Ablation of cardiac myosin binding protein-C disrupts the super-relaxed state of myosin in murine cardiomyocytes
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Final Accepted Manuscript
Author
McNamara, James W.
Li, Amy
Smith, Nicola J.
Lal, Sean
Graham, Robert M.
Kooiker, Kristina Bezold
van Dijk, Sabine J.
Remedios, Cristobal G. dos
Harris, Samantha P.
Cooke, Roger
Affiliation
Univ Arizona, Dept Cellular & Mol MedIssue Date
2016-05Keywords
Cardiac SRXHypertrophic cardiomyopathy
Myosin binding protein-C (MyBP-C)
Myosin II ATPase
Thick filament structure
Cardiac energetics
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ELSEVIER SCI LTDCitation
Ablation of cardiac myosin binding protein-C disrupts the super-relaxed state of myosin in murine cardiomyocytes 2016, 94:65 Journal of Molecular and Cellular CardiologyRights
Crown Copyright © 2016 Published by Elsevier Ltd. All rights reserved.Collection Information
This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.Abstract
Cardiac myosin binding protein-C (cMyBP-C) is a structural and regulatory component of cardiac thick filaments. It is observed in electron micrographs as seven to nine transverse stripes in the central portion of each half of the A band. Its C-terminus binds tightly to the myosin rod and contributes to thick filament structure, while the N-terminus can bind both myosin S2 and actin, influencing their structure and function. Mutations in the MYBPC3 gene (encoding cMyBP-C) are commonly associated with hypertrophic cardiomyopathy (HCM). In cardiac cells there exists a population of myosin heads in the super-relaxed (SRX) state, which are bound to the thick filament core with a highly inhibited ATPase activity. This report examines the role cMyBP-C plays in regulating the population of the SRX state of cardiac myosin by using an assay that measures single ATP turnover of myosin. We report a significant decrease in the proportion of myosin heads in the SRX state in homozygous cMyBP-C knockout mice, however heterozygous cMyBP-C knockout mice do not significantly differ from the wild type. A smaller, non-significant decrease is observed when thoracic aortic constriction is used to induce cardiac hypertrophy in mutation negative mice. These results support the proposal that cMyBP-C stabilises the thick filament and that the loss of cMyBP-C results in an untethering of myosin heads. This results in an increased myosin ATP turnover, further consolidating the relationship between thick filament structure and the myosin ATPase. Crown Copyright (C) 2016 Published by Elsevier Ltd. All rights reserved.Note
Available online 26 March 2016. 12 month embargo.ISSN
00222828PubMed ID
27021517Version
Final accepted manuscriptSponsors
NG Macintosh Memorial Fund; National Heart Foundation [GNT1093852, PB 12S 6939]; NIH [R01 HL080367]; American Heart Association [13POST14780089]Additional Links
http://linkinghub.elsevier.com/retrieve/pii/S0022282816300566ae974a485f413a2113503eed53cd6c53
10.1016/j.yjmcc.2016.03.009
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