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

Journal of Cellular and Molecular Medicine

Priya Muthu¹  Katarzyna Kazmierczak¹  Michelle Jones¹ 

[1] Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL, USA

关键词: cardiac hypertrophy;    mutation;    myosin regulatory light chain;    muscle fibres;    myosin light chain kinase;    phosphorylation;    transgenic mice;   

DOI  :  10.1111/j.1582-4934.2011.01371.x

来源: Wiley

【 摘 要 】

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 phosphorylation-induced 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.

【 授权许可】

Unknown   
© 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd