The effect of myosin RLC phosphorylation in normal and cardiomyopathic mouse hearts

Priya Muthu, Katarzyna Kazmierczak, Michelle Jones, Danuta Szczesna-Cordary

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

Phosphorylation of the myosin regulatory light chain (RLC) by Ca2+-calmodulin-activated myosin light chain kinase (MLCK) is known to be essential for the inotropic function of the heart. In this study, we have examined the effects of MLCK-phosphorylation of transgenic (Tg) mouse cardiac muscle preparations expressing the D166V (aspartic acid to valine)-RLC mutation, identified to cause familial hypertrophic cardiomyopathy with malignant outcomes. Our previous work with Tg-D166V mice demonstrated a large increase in the Ca2+ sensitivity of contraction, reduced maximal ATPase and force and a decreased level of endogenous RLC phosphorylation. Based on studies demonstrating the beneficial and/or protective effects of cardiac myosin phosphorylation for heart function, we hypothesized that an ex vivo phosphorylation of Tg-D166V cardiac muscle may rescue the detrimental contractile phenotypes observed earlier at the level of single myosin molecules and in Tg-D166V papillary muscle fibres. We showed that MLCK-induced phosphorylation of Tg-D166V cardiac myofibrils and muscle fibres was able to increase the reduced myofibrillar ATPase and reverse an abnormally increased Ca2+ sensitivity of force to the level observed for Tg-wild-type (WT) muscle. However, in contrast to Tg-WT, which displayed a phosphorylationinduced increase in steady-state force, the maximal tension in Tg-D166V papillary muscle fibres decreased upon phosphorylation. With the exception of force generation data, our results support the notion that RLC phosphorylation works as a rescue mechanism alleviating detrimental functional effects of a disease causing mutation. Further studies are necessary to elucidate the mechanism of this unexpected phosphorylation-induced decrease in maximal tension in Tg-D166V-skinned muscle fibres.

Original languageEnglish (US)
Pages (from-to)911-919
Number of pages9
JournalJournal of Cellular and Molecular Medicine
Volume16
Issue number4
DOIs
StatePublished - Dec 1 2012

Keywords

  • Cardiac hypertrophy
  • Muscle fibres
  • Mutation
  • Myosin light chain kinase
  • Myosin regulatory light chain
  • Phosphorylation
  • Transgenic mice

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Medicine

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