MYBPC3 mutations are associated with a reduced super-relaxed state in patients with hypertrophic cardiomyopathy

James W. McNamara, Amy Li, Sean Lal, J. Martijn Bos, Samantha - Harris, Jolanda Van Der Velden, Michael J. Ackerman, Roger Cooke, Cristobal G. Dos Remedios

Research output: Contribution to journalArticle

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Abstract

The "super-relaxed state" (SRX) of myosin represents a 'reserve' of motors in the heart. Myosin heads in the SRX are bound to the thick filament and have a very low ATPase rate. Changes in the SRX are likely to modulate cardiac contractility. We previously demonstrated that the SRX is significantly reduced in mouse cardiomyocytes lacking cardiac myosin binding protein±C (cMyBP-C). Here, we report the effect of mutations in the cMyBP-C gene (MYBPC3) using samples from human patients with hypertrophic cardiomyopathy (HCM). Left ventricular (LV) samples from 11 HCM patients were obtained following myectomy surgery to relieve LV outflow tract obstruction. HCM samples were genotyped as either MYBPC3 mutation positive (MYBPC3mut) or negative (HCMsmn) and were compared to eight non-failing donor hearts. Compared to donors, only MYBPC3mut samples display a significantly diminished SRX, characterised by a decrease in both the number of myosin heads in the SRX and the lifetime of ATP turnover. These changes were not observed in HCMsmn samples. There was a positive correlation (p < 0.01) between the expression of cMyBP-C and the proportion of myosin heads in the SRX state, suggesting cMyBP-C modulates and maintains the SRX. Phosphorylation of the myosin regulatory light chain in MYBPC3mut samples was significantly decreased compared to the other groups, suggesting a potential mechanism to compensate for the diminished SRX. We conclude that by altering both contractility and sarcomeric energy requirements, a reduced SRX may be an important disease mechanism in patients with MYBPC3 mutations.

Original languageEnglish (US)
Article numbere0180064
JournalPLoS One
Volume12
Issue number6
DOIs
StatePublished - Jun 1 2017

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Cardiac Myosins
Hypertrophic Cardiomyopathy
cardiomyopathy
Myosins
myosin
mutation
Mutation
Myosin Light Chains
Phosphorylation
Tissue Donors
Ventricular Outflow Obstruction
sampling
Surgery
Adenosine Triphosphatases
Cardiac Myocytes
Genes
Adenosine Triphosphate
heart
myosin light chains
energy requirements

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

McNamara, J. W., Li, A., Lal, S., Bos, J. M., Harris, S. ., Van Der Velden, J., ... Dos Remedios, C. G. (2017). MYBPC3 mutations are associated with a reduced super-relaxed state in patients with hypertrophic cardiomyopathy. PLoS One, 12(6), [e0180064]. https://doi.org/10.1371/journal.pone.0180064

MYBPC3 mutations are associated with a reduced super-relaxed state in patients with hypertrophic cardiomyopathy. / McNamara, James W.; Li, Amy; Lal, Sean; Bos, J. Martijn; Harris, Samantha -; Van Der Velden, Jolanda; Ackerman, Michael J.; Cooke, Roger; Dos Remedios, Cristobal G.

In: PLoS One, Vol. 12, No. 6, e0180064, 01.06.2017.

Research output: Contribution to journalArticle

McNamara, JW, Li, A, Lal, S, Bos, JM, Harris, S, Van Der Velden, J, Ackerman, MJ, Cooke, R & Dos Remedios, CG 2017, 'MYBPC3 mutations are associated with a reduced super-relaxed state in patients with hypertrophic cardiomyopathy', PLoS One, vol. 12, no. 6, e0180064. https://doi.org/10.1371/journal.pone.0180064
McNamara, James W. ; Li, Amy ; Lal, Sean ; Bos, J. Martijn ; Harris, Samantha - ; Van Der Velden, Jolanda ; Ackerman, Michael J. ; Cooke, Roger ; Dos Remedios, Cristobal G. / MYBPC3 mutations are associated with a reduced super-relaxed state in patients with hypertrophic cardiomyopathy. In: PLoS One. 2017 ; Vol. 12, No. 6.
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