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肌联蛋白丝，从巨大的肌联蛋白分子重叠端到端的Z盘和M带的肌节。肌节的组装和拆卸在肌肉生长的生理适应和疾病中都是重要的。已经提出了各种模型的sarcomerogenesis，不同的早期薄和厚丝组装，但最终同意的必要性衔接蛋白交联Z体和M带蛋白成周期性的A-和I-带。肌联蛋白首先在新生肌原纤维中检测到，其中其N-末端通过α-辅肌动蛋白和较少的粘着斑蛋白附着于Z体。到目前为止，对肌联蛋白整合到Z盘中的动力学以及肌联蛋白如何调节肌节的成熟知之甚少。在拟议的工作中，我们的目标是阐明肌联蛋白的作用，可视化肌联蛋白的顺序整合到Z-磁盘和M-带。我们将研究生物力学和肌节组装的相互关系，重点关注基于肌联蛋白的信号，这些信号控制肌节组装（P1，P2，P9），Z盘成熟（P7），肌节的连续与横向生长（P7），以及基于Z盘的机械传感器（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).