Abstract
Myosin-based mechanisms are increasingly recognized as supplementing their better-known actin-based counterparts to control the strength and time course of contraction in both skeletal and heart muscle. Here we use synchrotron small-angle X-ray diffraction to determine the structural dynamics of local domains of the myosin filament during contraction of heart muscle. We show that, although myosin motors throughout the filament contribute to force development, only about 10% of the motors in each filament bear the peak force, and these are confined to the filament domain containing myosin binding protein-C, the "C-zone." Myosin motors in domains further from the filament midpoint are likely to be activated and inactivated first in each contraction. Inactivated myosin motors are folded against the filament core, and a subset of folded motors lie on the helical tracks described previously. These helically ordered motors are also likely to be confined to the C-zone, and the associated motor conformation reforms only slowly during relaxation. Myosin filament stress-sensing determines the strength and time course of contraction in conjunction with actin-based regulation. These results establish the fundamental roles of myosin filament domains and the associated motor conformations in controlling the strength and dynamics of contraction in heart muscle, enabling those structures to be targeted to develop new therapies for heart disease.
Highlights
Myosin-based mechanisms are increasingly recognized as supplementing their better-known actin-based counterparts to control the strength and time course of contraction in both skeletal and heart muscle
Sarcomeres shortened during force development (Fig. 2B), and continued to shorten for about 100 ms after peak force (PF); sarcomere length (SL) recovery was slower than force relaxation
I11/I10 in intact trabeculae in diastole was the same as that in demembranated trabeculae at very low steady calcium concentration [Ca2+] (Fig. 2C, orange), but I11/I10 at PF was lower than that during steady activation at saturating [Ca2+] (Fig. 2C, blue) and much lower than when all myosin motors are attached to actin in rigor (SI Appendix, Table S1), indicating that only a small fraction of motors become attached to actin during contraction of intact trabeculae
Summary
Structural Dynamics of Contraction in Heart Muscle. Single trabeculae, consisting of highly uniform three-dimensional (3D) arrays of hundreds of electrically and mechanically coupled heart muscle cells with aligned contractile filaments (Fig. 1A) were dissected from the right ventricle of rat heart. Efforts to develop better therapeutics for heart failure have been held back by limited understanding of the normal control of contraction on the timescale of the heartbeat. We used synchrotron X-ray diffraction to determine the dynamic structural changes in the myosin motors that drive contraction in the heart muscle, and show that myosin filament-based control mechanisms determine the time course and strength of contraction, allowing those mechanisms to be targeted for developing new therapies for heart disease.
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