MYBPC3 mutations are associated with a reduced super-relaxed state in patients with hypertrophic cardiomyopathy
AuthorMcNamara, James W.
Bos, J. Martijn
Harris, Samantha P.
van der Velden, Jolanda
Ackerman, Michael J.
dos Remedios, Cristobal G.
AffiliationUniv Arizona, Dept Cellular & Mol Med
MetadataShow full item record
PublisherPUBLIC LIBRARY SCIENCE
CitationMYBPC3 mutations are associated with a reduced super-relaxed state in patients with hypertrophic cardiomyopathy 2017, 12 (6):e0180064 PLOS ONE
Rights© 2017 McNamara et al. This is an open access article distributed under the terms of the Creative Commons Attribution License.
Collection InformationThis 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 firstname.lastname@example.org.
AbstractThe "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 (MYBPC3(mut)) 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.
NoteOpen access journal.
VersionFinal published version
SponsorsNG Macintosh Memorial Fund (Discipline of Anatomy and Histology, The University of Sydney); National Heart Foundation [GNT1093852, PB 12S 6939]; Netherlands
- Ablation of cardiac myosin binding protein-C disrupts the super-relaxed state of myosin in murine cardiomyocytes.
- Authors: McNamara JW, Li A, Smith NJ, Lal S, Graham RM, Kooiker KB, van Dijk SJ, Remedios CGD, Harris SP, Cooke R
- Issue date: 2016 May
- Preserved cross-bridge kinetics in human hypertrophic cardiomyopathy patients with MYBPC3 mutations.
- Authors: van Dijk SJ, Boontje NM, Heymans MW, Ten Cate FJ, Michels M, Dos Remedios C, Dooijes D, van Slegtenhorst MA, van der Velden J, Stienen GJ
- Issue date: 2014 Aug
- Variable cardiac myosin binding protein-C expression in the myofilaments due to MYBPC3 mutations in hypertrophic cardiomyopathy.
- Authors: Parbhudayal RY, Garra AR, Götte MJW, Michels M, Pei J, Harakalova M, Asselbergs FW, van Rossum AC, van der Velden J, Kuster DWD
- Issue date: 2018 Oct
- Gene-specific increase in the energetic cost of contraction in hypertrophic cardiomyopathy caused by thick filament mutations.
- Authors: Witjas-Paalberends ER, Güçlü A, Germans T, Knaapen P, Harms HJ, Vermeer AM, Christiaans I, Wilde AA, Dos Remedios C, Lammertsma AA, van Rossum AC, Stienen GJ, van Slegtenhorst M, Schinkel AF, Michels M, Ho CY, Poggesi C, van der Velden J
- Issue date: 2014 Jul 15
- Cardiac myosin binding protein-C phosphorylation regulates the super-relaxed state of myosin.
- Authors: McNamara JW, Singh RR, Sadayappan S
- Issue date: 2019 Jun 11