Depressed Frank-Starling mechanism in the left ventricular muscle of the knock-in mouse model of dilated cardiomyopathy with troponin T deletion mutation δK210

Takahiro Inoue, Fuyu Kobirumaki-Shimozawa, Tatsuya Kagemoto, Teruyuki Fujii, Takako Terui, Yoichiro Kusakari, Kenichi Hongo, Sachio Morimoto, Iwao Ohtsuki, Kazuhiro Hashimoto, Norio Fukuda

研究成果: ジャーナルへの寄稿記事

18 引用 (Scopus)

抄録

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 (pCa 50 ) 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 pCa 50 , i.e., δpCa 50 , 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 δpCa 50 to ~0.21pCa units. The depressed Frank-Starling mechanism in δK210 hearts is the result of a reduction in thin filament cooperative activation.

元の言語英語
ページ(範囲)69-78
ページ数10
ジャーナルJournal of Molecular and Cellular Cardiology
63
DOI
出版物ステータス出版済み - 10 1 2013

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Starlings
Sarcomeres
Troponin T
Sequence Deletion
Dilated Cardiomyopathy
Muscles
Cardiac Myocytes
Connectin
Cyclic AMP-Dependent Protein Kinases
Adenosine Diphosphate
Heart Ventricles
Myocardium
Genes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

これを引用

Depressed Frank-Starling mechanism in the left ventricular muscle of the knock-in mouse model of dilated cardiomyopathy with troponin T deletion mutation δK210. / Inoue, Takahiro; Kobirumaki-Shimozawa, Fuyu; Kagemoto, Tatsuya; Fujii, Teruyuki; Terui, Takako; Kusakari, Yoichiro; Hongo, Kenichi; Morimoto, Sachio; Ohtsuki, Iwao; Hashimoto, Kazuhiro; Fukuda, Norio.

:: Journal of Molecular and Cellular Cardiology, 巻 63, 01.10.2013, p. 69-78.

研究成果: ジャーナルへの寄稿記事

Inoue, T, Kobirumaki-Shimozawa, F, Kagemoto, T, Fujii, T, Terui, T, Kusakari, Y, Hongo, K, Morimoto, S, Ohtsuki, I, Hashimoto, K & Fukuda, N 2013, 'Depressed Frank-Starling mechanism in the left ventricular muscle of the knock-in mouse model of dilated cardiomyopathy with troponin T deletion mutation δK210', Journal of Molecular and Cellular Cardiology, 巻. 63, pp. 69-78. https://doi.org/10.1016/j.yjmcc.2013.07.001
Inoue, Takahiro ; Kobirumaki-Shimozawa, Fuyu ; Kagemoto, Tatsuya ; Fujii, Teruyuki ; Terui, Takako ; Kusakari, Yoichiro ; Hongo, Kenichi ; Morimoto, Sachio ; Ohtsuki, Iwao ; Hashimoto, Kazuhiro ; Fukuda, Norio. / Depressed Frank-Starling mechanism in the left ventricular muscle of the knock-in mouse model of dilated cardiomyopathy with troponin T deletion mutation δK210. :: Journal of Molecular and Cellular Cardiology. 2013 ; 巻 63. pp. 69-78.
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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 (pCa 50 ) 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 pCa 50 , i.e., δpCa 50 , 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 δpCa 50 to ~0.21pCa units. The depressed Frank-Starling mechanism in δK210 hearts is the result of a reduction in thin filament cooperative activation.",
author = "Takahiro Inoue and Fuyu Kobirumaki-Shimozawa and Tatsuya Kagemoto and Teruyuki Fujii and Takako Terui and Yoichiro Kusakari and Kenichi Hongo and Sachio Morimoto and Iwao Ohtsuki and Kazuhiro Hashimoto and Norio Fukuda",
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T1 - Depressed Frank-Starling mechanism in the left ventricular muscle of the knock-in mouse model of dilated cardiomyopathy with troponin T deletion mutation δK210

AU - Inoue, Takahiro

AU - Kobirumaki-Shimozawa, Fuyu

AU - Kagemoto, Tatsuya

AU - Fujii, Teruyuki

AU - Terui, Takako

AU - Kusakari, Yoichiro

AU - Hongo, Kenichi

AU - Morimoto, Sachio

AU - Ohtsuki, Iwao

AU - Hashimoto, Kazuhiro

AU - Fukuda, Norio

PY - 2013/10/1

Y1 - 2013/10/1

N2 - 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 (pCa 50 ) 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 pCa 50 , i.e., δpCa 50 , 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 δpCa 50 to ~0.21pCa units. The depressed Frank-Starling mechanism in δK210 hearts is the result of a reduction in thin filament cooperative activation.

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