Sitbon Yoel H, Kazmierczak Katarzyna, Liang Jingsheng, Kloehn Andrew J, Vinod Judith, Kanashiro-Takeuchi Rosemeire, Szczesna-Cordary Danuta
Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
iScience. 2024 Jul 26;27(8):110591. doi: 10.1016/j.isci.2024.110591. eCollection 2024 Aug 16.
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.
我们研究了肌球蛋白必需轻链（N-ELC）的N端（第1至43位氨基酸残基）在肥厚型心肌病（HCM-A57G）和限制型心肌病（RCM-E143K）小鼠心脏功能调节中的作用。这两种模型均与N-ELC截短的Δ43小鼠进行交叉基因分型，并使用超声心动图和肌肉收缩力学对后代进行研究。在A57G×Δ43小鼠中，Δ43的表达改善了心脏功能，减轻了肥大和纤维化。与RCM-E143K小鼠相比，E143K×Δ43小鼠未见改善。HCM突变的病理机制包括N-ELC张力传感器受损、N-ELC与肌动蛋白的相互作用破坏、力-钙浓度关系改变以及肌球蛋白超松弛状态不稳定。去除功能失调的N-ELC传感器可使HCM截短突变心脏的功能得到挽救。然而，RCM突变不能通过N-ELC缺失得到挽救，这可能是由于其靠近肌球蛋白运动结构域，影响了杠杆臂的刚性和肌球蛋白功能。本研究深入探讨了N-ELC在ELC突变型心肌病发生发展及潜在挽救中的作用。
