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

Abnormalities of cardiomyocyte Ca(2 +) 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 repor...

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Autores principales: 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., Tardiff, J., Tesi, C., Vanzi, F., Cerbai, E., Pavone, F.S., Sacconi, L., Poggesi, C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Academic Press 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4767219/
https://www.ncbi.nlm.nih.gov/pubmed/26714042
http://dx.doi.org/10.1016/j.yjmcc.2015.12.013
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author 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.
Tardiff, J.
Tesi, C.
Vanzi, F.
Cerbai, E.
Pavone, F.S.
Sacconi, L.
Poggesi, C.
author_facet 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.
Tardiff, J.
Tesi, C.
Vanzi, F.
Cerbai, E.
Pavone, F.S.
Sacconi, L.
Poggesi, C.
author_sort Crocini, C.
collection PubMed
description Abnormalities of cardiomyocyte Ca(2 +) 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 Δ160E cTnT mouse model that expresses a clinically-relevant HCM mutation. Contractile function of intact ventricular trabeculae is assessed in Δ160E mice and wild-type siblings. As compared with wild-type, Δ160E 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 Ca(2 +) transient in terms of rise and duration are also observed in Δ160E trabeculae and isolated cardiomyocytes. Confocal imaging in cells isolated from Δ160E 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 Ca(2 +) release in isolated cardiomyocytes. In Δ160E cardiomyocytes, a significant number of T-tubules (> 20%) fails to propagate action potentials, with consequent delay of local Ca(2 +) release. At variance with wild-type, we also observe significantly increased variability of local Ca(2 +) transient rise as well as higher Ca(2 +)-spark frequency. Although T-tubule structural remodelling in Δ160E myocytes is modest, T-tubule functional defects determine non-homogeneous Ca(2 +) release and delayed myofilament activation that significantly contribute to mechanical dysfunction.
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spelling pubmed-47672192016-02-29 Novel insights on the relationship between T-tubular defects and contractile dysfunction in a mouse model of hypertrophic cardiomyopathy 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. Tardiff, J. Tesi, C. Vanzi, F. Cerbai, E. Pavone, F.S. Sacconi, L. Poggesi, C. J Mol Cell Cardiol Original Article Abnormalities of cardiomyocyte Ca(2 +) 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 Δ160E cTnT mouse model that expresses a clinically-relevant HCM mutation. Contractile function of intact ventricular trabeculae is assessed in Δ160E mice and wild-type siblings. As compared with wild-type, Δ160E 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 Ca(2 +) transient in terms of rise and duration are also observed in Δ160E trabeculae and isolated cardiomyocytes. Confocal imaging in cells isolated from Δ160E 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 Ca(2 +) release in isolated cardiomyocytes. In Δ160E cardiomyocytes, a significant number of T-tubules (> 20%) fails to propagate action potentials, with consequent delay of local Ca(2 +) release. At variance with wild-type, we also observe significantly increased variability of local Ca(2 +) transient rise as well as higher Ca(2 +)-spark frequency. Although T-tubule structural remodelling in Δ160E myocytes is modest, T-tubule functional defects determine non-homogeneous Ca(2 +) release and delayed myofilament activation that significantly contribute to mechanical dysfunction. Academic Press 2016-02 /pmc/articles/PMC4767219/ /pubmed/26714042 http://dx.doi.org/10.1016/j.yjmcc.2015.12.013 Text en © 2015 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Article
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.
Tardiff, J.
Tesi, C.
Vanzi, F.
Cerbai, E.
Pavone, F.S.
Sacconi, L.
Poggesi, C.
Novel insights on the relationship between T-tubular defects and contractile dysfunction in a mouse model of hypertrophic cardiomyopathy
title Novel insights on the relationship between T-tubular defects and contractile dysfunction in a mouse model of hypertrophic cardiomyopathy
title_full Novel insights on the relationship between T-tubular defects and contractile dysfunction in a mouse model of hypertrophic cardiomyopathy
title_fullStr Novel insights on the relationship between T-tubular defects and contractile dysfunction in a mouse model of hypertrophic cardiomyopathy
title_full_unstemmed Novel insights on the relationship between T-tubular defects and contractile dysfunction in a mouse model of hypertrophic cardiomyopathy
title_short Novel insights on the relationship between T-tubular defects and contractile dysfunction in a mouse model of hypertrophic cardiomyopathy
title_sort novel insights on the relationship between t-tubular defects and contractile dysfunction in a mouse model of hypertrophic cardiomyopathy
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4767219/
https://www.ncbi.nlm.nih.gov/pubmed/26714042
http://dx.doi.org/10.1016/j.yjmcc.2015.12.013
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