Meeting Abstract

42.1  Wednesday, Jan. 5  Is titin a “winding filament” in active msucle? A new twist on muscle contraction MONROY, JA; UYENO, TA; NISHIKAWA, KC*; Northern Arizona University Kiisa.Nishikawa@nau.edu

In striated muscle, titin contributes to passive tension, sarcomere integrity, and myofibrillar assembly. Previous studies suggest that titin plays a role in active muscle, but such a role remains to be demonstrated. In active muscle, Ca²⁺ has been shown to increase titin-based myofibrillar stiffness, but the observed increase is smaller than expected. Here, we present a “winding filament” hypothesis for titin’s role in active muscle. We propose (1) that titin’s N2A domain binds to thin filaments upon influx of Ca²⁺, thereby shortening and stiffening the titin spring. Upon activation, (2) the cross-bridges not only pull the thin filaments toward the M-lines, but also wind up the now stiffer titin on the thin filaments, storing elastic potential energy during isometric force development. Binding of PEVK titin to thin filaments prevents unwinding, so that the stored energy can be recovered during shortening. Ca²⁺-dependent binding of titin to actin prevents low-force straightening of proximal Ig domains that normally occurs upon passive stretch. This mechanism accounts for differences in length-tension relationship between skeletal myofibrils and cardiac myocytes. Skeletal myofibrils express N2A titin, whereas cardiac myocytes that express only N2B titin and lack the Ca²⁺-dependent actin binding domain. In mice, mdm mutants also fail to express N2A titin. These mutants show no increase in stiffness upon activation, and exhibit length-tension curves that resemble cardiac muscle. By regulating the rate of recovery of elastic energy from titin in a load-dependent manner, the cycling cross-bridges endow active muscle with intrinsic stability to perturbations in load. The winding filament model neatly accounts for enhancement of force with stretch and depression of force with shortening, and may help explain some unresolved questions of muscle energetics.