Department of Cell Physiology, The Jikei University School of Medicine, Tokyo, Japan.
J Gen Physiol. 2010 Oct;136(4):469-82. doi: 10.1085/jgp.201010502.
Cardiac sarcomeres produce greater active force in response to stretch, forming the basis of the Frank-Starling mechanism of the heart. The purpose of this study was to provide the systematic understanding of length-dependent activation by investigating experimentally and mathematically how the thin filament "on-off" switching mechanism is involved in its regulation. Porcine left ventricular muscles were skinned, and force measurements were performed at short (1.9 µm) and long (2.3 µm) sarcomere lengths. We found that 3 mM MgADP increased Ca(2+) sensitivity of force and the rate of rise of active force, consistent with the increase in thin filament cooperative activation. MgADP attenuated length-dependent activation with and without thin filament reconstitution with the fast skeletal troponin complex (sTn). Conversely, 20 mM of inorganic phosphate (Pi) decreased Ca(2+) sensitivity of force and the rate of rise of active force, consistent with the decrease in thin filament cooperative activation. Pi enhanced length-dependent activation with and without sTn reconstitution. Linear regression analysis revealed that the magnitude of length-dependent activation was inversely correlated with the rate of rise of active force. These results were quantitatively simulated by a model that incorporates the Ca(2+)-dependent on-off switching of the thin filament state and interfilament lattice spacing modulation. Our model analysis revealed that the cooperativity of the thin filament on-off switching, but not the Ca(2+)-binding ability, determines the magnitude of the Frank-Starling effect. These findings demonstrate that the Frank-Starling relation is strongly influenced by thin filament cooperative activation.
心肌肌节在拉伸时产生更大的主动力，这构成了心脏的弗兰克-斯塔林机制的基础。本研究的目的是通过实验和数学方法研究细肌丝“开-关”转换机制如何参与其调节，从而提供对长度依赖性激活的系统理解。猪左心室肌肉去皮肤，并在短（1.9 µm）和长（2.3 µm）肌节长度下进行力测量。我们发现 3 mM MgADP 增加了力的 Ca2+敏感性和主动力的上升速率，这与细肌丝协同激活的增加一致。MgADP 减弱了有和没有快速骨骼肌肌钙蛋白复合物（sTn）的细肌丝重建的长度依赖性激活。相反，20 mM 无机磷（Pi）降低了力的 Ca2+敏感性和主动力的上升速率，这与细肌丝协同激活的降低一致。Pi 增强了有和没有 sTn 重建的长度依赖性激活。线性回归分析表明，长度依赖性激活的幅度与主动力的上升速率呈反比。该模型定量模拟了这一结果，该模型结合了细肌丝状态的 Ca2+依赖性开-关转换和相间晶格间距调制。我们的模型分析表明，细肌丝开-关转换的协同性，而不是 Ca2+结合能力，决定了弗兰克-斯塔林效应的幅度。这些发现表明，弗兰克-斯塔林关系受细肌丝协同激活的强烈影响。
