Molecular mechanism of length-dependent activation in cardiac muscle

心肌长度依赖性激活的分子机制

• 批准号: 18500321
• 负责人: FUKUDA Norio
• 金额: $ 2.52万
• 依托单位: Jikei University School of Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18500321/
• 关键词: Cardiac muscle; Starling's law of the heart; Length-denendent activation; Troponin; Titin; Cross-bridges; Frank-Starling機構; 静止張力; 格子間隔; Cardiac muscle; Starling's law of the heart; Length-denendent activation; Troponin; Titin; Cross-bridges; Frank-Starling機構; 静止張力; 格子間隔

An increase in ventricular volume enhances the systolic performance of the heart ; this is known as the Frank-Starling law of the heart. "The Law" is a manifestation of the sarcomere length dependence of myocardial activation, in which active force is a function of the resting sarcomere length (i.e., length-dependent activation). We have reported that passive force resulting from extension of the giant elastic protein titin (also known as connectin) operates as a triggering factor in this phenomenon. In the present study, we investigated whether or not length-dependent activation is modulated at the thin filament level. Quasi-complete reconstitution of thin filaments with rabbit fast skeletal troponin (sTn) attenuated length-dependent activation in porcine left ventricular muscle to a magnitude similar to that observed in rabbit fast skeletal muscle, accompanied by an increase in Ca^<2+> sensitivity of force. We also found that sTn reconstitution accelerated cross-bridge kinetics at submaximal levels, suggesting that sTn reconstitution results in a decrease in the fraction of recruitable (i.e., resting) cross-bridges that can potentially produce active force. An increase in titin-based passive force, induced by manipulating the pre-history of stretch, enhanced length-dependent activation, with and without sTn reconstitution. Furthermore, reconstitution of rabbit fast skeletal muscle with porcine left ventricular Tn enhanced length-dependent activation, accompanied by a decrease in Ca^<2+> sensitivity of force. These results favor the interpretation that troponin plays an important role in length-dependent activation via on-off switching of the thin filament state, in concert with titin-based regulation.

心室体积的增加增强了心脏的收缩性能。这被称为坦率的心脏律法。 “定律”是心肌激活的肌节长度依赖性的表现，其中活性力是静止的肌节长度的函数（即长度依赖性激活）。我们报告说，由于巨型弹性蛋白滴定（也称为Connectin）的扩展而产生的被动力是这种现象中的触发因素。在本研究中，我们研究了长度依赖性激活是否在薄丝水平上进行了调节。与兔子快速骨骼肌钙蛋白（STN）对薄细丝的准完全重构减弱了长度依赖性激活，左心室肌肉的长度依赖性激活与兔子快速骨骼肌相似，伴随着ca^<2+>的敏感性。我们还发现，STN的重建在次最大水平上加速了跨桥动力学，这表明STN重构导致可募集的（即静止）跨支架的分数减少，从而可能产生活跃的力。通过有或没有STN重构的情况，通过操纵拉伸，增强的长度依赖性激活的史前史而引起的基于TITIN的被动力的增加。此外，用猪左心室TN重建兔子快速骨骼肌增强了长度依赖性激活，并伴随着ca^<2+>敏感性的降低。这些结果有利于以下解释：肌钙蛋白通过基于TITIN的调节结合使用薄丝状态的开关通过薄丝状态的开关依赖长度依赖性激活起着重要作用。