Cardiac redox imbalance upon disruption of selenocysteine decomposition in mice

Dietary selenium (Se) deficiency elevates the risk of cardiometabolic disorders driven by excessive caloric dietary intake. A high-fat diet leads to redox imbalance and elevates lipid deposits in the heart regardless of sex. Selenium maintains redox homeostasis by regulating the levels of antioxidant selenoproteins, such as glutathione peroxidases 1 and 4 (GPX1,4) and thioredoxin reductases 1 and 2. Se-dependent tissues such as the heart have a recycling mechanism to maintain selenoprotein synthesis, especially when Se is limiting, carried out by the enzyme selenocysteine lyase (SCLY). Despite being highly reliant on Se to function properly, it remains unclear if SCLY is required to modulate Se and selenoprotein synthesis in the heart, particularly in obesity. In this study, we analyzed cardiomyocyte (CM) function and molecular modifications in the hearts of male and female whole body <i>Scly</i> knockout (<i>Scly</i> KO) mice fed a Se-deficient, obesogenic diet. We found sex-specific differences demonstrating that the loss of SCLY activity is more detrimental to the hearts of female mice on an obesogenic diet than in male mice, due to reduced glutathione (GSH) peroxidase 1 and 4 expression and decreased circulating Se levels. In addition, overall GPX activity and total GSH levels in <i>Scly</i> KO female hearts resulted in significantly reduced CM contractility. In summary, the loss of <i>Scly</i>, coupled with Se deficiency and a high-fat diet reduces the ability of the GSH system to mitigate oxidative stress in female hearts, increasing redox imbalances that favor the establishment of cardiometabolic disorders.<b>NEW & NOTEWORTHY</b> Global loss of selenocysteine lyase controls the glutathione system in the heart, impacting glutathione peroxidase protein levels and activity, and glutathione levels in a mouse model of obesity. Loss of selenocysteine lyase and selenomethionine deficiency impacts cardiomyocyte function and selenoproteins in a sexually dimorphic nature, with females being affected more than males when mice are on a high-fat diet.