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Dual effect of N-terminal deletion of cardiac myosin essential light chain in mitigating cardiomyopathy.


ABSTRACT: We investigated the role of the N-terminus (residues 1-43) of the myosin essential light chain (N-ELC) in regulating cardiac function in hypertrophic (HCM-A57G) and restrictive (RCM-E143K) cardiomyopathy mice. Both models were cross-genotyped with N-ELC-truncated Δ43 mice, and the offspring were studied using echocardiography and muscle contractile mechanics. In A57G×Δ43 mice, Δ43 expression improved heart function and reduced hypertrophy and fibrosis. No improvements were seen in E143K×Δ43 compared to RCM-E143K mice. HCM-mutant pathology involved an impaired N-ELC tension sensor, disrupted N-ELC-actin interactions, an altered force-pCa relationship, and a destabilized myosin's super-relaxed state. Removal of the malfunctioning N-ELC sensor led to functional rescue in HCM-truncated mutant hearts. However, the RCM mutation could not be rescued by N-ELC deletion, likely due to its proximity to the myosin motor domain, affecting lever-arm rigidity and myosin function. This study provides insights into the role of N-ELC in the development and potential rescue of ELC-mutant cardiomyopathy.

SUBMITTER: Sitbon YH 

PROVIDER: S-EPMC11357882 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

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Dual effect of N-terminal deletion of cardiac myosin essential light chain in mitigating cardiomyopathy.

Sitbon Yoel H YH   Kazmierczak Katarzyna K   Liang Jingsheng J   Kloehn Andrew J AJ   Vinod Judith J   Kanashiro-Takeuchi Rosemeire R   Szczesna-Cordary Danuta D  

iScience 20240726 8


We investigated the role of the N-terminus (residues 1-43) of the myosin essential light chain (N-ELC) in regulating cardiac function in hypertrophic (HCM-A57G) and restrictive (RCM-E143K) cardiomyopathy mice. Both models were cross-genotyped with N-ELC-truncated Δ43 mice, and the offspring were studied using echocardiography and muscle contractile mechanics. In A57G×Δ43 mice, Δ43 expression improved heart function and reduced hypertrophy and fibrosis. No improvements were seen in E143K×Δ43 comp  ...[more]

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