Institute for Experimental Cardiovascular Medicine, University Heart Center and Faculty of Medicine, University of Freiburg, Freiburg, Germany; Centre for Integrative Biological Signalling Studies (CIBSS), University of Freiburg, Freiburg, Germany.
Department of Experimental and Clinical Medicine, Division of Physiology, University of Florence, Florence, Italy.
J Mol Cell Cardiol. 2024 Dec;197:125-135. doi: 10.1016/j.yjmcc.2024.10.014. Epub 2024 Nov 2.
Efficient excitation-contraction coupling of mammalian ventricular cardiomyocytes depends on the transverse-axial tubular system (TATS), a network of surface membrane invaginations. TATS enables tight coupling of sarcolemmal and sarcoplasmic reticulum membranes, which is essential for rapid Ca-induced Ca release, and uniform contraction upon electrical stimulation. The majority of TATS in healthy ventricular cardiomyocytes is composed of transverse tubules (TT, ∼90 % of TATS in rabbit). The remainder consists of mostly axial tubules (AT), which are less abundant and less well studied. In disease, however, the relative abundance of TT and AT changes. The mechanisms and relevance of this change are not known, and understanding them requires a more targeted effort to study the dynamics of AT structure and function. While TATS content is continuous with the interstitial space, it is contained within a domain of restricted diffusion. We have previously shown that TT are cyclically squeezed during stretch and contraction. This can contribute to TT content mixing and accelerates luminal content exchange with the environment. Here, we explore the effects of cardiomyocyte stretch and contraction on AT.
TATS structure and diffusion dynamics were studied using 3D electron tomography of rabbit left ventricular cardiomyocytes, preserved at rest or during contraction, and ventricular tissue preserved at rest or during stretch, as well as live-cell TATS content exchange measurements.
We show (i) that cardiomyocyte contraction is associated with an increase in the apparent speed of diffusion of TT content that scales with beating rate and degree of cell shortening. In contrast, (ii) AT develop membrane folds and constrictions during contraction, (iii) with no effect of contraction on luminal exchange dynamics, while (iv) cardiomyocyte stretch is associated with AT straightening and AT and TT 'squeezing' that (v) supports an acceleration of the apparent speed of diffusion in AT and TT. Finally, (vi) we present a simple computational model outlining the potential relevance of AT in healthy and diseased cells.
Our results indicate that TT and AT are differently affected by the cardiac contractile cycle, and suggest that AT may play a role in ensuring TATS network content homogeneity in diseased cardiomyocytes. Further research is needed to explore the interplay of structural and functional remodelling of different TATS components in failing myocardium.
哺乳动物心室肌细胞的高效兴奋-收缩偶联依赖于横轴向管状系统（TATS），这是一种细胞膜内陷的网络。TATS 使肌膜和肌浆网紧密偶联，这对于快速 Ca 诱导的 Ca 释放和电刺激时的均匀收缩至关重要。健康心室肌细胞中的大多数 TATS 由横管（TT，兔中 TATS 的约 90%）组成。其余部分由轴向管（AT）组成，其含量较少，研究也较少。然而，在疾病中，TT 和 AT 的相对丰度会发生变化。这种变化的机制和相关性尚不清楚，要理解这一点，就需要更有针对性地研究 AT 结构和功能的动态。虽然 TATS 含量与细胞间隙连续，但它包含在一个扩散受限的区域内。我们之前已经表明，在拉伸和收缩过程中，TT 会周期性地被挤压。这有助于 TT 含量混合，并加速管腔内容物与环境的交换。在这里，我们探讨了心肌细胞拉伸和收缩对 AT 的影响。
使用兔左心室心肌细胞的 3D 电子断层扫描、保存于静止或收缩状态的心室组织以及活细胞 TATS 含量交换测量来研究 TATS 结构和扩散动力学。
我们表明：（i）心肌细胞收缩与 TT 含量扩散的表观速度增加有关，该速度与搏动率和细胞缩短程度成正比。相比之下，（ii）AT 在收缩过程中会形成膜褶皱和缩窄，（iii）收缩对管腔交换动力学没有影响，而（iv）心肌细胞拉伸与 AT 变直和 TT“挤压”有关，（v）这支持 AT 和 TT 中扩散的表观速度加速。最后，（vi）我们提出了一个简单的计算模型，概述了 AT 在健康和患病细胞中的潜在相关性。
我们的结果表明，TT 和 AT 受到心脏收缩周期的不同影响，并表明 AT 可能在确保患病心肌细胞中 TATS 网络内容均匀性方面发挥作用。需要进一步研究来探索不同 TATS 成分的结构和功能重塑在衰竭心肌中的相互作用。
