scholarly journals Gene expression patterns in transgenic mouse models of hypertrophic cardiomyopathy caused by mutations in myosin regulatory light chain

2016 ◽  
Vol 601 ◽  
pp. 121-132 ◽  
Author(s):  
Wenrui Huang ◽  
Katarzyna Kazmierczak ◽  
Zhiqun Zhou ◽  
Vanessa Aguiar-Pulido ◽  
Giri Narasimhan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Hypertrophic Cardiomyopathy ◽  
Transgenic Mouse ◽  
Mouse Models ◽  
Light Chain ◽  
Expression Patterns ◽  
Regulatory Light Chain ◽  
Gene Expression Patterns ◽  
Myosin Regulatory Light Chain ◽  
Transgenic Mouse Models

scholarly journals Mavacamten Decreases Maximal Force and Ca2+-sensitivity in the N47K-Myosin Regulatory Light Chain Mouse Model of Hypertrophic Cardiomyopathy

2020 ◽  
Author(s):  
Peter O Awinda ◽  
Marissa Watanabe ◽  
Yemeserach M. Bishaw ◽  
Anna M Huckabee ◽  
Keinan B Agonias ◽  
...  
Keyword(s):  
Heart Disease ◽  
Hypertrophic Cardiomyopathy ◽  
Light Chain ◽  
Isometric Force ◽  
Regulatory Light Chain ◽  
Isometric Tension ◽  
Myosin Regulatory Light Chain ◽  
Cardiac Myosin ◽  
Cross Bridge ◽  
Obstructive Hypertrophic Cardiomyopathy

Morbidity and mortality associated with heart disease is a growing threat to the global population and novel therapies are needed. Mavacamten (formerly called MYK-461) is a small molecule that binds to cardiac myosin and inhibits myosin ATPase. Mavacamten is currently in clinical trials for the treatment of obstructive hypertrophic cardiomyopathy (HCM), and it may provide benefits for treating other forms of heart disease. We investigated the effect of mavacamten on cardiac muscle contraction in two transgenic mouse lines expressing the human isoform of cardiac myosin regulatory light chain (RLC) in their hearts. Control mice expressed wild-type RLC (WT-RLC), and HCM mice expressed the N47K RLC mutation. In the absence of mavacamten, skinned papillary muscle strips from WT-RLC mice produced greater isometric force than strips from N47K mice. Adding 0.3 µM mavacamten decreased maximal isometric force and reduced Ca2+-sensitivity of contraction for both genotypes, but this reduction in pCa50 was nearly twice as large for WT-RLC vs. N47K. We also used stochastic length-perturbation analysis to characterize cross-bridge kinetics. The cross-bridge detachment rate was measured as a function of [MgATP] to determine the effect of mavacamten on myosin nucleotide handling rates. Mavacamten increased the MgADP release and MgATP binding rates for both genotypes, thereby contributing to faster cross-bridge detachment, which could speed myocardial relaxation during diastole. Our data suggest that mavacamten reduces isometric tension and Ca2+-sensitivity of contraction via decreased strong cross-bridge binding. Mavacamten may become a useful therapy for patients with heart disease, including some forms of HCM.

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