scholarly journals Functional Consequences of Mutations in the Myosin Regulatory Light Chain Associated with Hypertrophic Cardiomyopathy

10.5772/29012 ◽  
2012 ◽  
Author(s):  
Priya Muthu ◽  
Wenrui Huang ◽  
Katarzyna Kazmierczak ◽  
Danuta Szczesna-Cordary
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Light Chain ◽  
Regulatory Light Chain ◽  
Myosin Regulatory Light Chain ◽  
Functional Consequences

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.

scholarly journals Myosin Regulatory Light Chain Phosphorylation Rescues Cardiac Dysfunction Caused by Familial Hypertrophic Cardiomyopathy-Linked Mutations

2012 ◽  
Vol 102 (3) ◽  
pp. 557a
Author(s):  
Priya Muthu ◽  
Katarzyna Kazmierczak ◽  
Wenrui Huang ◽  
Ana I. Rojas ◽  
Danuta Szczesna-Cordary
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Light Chain ◽  
Cardiac Dysfunction ◽  
Regulatory Light Chain ◽  
Familial Hypertrophic Cardiomyopathy ◽  
Myosin Regulatory Light Chain ◽  
Regulatory Light Chain Phosphorylation

scholarly journals Differential Effects of Alpha Vs Beta Myosin Heavy Chain on the Kinetcs and Mechanics of Familial Hypertrophic Cardiomyopathy Mutations in the Myosin Regulatory Light Chain

2010 ◽  
Vol 98 (3) ◽  
pp. 146a
Author(s):  
Michael J. Greenberg ◽  
James D. Watt ◽  
Katarzyna Kazmierczak ◽  
Michelle Jones ◽  
Danuta Szczesna-Cordary ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Myosin Heavy Chain ◽  
Heavy Chain ◽  
Light Chain ◽  
Regulatory Light Chain ◽  
Familial Hypertrophic Cardiomyopathy ◽  
Myosin Regulatory Light Chain ◽  
Differential Effects ◽  
Cardiomyopathy Mutations

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 Hypertrophic cardiomyopathy associated Lys104Glu mutation in the myosin regulatory light chain causes diastolic disturbance in mice

2014 ◽  
Vol 74 ◽  
pp. 318-329 ◽  
Author(s):  
Wenrui Huang ◽  
Jingsheng Liang ◽  
Katarzyna Kazmierczak ◽  
Priya Muthu ◽  
Divya Duggal ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Light Chain ◽  
Regulatory Light Chain ◽  
Myosin Regulatory Light Chain

scholarly journals Familial Hypertrophic Cardiomyopathy Mutations of the Myosin Regulatory Light Chain Remove Myosin Load Sensitivity

2010 ◽  
Vol 98 (3) ◽  
pp. 215a-216a
Author(s):  
Michael J. Greenberg ◽  
Katarzyna Kazmierczak ◽  
Danuta Szczesna-Cordary ◽  
Jeffrey R. Moore
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Light Chain ◽  
Regulatory Light Chain ◽  
Familial Hypertrophic Cardiomyopathy ◽  
Myosin Regulatory Light Chain ◽  
Cardiomyopathy Mutations

scholarly journals Hypertrophic cardiomyopathy associated E22K mutation in myosin regulatory light chain decreases calcium‐activated tension and stiffness and reduces myofilament Ca 2+ sensitivity

FEBS Journal ◽  
2021 ◽  
Author(s):  
Jiajia Zhang ◽  
Li Wang ◽  
Katarzyna Kazmierczak ◽  
Hang Yun ◽  
Danuta Szczesna‐Cordary ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Light Chain ◽  
Regulatory Light Chain ◽  
Myosin Regulatory Light Chain

scholarly journals In Vitro Motility Studies of C-terminal Myosin Regulatory Light Chain Mutants Implicated in Familial Hypertrophic Cardiomyopathy

2010 ◽  
Vol 98 (3) ◽  
pp. 715a
Author(s):  
William M. Schmidt ◽  
James Watt ◽  
Katarzyna Kazmierczak ◽  
Jeff Moore ◽  
Danuta Szczesna-Cordary
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Light Chain ◽  
Regulatory Light Chain ◽  
Familial Hypertrophic Cardiomyopathy ◽  
Myosin Regulatory Light Chain ◽  
In Vitro Motility
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