1. Novel insights on the relationship between T-tubular defects and contractile dysfunction in a mouse model of hypertrophic cardiomyopathy
- Author
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Long-Sheng Song, Francesco S. Pavone, Luca Mazzoni, Chiara Tesi, Josè Manuel Pioner, Claudia Crocini, Leonardo Sacconi, Jil C. Tardiff, Elisabetta Cerbai, Beatrice Scellini, Ping Yan, Leslie M. Loew, Erica Lazzeri, Cecilia Ferrantini, Francesco Vanzi, Raffaele Coppini, Ang Guo, Corrado Poggesi, and Marina Scardigli
- 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 - 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., 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.
- Published
- 2016