Depressed Frank-Starling mechanism in the left ventricular muscle of the knock-in mouse model of dilated cardiomyopathy with troponin T deletion mutation Delta K210

作者：Inoue Takahiro; Kobirumaki Shimozawa Fuyu; Kagemoto Tatsuya; Fujii Teruyuki; Terui Takako; Kusakari Yoichiro; Hongo Kenichi; Morimoto Sachio; Ohtsuki Iwao; Hashimoto Kazuhiro; Fukuda Norio^*

来源：Journal of Molecular and Cellular Cardiology, 2013, 63: 69-78.

DOI：10.1016/j.yjmcc.2013.07.001

• Sarcomere
• Muscle mechanics
• Ca2+ sensitivity
• Contractile function
• Titin

It has been reported that the Frank-Starling mechanism is coordinately regulated in cardiac muscle via thin filament %26quot;on-off%26quot; equilibrium and titin-based lattice spacing changes. In the present study, we tested the hypothesis that the deletion mutation Delta K210 in the cardiac troponin T gene shifts the equilibrium toward the %26quot;off%26quot; state and accordingly attenuate the sarcomere length (SL) dependence of active force production, via reduced cross-bridge formation. Confocal imaging in isolated hearts revealed that the cardiomyocytes were enlarged, especially in the longitudinal direction, in Delta K210 hearts, with striation patterns similar to those in wild type (WT) hearts, suggesting that the number of sarcomeres is increased in cardiomyocytes but the sarcomere length remains unaltered. For analysis of the SL dependence of active force, skinned muscle preparations were obtained from the left ventricle of WT and knock-in (Delta K210) mice. An increase in SL from 1.90 to 2.20 mu m shifted the mid-point (pCa(50)) of the force-pCa curve leftward by similar to 0.21 pCa units in WT preparations. In Delta K210 muscles, Ca2+ sensitivity was lower by similar to 0.37 pCa units, and the SL-dependent shift of pCa(50), i.e., Delta pCa(50), was less pronounced (similar to 0.11 pCa units), with and without protein kinase A treatment. The rate of active force redevelopment was lower in Delta K210 preparations than in WT preparations, showing blunted thin filament cooperative activation. An increase in thin filament cooperative activation upon an increase in the fraction of strongly bound cross-bridges by MgADP increased Delta pCa(50) to similar to 0.21 pCa units. The depressed Frank-Starling mechanism in Delta K210 hearts is the result of a reduction in thin filament cooperative activation.

• 出版日期2013-10