Department of Cell Physiology

Depressed Frank-Starling mechanism in left ventricular muscle of the knock-in mouse model of dilated cardiomyopathy with troponin T deletion mutation ΔK210 We have demonstrated that the Frank-Starling mechanism is coordinately regulated in cardiac muscle via thin-filament “on-off” switching and titin-based changes in interfilament lattice spacing. In the present study, we investigated how the sarcomere lengthdependence of active force production is altered in a knock-in mouse model of inherited dilated cardiomyopathy (DCM) with a deletion mutation ΔK210 in the cardiac troponin T gene. Confocal imaging revealed that the cardiomyocytes were significantly enlarged, especially in the longitudinal direction, in the hearts of ΔK210 knock-in mice, with striation patterns similar to those in wild-type hearts, suggesting that the number of sarcomeres is increased but their length remains unaltered. For analysis of the sarcomere length-dependence of active force, skinned muscles were prepared from the left ventricles of wild-type and ΔK210 mice. An increase in sarcomere length from 1.9 to 2.2 μm shifted the midpoint (pCa50) of the force-pCa curve leftward by 0.21 pCa units in wildtype preparations. In ΔK210 muscles, Ca sensitivity was lower by 0.37 pCa units, and the sarcomere length-dependent shift of pCa50, i.e., ΔpCa50, was less pronounced (0.11 pCa units), with and without treatment with protein kinase A. The rate of active force redevelopment was lower in ΔK210 preparations than in wild-type 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 ΔpCa50 to 0.21 pCa units. We therefore conclude that the depressed FrankStarling mechanism in the hearts of ΔK210 knock-in mice is the result of a reduction in thin-filament cooperative activation.