Unraveling Chamber-specific Differences in Intercalated Disc Ultrastructure and Molecular Organization and Their Impact on Cardiac Conduction.
Unraveling Chamber-specific Differences in Intercalated Disc Ultrastructure and Molecular Organization and Their Impact on Cardiac Conduction.
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揭示闰盘超微结构和分子组织的室特异性差异及其对心脏传导的影响。
DOI：
10.1101/2023.02.13.528369
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Veeraraghavan,Rengasayee
中科院分区：
文献类型：
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作者：
Struckman,HeatherL;Moise,Nicolae;King,DRyan;Soltisz,Andrew;Buxton,Andrew;Dunlap,Izabella;Chen,Zhenhui;Radwański,PrzemysławB;Weinberg,SethH;Veeraraghavan,Rengasayee
在每一次心跳期间，动作电位在心脏中的传播协调着数十亿个心肌细胞的收缩，因此是一个关键的生命过程。不出所料，间盘是细胞-细胞接触的场所，专门提供相邻心肌细胞之间的电和机械耦合，一直是许多研究的重点。传播减慢或中断会在多种病理中导致潜在的危及生命的心律失常，其中间盘重塑是常见的发现。因此，了解间盘结构及其对动作电位传播的影响具有重要意义和紧迫性。然而，令人惊讶的是，由于缺乏亚细胞到纳米尺度的定量结构数据，传统的建模方法不能预测由改变插入盘超微结构或分子结构的扰动引起的传播变化。为了解决这一关键的知识缺口，我们试图在健康成年小鼠心脏的这些更精细的空间尺度上量化间盘结构，并将它们与特定腔室的功能联系起来，作为了解病理性间盘重塑的影响的前兆。利用超分辨光学显微镜、电子显微镜和计算图像分析，我们在这里首次系统地、多尺度地定量了间盘的超微结构和分子组织。通过将这些数据结合到具有真实间盘结构的基于规则的心脏组织模型中，并将电传播的模型预测与传导速度的实验测量进行比较，我们揭示了心房间盘能够支持比其心室对应的更快的传导，而这通常被腔间心肌细胞几何形状的差异所掩盖。此外，我们确定了支持心房间盘支持更快传导能力的关键超微结构和分子组织特征。这些数据为阐明许多心律失常疾病中发生的病理性间盘重塑的特殊影响提供了第一块踏脚石。
During each heartbeat, the propagation of action potentials through the heart coordinates the contraction of billions of individual cardiomyocytes and is thus, a critical life process. Unsurprisingly, intercalated discs, which are cell-cell contact sites specialized to provide electrical and mechanical coupling between adjacent cardiomyocytes, have been the focus of much investigation. Slowed or disrupted propagation leads to potentially life-threatening arrhythmias in a wide range of pathologies, where intercalated disc remodeling is a common finding. Hence, the importance and urgency of understanding intercalated disc structure and its influence on action potential propagation. Surprisingly, however, conventional modeling approaches cannot predict changes in propagation elicited by perturbations that alter intercalated disc ultrastructure or molecular organization, owing to lack of quantitative structural data at subcellular through nano scales. In order to address this critical gap in knowledge, we sought to quantify intercalated disc structure at these finer spatial scales in the healthy adult mouse heart and relate them to function in a chamber-specific manner as a precursor to understanding the impacts of pathological intercalated disc remodeling. Using super-resolution light microscopy, electron microscopy, and computational image analysis, we provide here the first ever systematic, multiscale quantification of intercalated disc ultrastructure and molecular organization. By incorporating these data into a rule-based model of cardiac tissue with realistic intercalated disc structure, and comparing model predictions of electrical propagation with experimental measures of conduction velocity, we reveal that atrial intercalated discs can support faster conduction than their ventricular counterparts, which is normally masked by inter-chamber differences in myocyte geometry. Further, we identify key ultrastructural and molecular organization features underpinning the ability of atrial intercalated discs to support faster conduction. These data provide the first stepping stone to elucidating chamber-specific impacts of pathological intercalated disc remodeling, as occurs in many arrhythmic diseases.