Myosin filament activation in the heart is tuned to the mechanical task
Myosin filament activation in the heart is tuned to the mechanical task
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DOI：
10.1073/pnas.1619484114
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发表时间：
2017-03-21
影响因子：
11.1
通讯作者：
Piazzesi, Gabriella
中科院分区：
文献类型：
--
作者：
Reconditi, Massimo;Caremani, Marco;Piazzesi, Gabriella
哺乳动物的心脏将血液泵入血管，维持由两个串联泵驱动的循环系统的动态平衡。这一重要功能是基于Frank-Starling机制对心脏性能的微调，该机制将收缩心室施加的压力（收缩期末压力）与其容积（收缩期末容积）联系起来。在肌节（心肌细胞的结构单位）水平上，Frank-Starling机制包括随着肌节长度的增加而增加活动力（长度依赖性激活）。在肌节长度控制下，我们结合肌节力学和大鼠完整心室小梁同步光的微米-纳米尺度x射线衍射，测量了肌凝蛋白马达在舒张-收缩周期中的轴向运动。我们发现肌凝蛋白马达的数量离开关闭，ATP水解不可用的舒张状态特征被调整为肌节长度依赖的收缩力。这种基于机械传感的粗纤维调节使得收缩的能量消耗迅速调整到机械任务，揭示了弗兰克-斯塔林机制的一个主要方面。这种调节被认为受到心肌病引起的突变的损害，这些突变会影响控制马达关闭状态的分子内和分子间相互作用。
The mammalian heart pumps blood through the vessels, maintaining the dynamic equilibrium in a circulatory system driven by two pumps in series. This vital function is based on the fine-tuning of cardiac performance by the Frank-Starling mechanism that relates the pressure exerted by the contracting ventricle (end systolic pressure) to its volume (end systolic volume). At the level of the sarcomere, the structural unit of the cardiac myocytes, the Frank-Starling mechanism consists of the increase in active force with the increase of sarcomere length (length-dependent activation). We combine sarcomere mechanics and micrometer-nanometer-scaleX-ray diffraction from synchrotron light in intact ventricular trabeculae from the rat to measure the axial movement of the myosin motors during the diastole-systole cycle under sarcomere length control. We find that the number of myosin motors leaving the off, ATP hydrolysis-unavailable state characteristic of the diastole is adjusted to the sarcomere length-dependent systolic force. This mechanosensing-based regulation of the thick filament makes the energetic cost of the systole rapidly tuned to the mechanical task, revealing a prime aspect of the Frank-Starling mechanism. The regulation is putatively impaired by cardiomyopathy-causing mutations that affect the intramolecular and intermolecular interactions controlling the off state of the motors.