Beat-by-Beat Cardiomyocyte T-Tubule Deformation Drives Tubular Content Exchange.
Beat-by-Beat Cardiomyocyte T-Tubule Deformation Drives Tubular Content Exchange.
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DOI：
10.1161/circresaha.120.317266
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发表时间：
2021-01-22
影响因子：
20.1
通讯作者：
Kohl P
中科院分区：
文献类型：
--
作者：
Rog-Zielinska EA;Scardigli M;Peyronnet R;Zgierski-Johnston CM;Greiner J;Madl J;O'Toole ET;Morphew M;Hoenger A;Sacconi L;Kohl P
补充数字内容可在文本中找到。心肌细胞的肌膜含有许多蛋白质，这些蛋白质对于一般的机电功能，特别是兴奋-收缩偶联是必需的。这些蛋白质的分布是不均匀的散装肌膜表面和膜内陷称为横小管（TT）。TT形成了一个复杂的充满液体的管道网络，支持心肌细胞内的机电同步性。虽然与细胞外空间连续，但TT的狭窄管腔和曲折结构可形成受限扩散域。由于跨细胞表面和TT膜的不相等的离子通量，有限的扩散可能在TT内产生离子梯度，特别是在TT网络内深处和高起搏速率下。我们假设，可能有一个平流成分TT内容交换，其中周期性变形的TT在舒张期拉伸和收缩期缩短用于混合TT管腔内容物，并协助与大量细胞外液的平衡。使用电子断层扫描，我们探讨了TT在兔心室肌细胞的三维纳米结构，保存在细胞收缩和舒张的动态周期的不同阶段。我们发现，细胞变形影响TT形状的肌节长度依赖性的方式和节拍的节拍的时间尺度。使用光漂白显微镜后的荧光恢复，我们表明，表观扩散速度的心肌细胞的机械状态的影响，心肌细胞的周期性收缩活动加速TT扩散动力学。我们的数据证实存在一个平流分量TT内容交换。这指向心脏自动调节的新机制，由此先前暗示的在高电刺激速率下TT管腔浓度不平衡的增加的倾向将被在高机械搏动速率下升高的平流辅助扩散抵消。这种机制在健康和病理性重塑（如心脏肥大或衰竭）过程中的相关性形成了进一步研究的令人兴奋的目标。
Supplemental Digital Content is available in the text. The sarcolemma of cardiomyocytes contains many proteins that are essential for electromechanical function in general, and excitation-contraction coupling in particular. The distribution of these proteins is nonuniform between the bulk sarcolemmal surface and membrane invaginations known as transverse tubules (TT). TT form an intricate network of fluid-filled conduits that support electromechanical synchronicity within cardiomyocytes. Although continuous with the extracellular space, the narrow lumen and the tortuous structure of TT can form domains of restricted diffusion. As a result of unequal ion fluxes across cell surface and TT membranes, limited diffusion may generate ion gradients within TT, especially deep within the TT network and at high pacing rates. We postulate that there may be an advective component to TT content exchange, wherein cyclic deformation of TT during diastolic stretch and systolic shortening serves to mix TT luminal content and assists equilibration with bulk extracellular fluid. Using electron tomography, we explore the 3-dimensional nanostructure of TT in rabbit ventricular myocytes, preserved at different stages of the dynamic cycle of cell contraction and relaxation. We show that cellular deformation affects TT shape in a sarcomere length-dependent manner and on a beat-by-beat time-scale. Using fluorescence recovery after photobleaching microscopy, we show that apparent speed of diffusion is affected by the mechanical state of cardiomyocytes, and that cyclic contractile activity of cardiomyocytes accelerates TT diffusion dynamics. Our data confirm the existence of an advective component to TT content exchange. This points toward a novel mechanism of cardiac autoregulation, whereby the previously implied increased propensity for TT luminal concentration imbalances at high electrical stimulation rates would be countered by elevated advection-assisted diffusion at high mechanical beating rates. The relevance of this mechanism in health and during pathological remodeling (eg, cardiac hypertrophy or failure) forms an exciting target for further research.