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.
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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
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