title: Depressed Frank-Starling mechanism in the left ventricular muscle of the knock-in mouse model of dilated cardiomyopathy with troponin T deletion mutation ΔK210.
abstract: 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 ΔK210 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 ΔK210 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 (ΔK210) mice. An increase in SL from 1.90 to 2.20μm shifted the mid-point (pCa50) of the force-pCa curve leftward by ~0.21pCa units in WT preparations. In ΔK210 muscles, Ca(2+) sensitivity was lower by ~0.37pCa units, and the SL-dependent shift of pCa50, i.e., ΔpCa50, was less pronounced (~0.11pCa units), with and without protein kinase A treatment. The rate of active force redevelopment was lower in ΔK210 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 ΔpCa50 to ~0.21pCa units. The depressed Frank-Starling mechanism in ΔK210 hearts is the result of a reduction in thin filament cooperative activation.
authors.affiliation: Department of Cell Physiology, The Jikei University School of Medicine, Tokyo, Japan; Department of Cardiac Surgery, The Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Inoue
authors.forename: Fuyu
authors.initials: F
authors.lastname: Kobirumaki-Shimozawa
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kagemoto
authors.forename: Teruyuki
authors.initials: T
authors.lastname: Fujii
authors.forename: Takako
authors.initials: T
authors.lastname: Terui
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Kusakari
authors.forename: Kenichi
authors.initials: K
authors.lastname: Hongo
authors.forename: Sachio
authors.initials: S
authors.lastname: Morimoto
authors.forename: Iwao
authors.initials: I
authors.lastname: Ohtsuki
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Hashimoto
authors.forename: Norio
authors.initials: N
authors.lastname: Fukuda
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000503:physiopathology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004195:Disease Models, Animal; D006352:Heart Ventricles / Q000378:metabolism* / Q000503:physiopathology*; D066298:In Vitro Techniques; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000235:genetics; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D017384:Sequence Deletion; D020107:Troponin T / Q000235:genetics* / Q000378:metabolism
chemical_list: D020107:Troponin T; D000244:Adenosine Diphosphate; D017868:Cyclic AMP-Dependent Protein Kinases; D002118:Calcium
keywords: Ca(2+) sensitivity; Contractile function; DCM; LV; Muscle mechanics; SL; Sarcomere; Titin; Tn; dilated cardiomyopathy; fast skeletal troponin complex; left ventricle; sTn; sarcomere length; troponin