Cardiac Myosin Light Chain Kinase Is Necessary for Myosin Regulatory Light Chain Phosphorylation and Cardiac Performance in Vivo

• Published in: The Journal of biological chemistry 2010-12, Vol.285 (52), p.40819-40829
• Main Authors: Ding, Peiguo, Huang, Jian, Battiprolu, Pavan K., Hill, Joseph A., Kamm, Kristine E., Stull, James T.
• Format: Article
• Language: English
• Subjects: Animals; Calcium Calmodulin-dependent Protein Kinase (CaMK); Cardiac Hypertrophy; Cardiac Muscle; Cardiomegaly - diagnostic imaging; Cardiomegaly - enzymology; Cardiomegaly - genetics; Cardiomegaly - physiopathology; Cardiotonic Agents - pharmacology; Echocardiography; Female; Gene Expression Regulation, Enzymologic - genetics; Heart Atria - diagnostic imaging; Heart Atria - enzymology; Heart Atria - physiopathology; Heart Failure - diagnostic imaging; Heart Failure - enzymology; Heart Ventricles - diagnostic imaging; Heart Ventricles - enzymology; Heart Ventricles - physiopathology; Isoproterenol - pharmacology; Male; Mice; Mice, Knockout; Myocardium - enzymology; Myocytes, Cardiac - enzymology; Myosin; Myosin Light Chains - genetics; Myosin Light Chains - metabolism; Myosin-Light-Chain Kinase - genetics; Myosin-Light-Chain Kinase - metabolism; Organ Specificity; Phosphorylation; Protein Phosphorylation; Signal Transduction
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M110.160499

In contrast to studies on skeletal and smooth muscles, the identity of kinases in the heart that are important physiologically for direct phosphorylation of myosin regulatory light chain (RLC) is not known. A Ca2+/calmodulin-activated myosin light chain kinase is expressed only in cardiac muscle (cMLCK), similar to the tissue-specific expression of skeletal muscle MLCK and in contrast to the ubiquitous expression of smooth muscle MLCK. We have ablated cMLCK expression in male mice to provide insights into its role in RLC phosphorylation in normally contracting myocardium. The extent of RLC phosphorylation was dependent on the extent of cMLCK expression in both ventricular and atrial muscles. Attenuation of RLC phosphorylation led to ventricular myocyte hypertrophy with histological evidence of necrosis and fibrosis. Echocardiography showed increases in left ventricular mass as well as end-diastolic and end-systolic dimensions. Cardiac performance measured as fractional shortening decreased proportionally with decreased cMLCK expression culminating in heart failure in the setting of no RLC phosphorylation. Hearts from female mice showed similar responses with loss of cMLCK associated with diminished RLC phosphorylation and cardiac hypertrophy. Isoproterenol infusion elicited hypertrophic cardiac responses in wild type mice. In mice lacking cMLCK, the hypertrophic hearts showed no additional increases in size with the isoproterenol treatment, suggesting a lack of RLC phosphorylation blunted the stress response. Thus, cMLCK appears to be the predominant protein kinase that maintains basal RLC phosphorylation that is required for normal physiological cardiac performance in vivo.