scholarly journals The Slow Cardiac Myosin Regulatory Light Chain in Heart Failure

2011 ◽  
Vol 34 (1) ◽  
pp. 10-11 ◽  
Author(s):  
Daniel F. Pauly
Keyword(s):  
Heart Failure ◽  
Light Chain ◽  
Regulatory Light Chain ◽  
Myosin Regulatory Light Chain ◽  
Cardiac Myosin

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 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 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 Cardiac myosin regulatory light chain kinase modulates cardiac contractility by phosphorylating both myosin regulatory light chain and troponin I

2020 ◽  
Vol 295 (14) ◽  
pp. 4398-4410 ◽  
Author(s):  
Ivanka R. Sevrieva ◽  
Birgit Brandmeier ◽  
Saraswathi Ponnam ◽  
Mathias Gautel ◽  
Malcolm Irving ◽  
...  
Keyword(s):  
Light Chain ◽  
Troponin I ◽  
Regulatory Light Chain ◽  
Myosin Regulatory Light Chain ◽  
Cardiac Myosin ◽  
Sarcomeric Proteins ◽  
Ventricular Trabeculae

Heart muscle contractility and performance are controlled by posttranslational modifications of sarcomeric proteins. Although myosin regulatory light chain (RLC) phosphorylation has been studied extensively in vitro and in vivo, the precise role of cardiac myosin light chain kinase (cMLCK), the primary kinase acting upon RLC, in the regulation of cardiomyocyte contractility remains poorly understood. In this study, using recombinantly expressed and purified proteins, various analytical methods, in vitro and in situ kinase assays, and mechanical measurements in isolated ventricular trabeculae, we demonstrate that human cMLCK is not a dedicated kinase for RLC but can phosphorylate other sarcomeric proteins with well-characterized regulatory functions. We show that cMLCK specifically monophosphorylates Ser23 of human cardiac troponin I (cTnI) in isolation and in the trimeric troponin complex in vitro and in situ in the native environment of the muscle myofilament lattice. Moreover, we observed that human cMLCK phosphorylates rodent cTnI to a much smaller extent in vitro and in situ, suggesting species-specific adaptation of cMLCK. Although cMLCK treatment of ventricular trabeculae exchanged with rat or human troponin increased their cross-bridge kinetics, the increase in sensitivity of myofilaments to calcium was significantly blunted by human TnI, suggesting that human cTnI phosphorylation by cMLCK modifies the functional consequences of RLC phosphorylation. We propose that cMLCK-mediated phosphorylation of TnI is functionally significant and represents a critical signaling pathway that coordinates the regulatory states of thick and thin filaments in both physiological and potentially pathophysiological conditions of the heart.

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