Titin Mediates Sarcomere Length Dependence of Myocyte Power

Abstract

According to the Frank-Starling relationship, ventricular pressure increases with end-diastolic volume. This is controlled, in large part, by sarcomere length (SL) dependence of cardiac myofibrillar force, loaded shortening, and power. Consistent with this, both myofibrillar force and power fall at shorter SL, however, when Ca2+ activated force and presumably thin filament activation levels are matched between short and long SL (by increasing the activator [Ca2+]) short SL actually yields faster loaded shortening and greater peak normalized power output (PNPO). A potential mechanism for faster loaded shortening at short SL is that as SL decreases titin becomes less taut which reduces the impedance of cross-bridges, a process that may be mediated by titin's interactions with the thick filament. We propose a more slackened titin yields greater myosin head radial and azimuthal mobility and these flexible cross-bridges are more likely to maintain thin filament activation, which would allow more force-generating cross-bridges to work against a fixed load resulting in faster loaded shortening. We tested this idea by measuring SL dependence of power at matched forces in rat skinned cardiac myocytes containing either N2B titin or a longer, more compliant N2BA titin. We predicted less overshoot in power by short SL in N2BA titin myocytes. Consistent with this, peak power did not overshoot but was actually less at short versus long SL at matched thin filament activation levels in N2BA-containing myocytes (Wt: ΔPNPO = +0.0121 ± 0.0115 (n=5), N2BA titin: ΔPNPO = −0.0566 ± 0.0493 (n=5)). These findings are consistent with SL per se modulating the mechanical properties of cross-bridges with this modulation being mediated by titin. This myofibrillar mechanism may help sustain ventricular power during periods of low preloads, and perhaps a breakdown of this mechanism is involved in impaired function of failing hearts.