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Molecular mechanisms of cardiomyopathy phenotypes associated with myosin light chain mutations

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Abstract

We discuss here the potential mechanisms of action associated with hypertrophic (HCM) or dilated (DCM) cardiomyopathy causing mutations in the myosin regulatory (RLC) and essential (ELC) light chains. Specifically, we focus on four HCM mutations: RLC-A13T, RLC-K104E, ELC-A57G and ELC-M173V, and one DCM RLC-D94A mutation shown by population studies to cause different cardiomyopathy phenotypes in humans. Our studies indicate that RLC and ELC mutations lead to heart disease through different mechanisms with RLC mutations triggering alterations of the secondary structure of the RLC which further affect the structure and function of the lever arm domain and impose changes in the cross bridge cycling rates and myosin force generation ability. The ELC mutations exert their detrimental effects through changes in the interaction of the N-terminus of ELC with actin altering the cross talk between the thick and thin filaments and ultimately resulting in an altered force-pCa relationship. We also discuss the effect of mutations on myosin light chain phosphorylation. Exogenous myosin light chain phosphorylation and/or pseudo-phosphorylation were explored as potential rescue tools to treat hypertrophy-related cardiac phenotypes.

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Abbreviations

A13T:

Alanine-to-threonine mutation in myosin RLC

A57G:

Alanine-to-glycine mutation in myosin ELC

ANP:

Atrial natriuretic peptide

BNP:

Brain natriuretic peptide

CaM:

Calmodulin

CD:

Circular dichroism

CO:

Cardiac output

D94A:

Aspartic acid-to-alanine mutation in myosin RLC

D166V:

Aspartic acid-to-valine mutation in myosin RLC

DCM:

Dilated cardiomyopathy

E/A ratio:

Doppler transmitral blood velocities, early (E)/late (A) diastolic

ECG:

Echocardiography

EF:

Ejection fraction

ELC:

Essential light chain of myosin (MYL3 gene)

HCM:

Hypertrophic cardiomyopathy

IFS:

Interfilament lattice spacing

IVS:

Inter-ventricular septum

H&E:

Hematoxylin and eosin

HF:

Heart failure

K104E:

Lysine-to-glutamic acid mutation in myosin RLC

LV:

Left ventricle

M173V:

Methionine-to-valine mutation in myosin ELC

MHC:

Myosin heavy chain

MLC:

Myosin light chain

MLCK:

Myosin light chain kinase

MyBP-C:

Myosin binding protein-C

NTg:

Non-transgenic

PV:

Pressure volume

R58Q:

Arginine-to-glutamine mutation in myosin RLC

RLC:

Regulatory light chain of myosin (MYL2 gene)

S15D:

Serine-to-aspartic acid mutation to mimic phosphorylation

SCD:

Sudden cardiac death

SR:

Sarcoplasmic reticulum

SW:

Stroke work

SV:

Stroke volume

Tg:

Transgenic

Tm:

Tropomyosin

Tn:

Troponin

WT:

Wild-type

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Acknowledgments

The authors thank Michelle Jones for critical reading of the manuscript. This work was supported in part by grants from the National Institutes of Health HL108343 and HL123255 (D.S-C.); and the American Heart Association 12PRE12030412 (W.H.). The content is solely the responsibility of the authors and does not necessarily reflect the official views of the National Center for Research Resources or the NIH.

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  1. Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA

    Wenrui Huang & Danuta Szczesna-Cordary

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Correspondence to Danuta Szczesna-Cordary.

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Huang, W., Szczesna-Cordary, D. Molecular mechanisms of cardiomyopathy phenotypes associated with myosin light chain mutations. J Muscle Res Cell Motil 36, 433–445 (2015). https://doi.org/10.1007/s10974-015-9423-3

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