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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
Author(s) -
Sitbon Yoel H.,
Kazmierczak Katarzyna,
Liang Jingsheng,
Yadav Sunil,
Veerasammy Melanie,
KanashiroTakeuchi Rosemeire M.,
SzczesnaCordary Danuta
Publication year - 2020
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.15243
Subject(s) - myosin , hypertrophic cardiomyopathy , myosin atpase , actin , cardiac function curve , genetically modified mouse , cardiomyopathy , medicine , mutant , atpase , biology , fibrosis , transgene , chemistry , microbiology and biotechnology , biochemistry , heart failure , enzyme , gene
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.