A computational model of spatio-temporal cardiac intracellular calcium handling with realistic structure and spatial flux distribution from sarcoplasmic reticulum and t-tubule reconstructions.
A computational model of spatio-temporal cardiac intracellular calcium handling with realistic structure and spatial flux distribution from sarcoplasmic reticulum and t-tubule reconstructions.
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DOI：
10.1371/journal.pcbi.1005714
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发表时间：
2017-08
影响因子：
4.3
通讯作者：
Kitmitto A
中科院分区：
文献类型：
--
作者：
Colman MA;Pinali C;Trafford AW;Zhang H;Kitmitto A
细胞内钙循环是心脏兴奋-收缩耦合的重要组成部分。控制钙动力学的关键结构是细胞膜（包括表面肌膜和横小管），细胞内钙储存（肌浆网），以及这两种结构的共定位形成双体，其中钙诱导的钙释放发生。这些结构的组织严密地控制着细胞内钙的动态。在这项研究中，我们提出了一个三维（3-D）细胞内钙循环的计算模型，该模型结合了这些关键调节结构的高分辨率重建，通过使用连续块面扫描电子显微镜对羊左心室组织成像获得。研究人员开发了一种方法，通过将其完整的3-D结构减少到一维链的3-D网络，在全细胞尺度上模拟肌浆网结构。该模型再现了控制起搏期间细胞内钙动态，揭示了细胞质和肌浆网中钙梯度和细胞内通量的高分辨率三维空间结构。我们还证明了该模型在扰动条件下重现潜在的促心律失常动力学的能力，涉及钙瞬态交替和自发释放事件。与理想细胞模型的比较强调了结构在决定钙梯度和控制与钙瞬态交替相关的空间动力学中的重要性，其中二元激活和募集的概率性质受到限制。该模型进一步用于突出钙火花传播与双极间距离的关系。所提出的模型为未来研究全细胞内生理和病理生理钙处理现象的结构-功能关系提供了有力的工具。该方法首次允许将三维细胞内结构的高分辨率图像与钙循环模型直接集成，从而提供了在细胞尺度上直接评估结构重塑的功能影响的可能性。心脏细胞的膜组织和亚细胞结构密切地控制着其电和机械功能之间的耦合。细胞钙处理系统是负责这种机电耦合的计算模型，近年来已经发展起来研究潜在的结构-功能关系。以前的模型在结构上很大程度上是理想化的；我们提出了一个新的模型，其中包含了描述钙动力学中涉及的初级结构的高分辨率组织的实验数据。值得注意的是，细胞内钙储存的结构首次建模。该模型在正常和异常条件下都能重现控制细胞中的钙动力学，证明了其对未来结构-功能关系研究的适用性。因此，该模型为直接整合健康和病变细胞中实验获得的结构数据以及评估结构在调节正常和异常钙动力学中的作用提供了有力的工具。
Intracellular calcium cycling is a vital component of cardiac excitation-contraction coupling. The key structures responsible for controlling calcium dynamics are the cell membrane (comprising the surface sarcolemma and transverse-tubules), the intracellular calcium store (the sarcoplasmic reticulum), and the co-localisation of these two structures to form dyads within which calcium-induced-calcium-release occurs. The organisation of these structures tightly controls intracellular calcium dynamics. In this study, we present a computational model of intracellular calcium cycling in three-dimensions (3-D), which incorporates high resolution reconstructions of these key regulatory structures, attained through imaging of tissue taken from the sheep left ventricle using serial block face scanning electron microscopy. An approach was developed to model the sarcoplasmic reticulum structure at the whole-cell scale, by reducing its full 3-D structure to a 3-D network of one-dimensional strands. The model reproduces intracellular calcium dynamics during control pacing and reveals the high-resolution 3-D spatial structure of calcium gradients and intracellular fluxes in both the cytoplasm and sarcoplasmic reticulum. We also demonstrated the capability of the model to reproduce potentially pro-arrhythmic dynamics under perturbed conditions, pertaining to calcium-transient alternans and spontaneous release events. Comparison with idealised cell models emphasised the importance of structure in determining calcium gradients and controlling the spatial dynamics associated with calcium-transient alternans, wherein the probabilistic nature of dyad activation and recruitment was constrained. The model was further used to highlight the criticality in calcium spark propagation in relation to inter-dyad distances. The model presented provides a powerful tool for future investigation of structure-function relationships underlying physiological and pathophysiological intracellular calcium handling phenomena at the whole-cell. The approach allows for the first time direct integration of high-resolution images of 3-D intracellular structures with models of calcium cycling, presenting the possibility to directly assess the functional impact of structural remodelling at the cellular scale. The organisation of the membrane and sub-cellular structures of cells in the heart closely controls the coupling between its electrical and mechanical function. Computational models of the cellular calcium handling system, which is responsible for this electro-mechanical coupling, have been developed in recent years to study underlying structure-function relationships. Previous models have been largely idealised in structure; we present a new model which incorporates experimental data describing the high-resolution organisation of the primary structures involved in calcium dynamics. Significantly, the structure of the intracellular calcium store is modelled for the first time. The model is shown to reproduce calcium dynamics in control cells in both normal and abnormal conditions, demonstrating its suitability for future investigation of structure-function relationships. Thus, the model presented provides a powerful tool for the direct integration of experimentally acquired structural data in healthy and diseased cells and assessment of the role of structure in regulating normal and abnormal calcium dynamics.
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