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

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

doi:10.1016/j.yjmcc.2015.12.013

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

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

C. Crocini, C. Ferrantini, M. Scardigli, R. Coppini, L. Mazzoni, E. Lazzeri, J. M. Pioner, B. Scellini, A. Guo, L. S. Song, …

Journal of molecular and cellular cardiology, Vol.91, pp.42-51

02/01/2016

DOI: 10.1016/j.yjmcc.2015.12.013

PMCID: PMC4767219

PMID: 26714042

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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.

Cardiac & Cardiovascular Systems

Cardiovascular System & Cardiology

Cell Biology

Life Sciences & Biomedicine

Science & Technology

Details

Title: Subtitle: Novel insights on the relationship between T-tubular defects and contractile dysfunction in a mouse model of hypertrophic cardiomyopathy
Creators: C. Crocini - Florence (Netherlands)
C. Ferrantini - University of Florence
M. Scardigli - Florence (Netherlands)
R. Coppini - University of Florence
L. Mazzoni - University of Florence
E. Lazzeri - Florence (Netherlands)
J. M. Pioner - University of Florence
B. Scellini - University of Florence
A. Guo - Roy J. and Lucille A. Carver College of Medicine
L. S. Song - Roy J. and Lucille A. Carver College of Medicine
P. Yan - UConn Health
L. M. Loew - UConn Health
J. Tardiff - University of Arizona
C. Tesi - University of Florence
F. Vanzi - Florence (Netherlands)
E. Cerbai - University of Florence
F. S. Pavone - University of Florence
L. Sacconi - National Research Council
C. Poggesi - University of Florence
Resource Type: Journal article
Publication Details: Journal of molecular and cellular cardiology, Vol.91, pp.42-51
DOI: 10.1016/j.yjmcc.2015.12.013
PMID: 26714042
PMCID: PMC4767219
NLM abbreviation: J Mol Cell Cardiol
ISSN: 0022-2828
eISSN: 1095-8584
Publisher: Elsevier
Number of pages: 10
Grant note: R01EB001963 / NATIONAL INSTITUTE OF BIOMEDICAL IMAGING AND BIOENGINEERING; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Biomedical Imaging & Bioengineering (NIBIB) GGP13162 / Telethon-Italy; Fondazione Telethon R01 EB001963 / National Institutes of Health (NIH); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA WFR GR-2011-02350583 / Italian Ministry of Health; Ministry of Health, Italy Italian Ministry for Education, University and Research; Ministry of Education, Universities and Research (MIUR) 241577; 241526; 284464 / European Union Seventh Framework Programme; European Commission R01HL075619 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI)
Language: English
Date published: 02/01/2016
Academic Unit: Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Internal Medicine
Record Identifier: 9984288716102771

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