Ablation of cardiac myosin binding protein-C disrupts the super-relaxed state of myosin in murine cardiomyocytes. (May 2016)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Journal of molecular and cellular cardiology. Volume 94(2016:May)
• Page Start: 65
• Page End: 71
• Publication Date: 2016-05
• Subjects: SRX super-relaxed state -- DRX disordered-relaxed state -- cMyBP-C cardiac myosin binding protein-C -- MYBPC3/Mybpc3 cardiac myosin binding protein-C gene in human/mouse -- HCM hypertrophic cardiomyopathy -- MOPS 3-(N-morpholino) propanesulfonic acid -- DTT dithiothreitol -- BDM 2, 3-butanedione monoxime -- mATP 2′-(or-3′)–O–(N-methylanthraniloyl) adenosine 5-triphosphate; Cardiac SRX -- Hypertrophic cardiomyopathy -- Myosin binding protein-C (MyBP-C) -- Myosin II ATPase -- Thick filament structure -- Cardiac energetics; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2016.03.009
• Languages: English
• ISSNs: 0022-2828

Abstract

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. Highlights: The inhibited super-relaxed state of myosin was measured in permeabilised mouse left ventricles. Severe hypertrophy induced by cMyBP-C ablation was accompanied by a loss of SRX regulation. An intermediate, non-significant decrease in the SRX was noted in trans-aortic constricted mice.