrophic cardiomyopathy; T-tubules; Excitation-contraction coupling; Imaging; Non-linear microscopy
DOI: 10.1016/j.yjmcc.2015.12.013

Citations: 42
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