Constitutive phosphorylation of cardiac myosin regulatory light chain prevents development of hypertrophic cardiomyopathy in mice

Chen Ching Yuan, Priya Muthu, Katarzyna Kazmierczak, Jingsheng Liang, Wenrui Huang, Thomas C. Irving, Rosemeire Takeuchi, Joshua Hare, Danuta Szczesna-Cordary

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

Myosin light chain kinase (MLCK)-dependent phosphorylation of the regulatory light chain (RLC) of cardiac myosin is known to play a beneficial role in heart disease, but the idea of a phosphorylation-mediated reversal of a hypertrophic cardiomyopathy (HCM) phenotype is novel. Our previous studies on transgenic (Tg) HCM-RLC mice revealed that the D166V (Aspartate166 →Valine) mutation-induced changes in heart morphology and function coincided with largely reduced RLC phosphorylation in situ. We hypothesized that the introduction of a constitutively phosphorylated Serine15 (S15D) into the hearts of D166V mice would prevent the development of a deleterious HCM phenotype. In support of this notion, MLCK-induced phosphorylation of D166V-mutated hearts was found to rescue some of their abnormal contractile properties. Tg-S15D-D166V mice were generated with the human cardiac RLC-S15D-D166V construct substituted for mouse cardiac RLC and were subjected to functional, structural, and morphological assessments. The results were compared with Tg-WT and Tg-D166V mice expressing the human ventricular RLC-WT or its D166V mutant, respectively. Echocardiography and invasive hemodynamic studies demonstrated significant improvements of intact heart function in S15D-D166V mice compared with D166V, with the systolic and diastolic indices reaching those monitored in WT mice. A largely reduced maximal tension and abnormally high myofilament Ca<sup>2+</sup> sensitivity observed in D166V-mutated hearts were reversed in S15D-D166V mice. Lowangle X-ray diffraction study revealed that altered myofilament structures present in HCM-D166V mice were mitigated in S15D-D166V rescue mice. Our collective results suggest that expression of pseudophosphorylated RLC in the hearts of HCM mice is sufficient to prevent the development of the pathological HCM phenotype.

Original languageEnglish (US)
Pages (from-to)E4138-E4146
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number30
DOIs
StatePublished - Jul 28 2015

Keywords

  • Cardiomyopathy
  • Hemodynamics
  • Myocardial contraction
  • Myosin RLC
  • X-ray structure

ASJC Scopus subject areas

  • General

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