Titin isoforms in heart failure: are there benefits to supersizing?

Abstract

Titin is a giant sarcomeric protein that functions as a complex, molecular spring. Its presence in the sarcomere of striated muscle was recognized in the 1980s,1 but its functions have been appreciated only over the past decade, in considerable measure because of the efforts of Granzier, Labeit, Linke, and coworkers.2–4 Earlier work by these investigators and others4 delineated the spring properties of titin and its role as the prime source of passive tension in the cardiomyocyte and, along with collagen, in myocardium. Titin also interacts and/or binds with a host of other proteins,4 including actin, a number of Z-disc proteins,5 obscurin,6 muscle LIM protein,4 and the group of muscle ankyrin repeat proteins.4,7 These interactions suggest additional functions, and recent evidence indicates that titin directly modifies sarcomere shortening and has intriguing and potentially diverse roles in mechanical sensing and signaling pathways.4 See p 155 Titin is encoded by a single gene containing 363 exons.8 Differential splicing results in two major isoforms, the shorter and stiffer N2B and the longer, more compliant N2BA.4,8 N2BA titin has numerous fetal-neonatal variants, but most variation is lost in adult life. Titin is positioned within the sarcomere such that its N-terminal segments are anchored in the Z disc and its C-terminal segments are bound to the thick filament in the M-line region (see Figure 1 in Granzier and Labeit4). The N-terminal segment penetrating the Z-disc is capped by telethonin (T-cap), a protein that may have a role in mechanical signaling and maintenance of important structural relationships4,8—for example, with the T-tubule system and sarcoplasmic reticulum. Adjacent to the Z disc is a nonextensible segment followed by titin’s complex, extensible I-band sequences consisting of tandem immunoglobulin (Ig)- and PEVK-rich segments, and the N2B sequence …