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

PLoS One. 2017 Jun 28;12(6):e0180064. doi: 10.1371/journal.pone.0180064. eCollection 2017.

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.

MeSH terms

  • Adolescent
  • Adult
  • Cardiomyopathy, Hypertrophic / genetics*
  • Carrier Proteins / genetics*
  • Carrier Proteins / physiology
  • Female
  • Genotyping Techniques
  • Humans
  • Male
  • Middle Aged
  • Muscle Relaxation / genetics
  • Muscle Relaxation / physiology
  • Mutation / genetics
  • Myocardial Contraction / genetics
  • Myocardial Contraction / physiology
  • Myocytes, Cardiac / physiology
  • Myosins / metabolism
  • Myosins / physiology
  • Young Adult

Substances

  • Carrier Proteins
  • myosin-binding protein C
  • Myosins

Grants and funding

JWM, AL and SL were supported by the NG Macintosh Memorial Fund (Discipline of Anatomy and Histology, The University of Sydney). The National Heart Foundation supports SL (GNT1093852) and AL (PB 12S 6939). We thank Medical Advances Without Animals for funding the Sydney Heart Bank equipment. The study was supported in part by a grant from The Netherlands Cardiovascular Research Institute [ARENA CVON 2011-11] to JvdV. SPH is supported by National Institute of Health HL080367. RC is supported by National Institute of Health AR062279. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.