Ablation of cardiac myosin binding protein-C disrupts the super-relaxed state of myosin in murine cardiomyocytes

James W. McNamara, Amy Li, Nicola J. Smith, Sean Lal, Robert M. Graham, Kristina Bezold Kooiker, Sabine J. van Dijk, Cristobal G dos Remedios, Samantha P. Harris, Roger Cooke

Research output: Contribution to journalArticle

35 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)65-71
Number of pages7
JournalJournal of Molecular and Cellular Cardiology
Volume94
DOIs
StatePublished - May 1 2016

Keywords

  • Cardiac energetics
  • Cardiac SRX
  • Hypertrophic cardiomyopathy
  • Myosin binding protein-C (MyBP-C)
  • Myosin II ATPase
  • Thick filament structure

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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    McNamara, J. W., Li, A., Smith, N. J., Lal, S., Graham, R. M., Kooiker, K. B., van Dijk, S. J., Remedios, C. G. D., Harris, S. P., & Cooke, R. (2016). Ablation of cardiac myosin binding protein-C disrupts the super-relaxed state of myosin in murine cardiomyocytes. Journal of Molecular and Cellular Cardiology, 94, 65-71. https://doi.org/10.1016/j.yjmcc.2016.03.009