Ablation of the N terminus of cardiac essential light chain promotes the super-relaxed state of myosin and counteracts hypercontractility in hypertrophic cardiomyopathy mutant mice

Yoel H. Sitbon, Katarzyna Kazmierczak, Jingsheng Liang, Sunil Yadav, Melanie Veerasammy, Rosemeire M. Kanashiro-Takeuchi, Danuta Szczesna-Cordary

Research output: Contribution to journalArticlepeer-review

Abstract

In this study, we focus on the molecular mechanisms associated with the A57G (Ala57-to-Gly57) mutation in myosin essential light chains (ELCs), found to cause hypertrophic cardiomyopathy (HCM) in humans and in mice. Specifically, we studied the effects of A57G on the super-relaxed (SRX) state of myosin that may contribute to the hypercontractile cross-bridge behavior and ultimately lead to pathological cardiac remodeling in transgenic Tg-A57G mice. The disease model was compared to Tg-WT mice, expressing the wild-type human ventricular ELC, and analyzed against Tg-Δ43 mice, expressing the N-terminally truncated ELC, whose hearts hypertrophy with time but do not show any abnormalities in cardiac morphology or function. Our data suggest a new role for the N terminus of cardiac ELC (N-ELC) in modulation of myosin cross-bridge function in the healthy as well as in HCM myocardium. The lack of N-ELC in Tg-Δ43 mice was found to significantly stabilize the SRX state of myosin and increase the number of myosin heads occupying a low-energy state. In agreement, Δ43 hearts showed significantly decreased ATP utilization and low actin-activated myosin ATPase compared with A57G and WT hearts. The hypercontractile activity of A57G-ELC cross-bridges was manifested by the inhibition of the SRX state, increased number of myosin heads available for interaction with actin, and higher ATPase activity. Fiber mechanics studies, echocardiography examination, and assessment of fibrosis confirmed the development of two distinct forms of cardiac remodeling in these two ELC mouse models, with pathological cardiac hypertrophy in Tg-A57G, and near physiologic cardiac growth in Tg-Δ43 animals.

Original languageEnglish (US)
Pages (from-to)3989-4004
Number of pages16
JournalFEBS Journal
Volume287
Issue number18
DOIs
StatePublished - Sep 1 2020

Keywords

  • hypertrophic cardiomyopathy
  • myosin essential light chain
  • super-relaxed state
  • Tg-A57G mice
  • Tg-Δ43 mice

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Ablation of the N terminus of cardiac essential light chain promotes the super-relaxed state of myosin and counteracts hypercontractility in hypertrophic cardiomyopathy mutant mice'. Together they form a unique fingerprint.

Cite this