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Novel insights on the relationship between T-tubular defects and contractile dysfunction in a mouse model of hypertrophic cardiomyopathy
- Source :
- Journal of Molecular and Cellular Cardiology 91 (2016): 42–51. doi:10.1016/j.yjmcc.2015.12.013, info:cnr-pdr/source/autori: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./titolo:Novel insights on the relationship between T-tubular defects and contractile dysfunction in a mouse model of hypertrophic cardiomyopathy/doi:10.1016%2Fj.yjmcc.2015.12.013/rivista:Journal of Molecular and Cellular Cardiology/anno:2016/pagina_da:42/pagina_a:51/intervallo_pagine:42–51/volume:91, Journal of Molecular and Cellular Cardiology
- Publication Year :
- 2016
- Publisher :
- Elsevier BV, 2016.
-
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 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 Ca2 + 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 Ca2 + release in isolated cardiomyocytes. In Δ160E 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 Δ160E myocytes is modest, T-tubule functional defects determine non-homogeneous Ca2 + release and delayed myofilament activation that significantly contribute to mechanical dysfunction.<br />Highlights • Contraction and Ca2 + transient kinetics are impaired in myocardial preparations from mice carrying the cardiac troponin T ∆ 160E mutation. • T-tubules architecture is mildly altered in ∆160E cardiomyocytes. • 20% of T-tubules fail to propagate action potential and produce delay of local Ca2 + rise. • Higher spatio-temporal variability of local Ca2 + rise and increased Ca2 + sparks frequency are found in ∆160E cardiomyocytes.
- Subjects :
- AP −, Failing T-tubules
0301 basic medicine
Myofilament
Action Potentials
Gene Expression
030204 cardiovascular system & hematology
Imaging
T-tubule
Mice
Sarcolemma
0302 clinical medicine
Myofibrils
TATS, Transverse-axial tubular system
Myocyte
Myocytes, Cardiac
TTP, Time-to-peak
EXCITATION-CONTRACTION COUPLING
IMAGING, NON-LINEAR MICROSCOPY, HYPERTROPHIC CARDIOMYOPATHY, T-TUBULE
Excitation Contraction Coupling
AP, Action potential
HCM, Hypertrophic cardiomyopathy
Mice, Knockout
Microscopy, Confocal
Chemistry
Optical Imaging
Hypertrophic cardiomyopathy
Actin Cytoskeleton
medicine.anatomical_structure
AP +, Electrically coupled T-tubules
Non-linear microscopy
T-tubules
Original Article
Cardiology and Cardiovascular Medicine
RAMP, Random access multi-photon
medicine.medical_specialty
HF, Heart failure
Excitation–contraction coupling
03 medical and health sciences
Troponin T
AOD, Acousto-optic deflector
Internal medicine
medicine
Animals
Humans
Calcium Signaling
Molecular Biology
CaT50, Time of 50% Ca2 + decay
Ion Transport
TT, T-tubule
S/N, Signal-to-noise ratio
Cardiomyopathy, Hypertrophic
Actin cytoskeleton
medicine.disease
Myocardial Contraction
Excitation-contraction coupling
Disease Models, Animal
030104 developmental biology
Endocrinology
SS, Surface sarcolemma
Mutation
Calcium
cTnT, Cardiac troponin T
E–C, Excitation–contraction
Myofibril
VSD, Voltage sensitive dye
Homeostasis
Subjects
Details
- ISSN :
- 00222828
- Volume :
- 91
- Database :
- OpenAIRE
- Journal :
- Journal of Molecular and Cellular Cardiology
- Accession number :
- edsair.doi.dedup.....0622cba30ea6e03df3a8690c8d7c751e