| First Author | Inoue T | Year | 2013 |
| Journal | J Mol Cell Cardiol | Volume | 63 |
| Pages | 69-78 | PubMed ID | 23863340 |
| Mgi Jnum | J:302903 | Mgi Id | MGI:6510916 |
| Doi | 10.1016/j.yjmcc.2013.07.001 | Citation | Inoue T, et al. (2013) Depressed Frank-Starling mechanism in the left ventricular muscle of the knock-in mouse model of dilated cardiomyopathy with troponin T deletion mutation DeltaK210. J Mol Cell Cardiol 63:69-78 |
| abstractText | It has been reported that the Frank-Starling mechanism is coordinately regulated in cardiac muscle via thin filament "on-off" equilibrium and titin-based lattice spacing changes. In the present study, we tested the hypothesis that the deletion mutation DeltaK210 in the cardiac troponin T gene shifts the equilibrium toward the "off" 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 DeltaK210 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 (DeltaK210) mice. An increase in SL from 1.90 to 2.20mum shifted the mid-point (pCa50) of the force-pCa curve leftward by ~0.21pCa units in WT preparations. In DeltaK210 muscles, Ca(2+) sensitivity was lower by ~0.37pCa units, and the SL-dependent shift of pCa50, i.e., DeltapCa50, was less pronounced (~0.11pCa units), with and without protein kinase A treatment. The rate of active force redevelopment was lower in DeltaK210 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 DeltapCa50 to ~0.21pCa units. The depressed Frank-Starling mechanism in DeltaK210 hearts is the result of a reduction in thin filament cooperative activation. |
