Predicting Effects of Tropomyosin Mutations on Cardiac Muscle Contraction through Myofilament Modeling.
Predicting Effects of Tropomyosin Mutations on Cardiac Muscle Contraction through Myofilament Modeling.
复制标题
通过肌丝建模预测肌动蛋白突变对心肌收缩的影响。
DOI：
10.3389/fphys.2016.00473
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发表时间：
2016
影响因子：
4
通讯作者：
Campbell SG
中科院分区：
文献类型：
--
作者：
Sewanan LR;Moore JR;Lehman W;Campbell SG
人类基因TPM1的点突变与肥厚型和扩张型心肌病的发生有关。这样的观察导致了研究单一残基变化与原肌球蛋白分子的生物物理行为之间的联系。然而，这些分子扰动在多大程度上解释了含有突变原肌球蛋白的完整肌节的性能仍然不确定。在这里，我们提出了一种建模方法，将原肌球蛋白分子属性的各个方面整合到一个凝聚力范例中，表示它们对肌肉功能的影响。特别是，我们考虑了原肌球蛋白突变对(1)持续长度，(2)细丝阻断和闭合调节状态之间的平衡，以及(3)交叉桥占空比的影响。在展示了新模型在动态和稳态激活过程中捕获依赖钙的肌丝反应的能力后，我们使用它来捕获肥厚型心肌病(HCM)相关的E180G和D175N突变对皮肤肌纤维力学的影响。我们的分析表明，这两个突变的纤维水平效应可以通过模型中所代表的三种原肌球蛋白属性的组合来准确描述。随后，我们使用该模型来预测肌肉抽动的突变效应。由于细丝调节单位之间的协同抑制减弱，这两个突变都导致了抽动收缩能力的增加。总体而言，模拟表明，HCM相关原肌球蛋白突变的一种常见的抽动表型包括收缩能力增强和舒张压升高。
Point mutations to the human gene TPM1 have been implicated in the development of both hypertrophic and dilated cardiomyopathies. Such observations have led to studies investigating the link between single residue changes and the biophysical behavior of the tropomyosin molecule. However, the degree to which these molecular perturbations explain the performance of intact sarcomeres containing mutant tropomyosin remains uncertain. Here, we present a modeling approach that integrates various aspects of tropomyosin's molecular properties into a cohesive paradigm representing their impact on muscle function. In particular, we considered the effects of tropomyosin mutations on (1) persistence length, (2) equilibrium between thin filament blocked and closed regulatory states, and (3) the crossbridge duty cycle. After demonstrating the ability of the new model to capture Ca-dependent myofilament responses during both dynamic and steady-state activation, we used it to capture the effects of hypertrophic cardiomyopathy (HCM) related E180G and D175N mutations on skinned myofiber mechanics. Our analysis indicates that the fiber-level effects of the two mutations can be accurately described by a combination of changes to the three tropomyosin properties represented in the model. Subsequently, we used the model to predict mutation effects on muscle twitch. Both mutations led to increased twitch contractility as a consequence of diminished cooperative inhibition between thin filament regulatory units. Overall, simulations suggest that a common twitch phenotype for HCM-linked tropomyosin mutations includes both increased contractility and elevated diastolic tension.
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影响因子：
4
作者：
Loong CK;Badr MA;Chase PB
通讯作者：
Chase PB
家族性肥厚性心肌病相关的E180G突变增加了人类心脏α-胶质素的柔韧性。
影响因子：
3.5
作者：
Loong CK;Zhou HX;Chase PB
通讯作者：
Chase PB
影响因子：
3
作者：
Li, Xiaochuan (Edward);Lehman, William;Fischer, Stefan
通讯作者：
Fischer, Stefan
影响因子：
--
作者：
Alves, Marco L.;Dias, Fernando A. L.;Wolska, Beata M.
通讯作者：
Wolska, Beata M.
DOI：
10.1152/ajpheart.1997.272.4.h1892
发表时间：
1997-04-01
影响因子：
4.8
作者：
Janssen, PML;deTombe, PP
通讯作者：
deTombe, PP