Modulation of Cardiac Function: Titin Springs into Action

Sympathetic stimulation has become a central tenet in our understanding of how cardiac contractility is dynamically altered to accommodate the changing demands of the organism. The mechanisms by which acute and chronic sympathetic stimulation of the heart modulates cardiac output remain incompletely understood, however. Beyond the increase in heart rate driven by sympathetic stimulation of the sino-atrial node, the -adrenergic receptor ( -AR)–mediated cascade increases contractile force development (inotropy) and accelerates relaxation (lusitropy). Numerous proteins have been discovered to be involved in the -AR–stimulated response, including calcium handling proteins, myofilament proteins, G-proteins, and regulators of myocardial metabolism (Bers, 2002). The newest player on the field is titin (Fig. 1), the giant myofilament protein that serves as an entropic spring that imparts both the passive and the restoring forces during diastole and systole, respectively. Additional roles for titin have been proposed, including regulation of sarcomere length dependence of myofilament calcium sensitivity, a molecular template for thick filament assembly and sarcomere integrity, and centering of the A-band (Tskhovrebova and Trinick, 2003; Granzier and Labeit, 2004). Granzier and colleagues recently have demonstrated that titin is a target of PKA phosphorylation downstream of -AR activation, resulting in a change in the titin-based passive force that increases myofilament compliance during sarcomere elongation (Yamasaki et al., 2002). In this issue, Granzier and colleagues have refined our understanding further, demonstrating that the effect of titin phosphorylation on the passive as well as the restoring force is isoform specific (Fukuda et al., 2005). This article adds to the expanding literature that demonstrates the complex role(s) of this giant protein as an important determinant of not only sarcomere structure, but also as a key regulator of dynamic changes in cardiac function over both short (beat to beat) and long (day to day) time frames. Differential and Developmental Expression of Titin Isoforms