Adaptations in titin's spring elements in normal and cardiomyopathic hearts


  • H. Granzier
  • D. Labeit
  • Y. Wu
  • C. Witt
  • K. Watanabe
  • S. Lahmers
  • M. Gotthardt
  • S. Labeit


  • Advances in Experimental Medicine and Biology


  • Adv Exp Med Biol 538 (538): 517-530; discussion 530-531


  • Titin (also known as connectin) is a giant elastic protein located in the striated-muscle sarcomere where it spans from Z-line to M-line. A large part of the I-band region of the titin molecule is extensible and functions as a molecular spring that underlies passive muscle stiffness when sarcomeres are stretched. This spring has a complex composition. In cardiac titin it consists of three extensible elements: tandem Ig segments, the PEVK segment and the N2B unique sequence. Here we discuss our recent work focused on understanding the molecular basis of titin's extensibility and in which force-extension curves were measured by using an atomic force microscope specialized for stretching single molecules. We will discuss results from recombinant proteins that represent the various elements of titin's extensible region. The obtained single molecule mechanical characteristics of titin's various spring elements explain well their measured extension in the cardiac sarcomere when stretched within their physiological length range. We also examined how titin's contribution to passive muscle stiffness may be adjusted. We discuss evidence that suggests that calcium/S100 may adjust titin-based stiffness and that phosphorylation of cardiac titin’s N2B spring elements reduces titin-based passive stiffness in cardiac muscle. Finally, we show that the cardiac sarcomere of large mammals co-expresses titin isoforms and that differential splicing of titin's spring elements is a long-term mechanism of adjustment, which plays a role in passive stiffness modulation during heart disease.