Department of Biomedical Sciences, Padova University, Via Marzolo 3, 35131, Padova, Italy.
Center for Mechanics of Biological Materials, Padova University, Via Marzolo 9, 35131, Padova, Italy.
Sci Rep. 2019 Feb 4;9(1):1317. doi: 10.1038/s41598-018-36706-4.
The molecular bases of the Frank-Starling law of the heart and of its cellular counterpart, the length dependent activation (LDA), are largely unknown. However, the recent discovery of the thick filament activation, a second pathway beside the well-known calcium mediated thin filament activation, is promising for elucidating these mechanisms. The thick filament activation is mediated by the tension acting on it through the mechano-sensing (MS) mechanism and can be related to the LDA via the titin passive tension. Here, we propose a mechanism to explain the higher maximum tension at longer sarcomere lengths generated by a maximally activated muscle and test it in-silico with a single fiber and a ventricle model. The active tension distribution along the thick filament generates a reservoir of inactive motors at its free-end that can be activated by passive tension on a beat-to-beat timescale. The proposed mechanism is able to quantitatively account for the observed increment in tension at the fiber level, however, the ventricle model suggests that this component of the LDA is not crucial in physiological conditions.
心脏的弗兰克-斯塔尔定律（Frank-Starling law）及其细胞对应物——长度依赖性激活（length dependent activation，LDA）的分子基础在很大程度上尚不清楚。然而，最近发现的厚丝激活途径是除了众所周知的钙介导的细丝激活途径之外的第二条途径，这为阐明这些机制带来了希望。厚丝激活是通过机械感应（mechano-sensing，MS）机制对其施加的张力介导的，并且可以通过titin 被动张力与 LDA 相关。在这里，我们提出了一种机制来解释在最大激活的肌肉中产生的更长肌节长度下的更高最大张力，并通过单纤维和心室模型进行了计算机模拟测试。在厚丝上沿主动张力分布在其自由端产生了一个不活跃的马达储备库，这些马达可以在每次心跳的时间尺度上通过被动张力激活。所提出的机制能够定量解释在纤维水平上观察到的张力增加，但心室模型表明，在生理条件下，LDA 的这一部分并不重要。
