Powers Joseph D, Williams C David, Regnier Michael, Daniel Thomas L
Department of Bioengineering, University of Washington, 3720 15th Avenue NE, Seattle, WA 98105, USA.
Allen Institute for Cell Science, Seattle, WA 98109, USA.
Integr Comp Biol. 2018 Aug 1;58(2):186-193. doi: 10.1093/icb/icy055.
In striated muscle, the giant protein titin spans the entire length of a half-sarcomere and extends from the backbone of the thick filament, reversibly attaches to the thin filaments, and anchors to the dense protein network of the z-disk capping the end of the half-sarcomere. However, little is known about the relationship between the basic mechanical properties of titin and muscle contractility. Here, we build upon our previous multi-filament, spatially explicit computational model of the half-sarcomere by incorporating the nonlinear mechanics of titin filaments in the I-band. We vary parameters of the nonlinearity to understand the effects of titin stiffness on contraction dynamics and efficiency. We do so by simulating isometric contraction for a range of sarcomere lengths (SLs; 1.6-3.25 µm). Intermediate values of titin stiffness accurately reproduce the passive force-SL relation for skeletal muscle. The maximum force-SL relation is not affected by titin for SL≤2.5 µm. However, as titin stiffness increases, maximum force for the four thick filament system at SL = 3.0 µm significantly decreases from 103.2 ± 2 to 58.8 ± 1 pN. Additionally, by monitoring ATP consumption, we measure contraction efficiency as a function of titin stiffness. We find that at SL = 3.0 µm, efficiency significantly decreases from 13.9 ± 0.4 to 7.0 ± 0.3 pN/ATP when increasing titin stiffness, with little or no effect below 2.5 µm. Taken together, our results suggest that, despite an increase in the fraction of motors bound to actin along the descending limb when titin is stiffer, the force-generating capacity of the motors is reduced. These results suggest that titin stiffness has the potential to affect contractile efficiency.
在横纹肌中，巨大的肌联蛋白分子跨越半个肌节的全长，从粗肌丝的主干延伸出来，可逆地附着于细肌丝，并锚定到位于半个肌节末端的致密z盘蛋白网络上。然而，关于肌联蛋白的基本力学特性与肌肉收缩性之间的关系，人们所知甚少。在此，我们基于之前的多丝、空间明确的半个肌节计算模型，通过纳入I带中肌联蛋白丝的非线性力学来进行构建。我们改变非线性参数，以了解肌联蛋白刚度对收缩动力学和效率的影响。我们通过模拟一系列肌节长度（SLs；1.6 - 3.25 µm）下的等长收缩来实现这一点。肌联蛋白刚度的中间值准确地再现了骨骼肌的被动力 - SL关系。对于SL≤2.5 µm，最大力 - SL关系不受肌联蛋白影响。然而，随着肌联蛋白刚度增加，在SL = 3.0 µm时，四粗肌丝系统的最大力从103.2 ± 2 pN显著降低至58.8 ± 1 pN。此外，通过监测ATP消耗，我们测量了作为肌联蛋白刚度函数的收缩效率。我们发现，在SL = 3.0 µm时，增加肌联蛋白刚度会使效率从13.9 ± 0.4 pN/ATP显著降低至7.0 ± 0.3 pN/ATP，而在低于2.5 µm时影响很小或没有影响。综上所述，我们的结果表明，尽管当肌联蛋白更硬时，沿着下降支与肌动蛋白结合的马达比例增加，但马达的力产生能力却降低了。这些结果表明肌联蛋白刚度有可能影响收缩效率。
