Cardiac Myosin Light Chain Kinase is Essential for Myosin Regulatory Light Chain Phosphorylation and Normal Cardiac Function in vivo

Abstract

In contrast to studies on skeletal and smooth muscles, protein kinases that are important physiologically for direct phosphorylation of myosin regulatory light chain (RLC) in the heart are not known. Expression of a Ca2+/calmodulin-activated myosin light chain kinase found only in cardiac muscle (cMLCK) was ablated in mice. The extent of RLC phosphorylation was dependent on the extent of cMLCK expression in both ventricular and atrial muscles. Lack of cMLCK and RLC phosphorylation led to (1) ventricular hypertrophy demonstrated by increased heart weight to tibial length ratios, (2) myocyte hypertrophy and (3) histological evidence of necrosis and fibrosis. Loss of MLC2v phosphorylation led to compromised cardiac function evidenced by echocardiography showing a proportional decrease in systolic performance assessed as percent fractional shortening from 71% in wildtype mice to 34% for hearts with no cMLCK. Declines in cardiac function were associated with ventricular dilation and progressive increases in left ventricular end-systolic and end-diastolic dimensions. Hearts from female mice showed similar responses to loss of cMLCK including diminished RLC phosphorylation and significant ventricular hypertrophy. Prolonged isoproterenol infusion elicited hypertrophic cardiac responses in wildtype 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 which is required for normal physiological cardiac performance in vivo. Supported by NIH NHLBI.