Deficiency of methionine sulfoxide reductase A causes cellular dysfunction and mitochondrial damage in cardiac myocytes under physical and oxidative stresses

Methionine sulfoxide reductase A (MsrA) is an enzyme that reverses oxidation of methionine in proteins. Using a MsrA gene knockout (MsrA−/−) mouse model, we have investigated the role of MsrA in the heart. Our data indicate that cellular contractility and cardiac function are not significantly changed in MsrA−/− mice if the hearts are not stressed. However, the cellular contractility, when stressed using a higher stimulation frequency (2 Hz), is significantly reduced in MsrA−/− cardiac myocytes. MsrA−/− cardiac myocytes also show a significant decrease in contractility after oxidative stress using H2O2. Corresponding changes in Ca2+ transients are observed in MsrA−/− cardiomyocytes treated with 2 Hz stimulation or with H2O2. Electron microscope analyses reveal a dramatic morphological change of mitochondria in MsrA−/− mouse hearts. Further biochemical measurements indicate that protein oxidation levels in MsrA−/− mouse hearts are significantly higher than those in wild type controls. Our study demonstrates that the lack of MsrA in cardiac myocytes reduces myocardial cell’s capability against stress stimulations resulting in a cellular dysfunction in the heart.

Research highlights
► Deficiency of MsrA in the heart renders myocardial cells more sensitive to oxidative stress.
► Mitochondrial damage happens in the heart lacking MsrA.
► More protein oxidation in myocardial cells lacking MsrA.
► MsrA protects the heart against oxidative stress.