Mog1 deficiency promotes cardiac contractile dysfunction and isoproterenol-induced arrhythmias associated with cardiac fibrosis and Cx43 remodeling
Our earlier studies identified MOG1 as a Nav1.5-binding protein that promotes Nav1.5 intracellular trafficking to plasma membranes. Genetic studies have identified MOG1 variants responsible for cardiac arrhythmias. However, the physiological functions of MOG1 in vivo remain incompletely characterized. In this study, we generated Mog1 knockout ( Mog1 −/− ) mice. Mog1 −/− mice did not develop spontaneous arrhythmias at the baseline, but exhibited a prolongation of QRS duration. Mog1 −/− mice treated with isoproterenol (ISO), but not with flecainide, exhibited an increased risk of arrhythmias and even sudden death. Mog1 −/− mice had normal cardiac morphology, however, LV systolic dysfunction was identified and associated with an increase in ventricular fibrosis. Whole-cell patch-clamping and Western blotting analysis clearly demonstrated the normal cardiac expression and function of Nav1.5 in Mog1 −/− mice. Further RNA-seq and iTRAQ analysis identified critical pathways and genes, including extracellular matrix ( Mmp2 ), gap junction ( Gja1 ), and mitochondrial components that were dysregulated in Mog1 −/− mice. RT-qPCR, Western blotting, and immunofluorescence assays revealed reduced cardiac expression of Gja1 in Mog1 −/− mice. Dye transfer assays confirmed impairment of gap-junction function; Cx43 gap-junction enhancer ZP123 decreased arrhythmia inducibility in ISO-treated Mog1 −/− mice. Transmission electron microscopy analysis revealed abnormal sarcomere ultrastructure and altered mitochondrial morphology in Mog1 −/− mice. Mitochondrial dynamics was found to be disturbed, and associated with a trend toward increased mitochondrial fusion in Mog1 −/− mice. Meanwhile, the level of ATP supply was increased in the hearts of Mog1 −/− mice. These results indicate that MOG1 plays an important role in cardiac electrophysiology and cardiac contractile function.
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