Z-disc Titin in Sarcomere Assembly and Mechanotransduction

肌丝是一种高度有序的周期性结构。它是基于一个连续的Titin细丝，它是由巨大的Titin分子在肌节的Z-Disk和M-band端到端重叠而产生的。肌节的组装和分解在肌肉生长的生理适应和疾病中都是重要的。各种不同的肌瘤发生模型在早期的细丝和粗丝组装方面有所不同，但最终一致认为接头蛋白有必要将Z-小体和M-带蛋白交叉连接成周期性的A-带和I-带。肌动蛋白首先在新生的肌原纤维中被检测到，它的N端通过α-肌动蛋白和较弱的纽蛋白与Z小体相连。到目前为止，人们对Titin整合到Z盘中的动力学以及Titin如何调节肌节的成熟知之甚少。在这项拟议的工作中，我们旨在阐明Titin在肉瘤发生中的作用，可视化Titin在Z盘和M带中的顺序整合。我们将研究生物力学和肌节组装的相互关系，重点是基于肌蛋白的信号，这些信号控制肌节组装(P1，P2，P9)，Z-盘成熟(P7)，肌节的顺行和侧向生长(P7)，以及基于Z-Disk的机械传感器(P8，P9)。

The myofilament is a highly ordered periodic structure. It is based on a continuous titin filament that results from giant titin molecules overlapping end-to-end at Z-disc and M-band of the sarcomere. Assembly and disassembly of the sarcomere are important in both the physiological adaptation of muscle growth and in disease. Various models of sarcomerogenesis have been proposed that differ with respect to early thin and thick filament assembly, but ultimately agree on the necessity of adaptor proteins to cross-link Z-bodies and M-band proteins into periodic A- and I-bands. Titin is first detected in the nascent myofibril where its N-terminus attaches to the Z-bodies via alpha-actinin and less avidly vinculin. So far only little is known about the kinetics of titin’s integration into the Z-disc and how titin regulates the maturation of the sarcomere. In the proposed work we aim at elucidating titin’s role in sarcomerogenesis, visualizing the sequential integration of titin into the Z-disk and M-band. We will investigate the interrelation of biomechanics and sarcomere assembly focussing on titin based signals that govern sarcomere assembly (P1, P2, P9), Z-disc maturation (P7), serial vs. lateral growth of the sarcomere (P7), and the Z-disk based mechanosensor (P8, P9).