Force-Dependent Recruitement from the Myosin off State Contributes to Length-Dependent Activation
Force-Dependent Recruitement from the Myosin off State Contributes to Length-Dependent Activation
复制标题
DOI：
10.1016/j.bpj.2018.07.006
复制
发表时间：
2018-08-07
影响因子：
3.4
通讯作者：
Campbell, Stuart G.
中科院分区：
文献类型：
--
作者：
Campbell, Kenneth S.;Janssen, Paul M. L.;Campbell, Stuart G.
当心肌在较长时间内被激活时，它会产生更大的力量。发展半最大力所需的Ca2+浓度也降低。这些效应被称为长度依赖性激活，被认为在Frank-Starling关系和心血管稳态中起着关键作用。支持长度依赖性激活的分子机制尚不清楚，但最近的实验表明，它们可能包括从关闭（有时称为超放松）状态招募肌凝蛋白头。这篇手稿提出了一个肌肉收缩的数学模型，该模型是为了研究这一假设而开发的。模型中的肌球蛋白头部在关闭状态（不能与肌动蛋白相互作用）、打开状态（可以与肌动蛋白结合）和单个附着状态之间转换。采用多维参数优化方法对实验数据进行拟合。统计分析表明，与恒定的开关转换率模型相比，开关转换率随力线性增加的模型更能再现化学渗透心肌的长度依赖性行为（f检验，p < 0.001）。这一结果表明，粗丝跃迁是由力调制的。额外的计算表明，该模型结合了机械敏感的粗纤维，也可以重现在拉伸到不同长度的小梁中测量到的抽搐反应。最后一组模拟被用来测试模型。这些计算预测了减少被动刚度将如何影响收缩力的钙敏感性的长度依赖性。预测结果（& Unknown；pCa减少60%(50)）模拟了& Unknown；pCa减少58%的结果。表达巨大同种异构体titin并具有低静息张力的大鼠心肌pCa（50）。总之，这些计算结果表明，肌凝蛋白头部从粗丝关闭状态的力依赖性招募有助于长度依赖性激活和Frank-Starling关系。
Cardiac muscle develops more force when it is activated at longer lengths. The concentration of Ca2+ required to develop half-maximal force also decreases. These effects are known as length-dependent activation and are thought to play critical roles in the Frank-Starling relationship and cardiovascular homeostasis. The molecular mechanisms underpinning length-dependent activation remain unclear, but recent experiments suggest that they may include recruitment of myosin heads from the off (sometimes called super-relaxed) state. This manuscript presents a mathematical model of muscle contraction that was developed to investigate this hypothesis. Myosin heads in the model transitioned between an off state (that could not interact with actin), an on state (that could bind to actin), and a single attached state. Simulations were fitted to experimental data using multidimensional parameter optimization. Statistical analysis showed that a model in which the rate of the off-to-on transition increased linearly with force reproduced the length-dependent behavior of chemically permeabilized myocardium better than a model with a constant off-to-on transition rate (F-test, p < 0.001). This result suggests that the thick-filament transitions are modulated by force. Additional calculations showed that the model incorporating a mechanosensitive thick filament could also reproduce twitch responses measured in a trabecula stretched to different lengths. A final set of simulations was then used to test the model. These calculations predicted how reducing passive stiffness would impact the length dependence of the calcium sensitivity of contractile force. The prediction (a 60% reduction in & Unknown;pCa(50)) mimicked the 58% reduction in & Unknown;pCa(50) in myocardium from rats that expressed a giant isoform of titin and had low resting tension. Together, these computational results suggest that force-dependent recruitment of myosin heads from the thick-filament off state contributes to length-dependent activation and the Frank-Starling relationship.