Titin and Muscle Transcriptional Regulation

During muscle differentiation, gene expression leads to the translation of myofibrillar proteins and their assembly into contractile units, the sarcomeres, which are constantly remodeled to adapt to changes in mechanical load. The giant protein titin acts as a molecular blueprint for sarcomere assembly by providing specific attachment sites for sarcomeric proteins, as well as acting as a molecular spring. Lange et al. identify the components of a novel sarcomere-associated pathway that links the sarcomere to the control of muscle gene transcription. The kinase domain of titin initiates a signal transduction cascade that controls sarcomere assembly, protein turnover, and transcriptional control in response to mechanical changes. A mutation in the titin kinase domain affects this signal transduction pathway and leads to a lethal hereditary human myopathy. S. Lange, F. Xiang, A. Yakovenko, A. Vihola, P. Hackman, E. Rostkova, J. Kristensen, B. Brandmeier, G. Franzen, B. Hedberg, L. G. Gunnarsson, S. M. Hughes, S. Marchand, T. Sejersen, I. Richard, L. Edström, E. Ehler, B. Udd, M. Gautel, The kinase domain of titin controls muscle gene expression and protein turnover. Science 308 , 1599-1603 (2005). [Abstract] [Full Text]