Z-disc Titin in Sarcomere Assembly and Mechanotransduction

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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).