Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba 277-8581, Japan.
J Biomech. 2012 Mar 15;45(5):815-23. doi: 10.1016/j.jbiomech.2011.11.022. Epub 2012 Jan 5.
T-tubules in mammalian ventricular myocytes constitute an elaborate system for coupling membrane depolarization with intracellular Ca(2+) signaling to control cardiac contraction. Deletion of t-tubules (detubulation) has been reported in heart diseases, although the complex nature of the cardiac excitation-contraction (E-C) coupling process makes it difficult to experimentally establish causal relationships between detubulation and cardiac dysfunction. Alternatively, numerical simulations incorporating the t-tubule system have been proposed to elucidate its functional role. However, the majority of models treat the subcellular spaces as lumped compartments, and are thus unable to dissect the impact of morphological changes in t-tubules. We developed a 3D finite element model of cardiomyocytes in which subcellular components including t-tubules, myofibrils, sarcoplasmic reticulum, and mitochondria were modeled and realistically arranged. Based on this framework, physiological E-C coupling was simulated by simultaneously solving the reaction-diffusion equation and the mechanical equilibrium for the mathematical models of electrophysiology and contraction distributed among these subcellular components. We then examined the effect of detubulation in this model by comparing with and without the t-tubule system. This model reproduced the Ca(2+) transients and contraction observed in experimental studies, including the response to beta-adrenergic stimulation, and provided detailed information beyond the limits of experimental approaches. In particular, the analysis of sarcomere dynamics revealed that the asynchronous contraction caused by a large detubulated region can lead to impairment of myocyte contractile efficiency. These data clearly demonstrate the importance of the t-tubule system for the maintenance of contractile function.
哺乳动物心室肌细胞中的 T 小管构成了一个精细的系统，用于将膜去极化与细胞内 Ca(2+)信号偶联，以控制心脏收缩。尽管心脏兴奋-收缩（E-C）偶联过程的复杂性使得难以在实验中建立去管化与心脏功能障碍之间的因果关系，但已有研究报道在心脏疾病中存在 T 小管的缺失（去管化）。替代方法是，提出了包含 T 小管系统的数值模拟，以阐明其功能作用。然而，大多数模型将亚细胞空间视为集中的腔室，因此无法剖析 T 小管形态变化的影响。我们开发了一种 3D 有限元模型，其中包括 T 小管、肌原纤维、肌浆网和线粒体等亚细胞成分，并进行了真实的排列。基于这个框架，通过同时求解分布在这些亚细胞成分中的电生理学和收缩数学模型的反应扩散方程和力学平衡方程，模拟了生理 E-C 偶联。然后，我们通过比较有无 T 小管系统的情况，研究了该模型中去管化的效果。该模型再现了实验研究中观察到的 Ca(2+)瞬变和收缩，包括对β肾上腺素刺激的反应，并且提供了实验方法无法提供的详细信息。特别是，对肌节动力学的分析表明，由于大的去管化区域引起的异步收缩可能导致心肌收缩效率的损害。这些数据清楚地表明了 T 小管系统对维持收缩功能的重要性。
