RT Journal Article
SR Electronic
T1 Controlling load-dependent contractility of the heart at the single molecule level
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 258020
DO 10.1101/258020
A1 Chao Liu
A1 Masataka Kawana
A1 Dan Song
A1 Kathleen M. Ruppel
A1 James A. Spudich
YR 2018
UL http://biorxiv.org/content/early/2018/04/05/258020.abstract
AB Concepts in molecular tension sensing in biology are growing and have their origins in studies of muscle contraction. In the heart muscle, a key parameter of contractility is the detachment rate from actin of myosin, which determines the time that myosin is bound to actin in a force-producing state and, importantly, depends on the load (force) against which myosin works. Here, we measure the detachment rate of single molecules of human β-cardiac myosin and its load dependence. We find that both can be modulated by both small molecule compounds and cardiomyopathy-causing mutations. Furthermore, effects of mutations can be reversed by introducing appropriate compounds. Our results suggest that activating vs. inhibitory perturbations of cardiac myosin are discriminated by the aggregate result on duty ratio, average force, and ultimately average power output and that cardiac contractility can be controlled by tuning the load-dependent kinetics of single myosin molecules.