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 |
| 巻 | 63 |
| DOI | |
| 出版物ステータス | 出版済み - 10 1 2013 |
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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
}
TY - JOUR
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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84884810564&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84884810564&partnerID=8YFLogxK
U2 - 10.1016/j.yjmcc.2013.07.001
DO - 10.1016/j.yjmcc.2013.07.001
M3 - Article
C2 - 23863340
AN - SCOPUS:84884810564
VL - 63
SP - 69
EP - 78
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
SN - 0022-2828
ER -