National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, United Kingdom.
Department of Physiology, University of Kentucky, Lexington, Kentucky.
Biophys J. 2024 Sep 17;123(18):2996-3009. doi: 10.1016/j.bpj.2024.05.025. Epub 2024 May 28.
The length-dependent activation (LDA) of maximum force and calcium sensitivity are established features of cardiac muscle contraction but the dominant underlying mechanisms remain to be fully clarified. Alongside the well-documented regulation of contraction via the thin filaments, experiments have identified an additional force-dependent thick-filament activation, whereby myosin heads parked in a so-called off state become available to generate force. This process produces a feedback effect that may potentially drive LDA. Using biomechanical modeling of a human left-ventricular myocyte, this study investigates the extent to which the off-state dynamics could, by itself, plausibly account for LDA, depending on the specific mathematical formulation of the feedback. We hypothesized four different models of the off-state regulatory feedback based on (A) total force, (B) active force, (C) sarcomere strain, and (D) passive force. We tested if these models could reproduce the isometric steady-state and dynamic LDA features predicted by an earlier published model of a human left-ventricle myocyte featuring purely phenomenological length dependences. The results suggest that only total-force feedback (A) is capable of reproducing the expected behaviors, but that passive tension could provide a length-dependent signal on which to initiate the feedback. Furthermore, by attributing LDA to off-state dynamics, our proposed model also qualitatively reproduces experimentally observed effects of the off-state-stabilizing drug mavacamten. Taken together, these results support off-state dynamics as a plausible primary mechanism underlying LDA.
长度依赖性激活（LDA）是心肌收缩的固有特征，可激活最大力和钙敏感性，但潜在的主导机制仍有待充分阐明。除了通过细肌丝对收缩进行的良好记录的调节外，实验还确定了另一种依赖力的粗肌丝激活，由此可以利用停留在所谓的关闭状态的肌球蛋白头部来产生力。该过程产生了潜在的反馈效应，可能会驱动 LDA。本研究使用人类左心室心肌细胞的生物力学模型，根据反馈的具体数学表述，研究了关闭状态动力学本身在多大程度上可以合理地解释 LDA。我们根据（A）总力、（B）主动力、（C）肌节应变和（D）被动力，假设了关闭状态调节反馈的四个不同模型。我们测试了这些模型是否可以再现以前发表的具有纯现象学长度依赖性的人类左心室心肌细胞模型所预测的等长稳态和动态 LDA 特征。结果表明，只有总力反馈（A）能够再现预期的行为，但被动张力可以提供一个依赖长度的信号来启动反馈。此外，通过将 LDA 归因于关闭状态动力学，我们提出的模型还定性地再现了实验观察到的关闭状态稳定药物 mavacamten 的作用。总之，这些结果支持关闭状态动力学是 LDA 的潜在主要机制。
