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 (C) 2010 Elsevier Inc All rights reserved