Modeling Thick Filament Activation Suggests a Molecular Basis for Force Depression.
Modeling Thick Filament Activation Suggests a Molecular Basis for Force Depression.
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粗丝激活模型提出了力抑制的分子基础。
DOI：
10.1101/2023.09.27.559764
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Walcott,Sam
中科院分区：
文献类型：
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作者：
Liu,Shuyue;Marang,Chris;Woodward,Mike;Joumaa,Venus;Leonard,Tim;Scott,Brent;Debold,Edward;Herzog,Walter;Walcott,Sam
旨在连接肌肉分子和细胞功能的多尺度模型一直难以开发，部分原因是缺乏自一致的多尺度数据。为了解决这一差距，我们测量了在力-长度关系的高原区域进行的单个剥皮兔腰肌纤维对斜坡缩短和台阶拉伸的力响应。我们从相同的肌肉中分离出肌凝蛋白，并在相似的条件下，使用激光捕获和体外运动性测定对肌凝蛋白与肌动蛋白的atp依赖性相互作用进行单分子和整体测量。我们通过开发一个包括粗丝激活的偏微分方程模型来拟合纤维数据，其中粗丝上的力的增加将肌凝蛋白拉出抑制状态。该模型还包括串联弹性单元和平行弹性单元。这种平行弹性元件模拟了一种titin-actin相互作用，用于解释拉伸后等距力的增加（残余力增强）。通过优化模型以适应我们的纤维测量的一个子集，我们指定了七个未知参数。然后，该模型成功地预测了我们剩余的光纤测量结果，以及我们从激光阱和体外运动中获得的分子测量结果。该模型的成功表明，我们的多尺度数据是自洽的，可以作为其他多尺度模型的测试平台。此外，该模型捕获了主动缩短（力抑制）后肌纤维中观察到的等距力的减少，这表明了力抑制的分子机制，即平行弹性元件与厚纤维激活相结合，以减少循环交叉桥的数量。
Multiscale models aiming to connect muscle's molecular and cellular function have been difficult to develop, in part due to a lack of self-consistent multiscale data. To address this gap, we measured the force response from single, skinned rabbit psoas muscle fibers to ramp shortenings and step stretches performed on the plateau region of the force-length relationship. We isolated myosin from the same muscles and, under similar conditions, performed single-molecule and ensemble measurements of myosin's ATP-dependent interaction with actin using laser trapping and in vitro motility assays. We fit the fiber data by developing a partial differential equation model that includes thick filament activation, whereby an increase in force on the thick filament pulls myosin out of an inhibited state. The model also includes a series elastic element and a parallel elastic element. This parallel elastic element models a titin-actin interaction proposed to account for the increase in isometric force after stretch (residual force enhancement). By optimizing the model fit to a subset of our fiber measurements, we specified seven unknown parameters. The model then successfully predicted the remainder of our fiber measurements and also our molecular measurements from the laser trap and in vitro motility. The success of the model suggests that our multiscale data are self-consistent and can serve as a testbed for other multiscale models. Moreover, the model captures the decrease in isometric force observed in our muscle fibers after active shortening (force depression), suggesting a molecular mechanism for force depression, whereby a parallel elastic element combines with thick filament activation to decrease the number of cycling cross-bridges.