FBS Colloquia No.275Laboratory of Medical Biochemistry

Cardiac myosin light chain kinase regulates the sarcomere contractility and organization in cardiomyocytes

We previously identified the MYLK3 gene that encodes cardiac-specific myosin light chain kinase (cMLCK) by analyzing the gene expression profile of cardiac tissue from patients with severe heart failure who underwent heart transplantation (Takashima S et al. JCI. 2007; 117: 2812-2824). cMLCK is the kinase predominantly responsible for the maintenance of the basal phosphorylation level of cardiac myosin regulatory light chain (MLC). By Phosphorylating the ventricular isoform of MLC (MLC2v), cMLCK not only enhances the contractility but also regulates sarcomere assembly in the vertebrate cardiac myocytes. In fact, the ablation of MYLK3 gene results in reduced contractility and dilation of the left ventricle in mice. Intriguingly, MLC2v phosphorylation level was reduced in human failing hearts. However, the pathophysiological role of cMLCK in human heart failure still remains largely unknown. We have recently identified the dilated cardiomyopathy (DCM) family associated with a frameshift mutation in MYLK3 (c1951-1 g>t; p.Pro639Valfs*15), which results in a defect of the kinase activity (Hodatsu A et al. ESC Heart Fail. 2019;6:406-415). However, the functional consequences of the p.Pro639Valfs*15 mutation remains unknown. In this study, we performed the functional analysis of the p.Pro639Valfs*15 mutation to elucidate the importance of cMLCK in heart failure.