scholarly journals Regulatory Light Chain Mutants Linked to Heart Disease Modify the Cardiac Myosin Lever Arm

Biochemistry ◽  
2013 ◽  
Vol 52 (7) ◽  
pp. 1249-1259 ◽  
Author(s):  
Thomas P. Burghardt ◽  
Laura A. Sikkink
Keyword(s):  
Heart Disease ◽  
Light Chain ◽  
Regulatory Light Chain ◽  
Cardiac Myosin ◽  
Lever Arm

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 GFP-Tagged Regulatory Light Chain Monitors Single Myosin Lever-Arm Orientation in a Muscle Fiber

2007 ◽  
Vol 93 (6) ◽  
pp. 2226-2239 ◽  
Author(s):  
Thomas P. Burghardt ◽  
Katalin Ajtai ◽  
Daniel K. Chan ◽  
Miriam F. Halstead ◽  
Jinhui Li ◽  
...  
Keyword(s):  
Muscle Fiber ◽  
Light Chain ◽  
Regulatory Light Chain ◽  
Lever Arm

scholarly journals The HCM-Linked Ala13thr Mutation in the Cardiac Myosin Regulatory Light Chain Increases Isometric Force Production

2011 ◽  
Vol 100 (3) ◽  
pp. 111a
Author(s):  
Katarzyna Kazmierczak ◽  
Priya Muthu ◽  
Wenrui Huang ◽  
Ana Rojas ◽  
Michelle Jones ◽  
...  
Keyword(s):  
Light Chain ◽  
Isometric Force ◽  
Force Production ◽  
Regulatory Light Chain ◽  
Myosin Regulatory Light Chain ◽  
Cardiac Myosin ◽  
Isometric Force Production

scholarly journals Regulatory light chain phosphorylation augments length-dependent contraction in PTU-treated rats

2018 ◽  
Vol 151 (1) ◽  
pp. 66-76 ◽  
Author(s):  
Jason J. Breithaupt ◽  
Hannah C. Pulcastro ◽  
Peter O. Awinda ◽  
David C. DeWitt ◽  
Bertrand C.W. Tanner
Keyword(s):  
Myosin Heavy Chain ◽  
Heavy Chain ◽  
Light Chain ◽  
Myosin Heavy Chain Isoforms ◽  
Regulatory Light Chain ◽  
Cardiac Myosin ◽  
Myosin Heavy Chain Isoform ◽  
Cross Bridge ◽  
Detachment Rate ◽  
Length Dependent Activation

Force production by actin–myosin cross-bridges in cardiac muscle is regulated by thin-filament proteins and sarcomere length (SL) throughout the heartbeat. Prior work has shown that myosin regulatory light chain (RLC), which binds to the neck of myosin heavy chain, increases cardiac contractility when phosphorylated. We recently showed that cross-bridge kinetics slow with increasing SLs, and that RLC phosphorylation amplifies this effect, using skinned rat myocardial strips predominantly composed of the faster α-cardiac myosin heavy chain isoform. In the present study, to assess how RLC phosphorylation influences length-dependent myosin function as myosin motor speed varies, we used a propylthiouracil (PTU) diet to induce >95% expression of the slower β-myosin heavy chain isoform in rat cardiac ventricles. We measured the effect of RLC phosphorylation on Ca2+-activated isometric contraction and myosin cross-bridge kinetics (via stochastic length perturbation analysis) in skinned rat papillary muscle strips at 1.9- and 2.2-µm SL. Maximum tension and Ca2+ sensitivity increased with SL, and RLC phosphorylation augmented this response at 2.2-µm SL. Subtle increases in viscoelastic myocardial stiffness occurred with RLC phosphorylation at 2.2-µm SL, but not at 1.9-µm SL, thereby suggesting that RLC phosphorylation increases β-myosin heavy chain binding or stiffness at longer SLs. The cross-bridge detachment rate slowed as SL increased, providing a potential mechanism for prolonged cross-bridge attachment to augment length-dependent activation of contraction at longer SLs. Length-dependent slowing of β-myosin heavy chain detachment rate was not affected by RLC phosphorylation. Together with our previous studies, these data suggest that both α- and β-myosin heavy chain isoforms show a length-dependent activation response and prolonged myosin attachment as SL increases in rat myocardial strips, and that RLC phosphorylation augments length-dependent activation at longer SLs. In comparing cardiac isoforms, however, we found that β-myosin heavy chain consistently showed greater length-dependent sensitivity than α-myosin heavy chain. Our work suggests that RLC phosphorylation is a vital contributor to the regulation of myocardial contractility in both cardiac myosin heavy chain isoforms.

scholarly journals Slow Cardiac Myosin Regulatory Light Chain 2 (MYL2) was Down-Expressed in Chronic Heart Failure Patients

2010 ◽  
Vol 34 (1) ◽  
pp. 30-34 ◽  
Author(s):  
Yuanhong Li ◽  
Gang Wu ◽  
Qizhu Tang ◽  
Congxin Huang ◽  
Hong Jiang ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Light Chain ◽  
Regulatory Light Chain ◽  
Myosin Regulatory Light Chain ◽  
Cardiac Myosin ◽  
Heart Failure Patients

scholarly journals Impact of Regulatory Light Chain Mutation (K104E) on the Atpase and Motor Properties of Human Cardiac Myosin

2020 ◽  
Vol 118 (3) ◽  
pp. 425a
Author(s):  
David Rasicci ◽  
Orville Kirkland ◽  
Wanjian Tang ◽  
Rohini Desetty ◽  
Christopher M. Yengo
Keyword(s):  
Light Chain ◽  
Regulatory Light Chain ◽  
Cardiac Myosin
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