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Myosin filament-based regulation of the dynamics of contraction in heart muscle

Research output: Contribution to journalArticlepeer-review

Original languageEnglish
Pages (from-to)8177-8186
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number14
Early online date27 Mar 2020
DOIs
Accepted/In press27 Mar 2020
E-pub ahead of print27 Mar 2020
Published7 Apr 2020

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King's Authors

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.

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