An optimized plasmalogen modulating dietary supplement provides greater protection in a male than female mouse model of dilated cardiomyopathy

We previously reported that plasmalogens, a class of phospholipids, were decreased in a setting of dilated cardiomyopathy (DCM). Plasmalogen levels can be modulated via a dietary supplement called alkylglycerols (AG) which has demonstrated benefits in some disease settings. However, its therapeutic potential in DCM remained unknown. To determine whether an optimized AG supplement could restore plasmalogen levels and attenuate cardiac dysfunction/pathology, we placed a cardiac-specific transgenic DCM mouse model of both sexes on chow +/−1.5 % AG supplementation at ∼10 weeks of age for 16 weeks. Cardiac function was assessed by echocardiography, tissues were collected for histological and molecular analyses including lipidomics and proteomics via liquid chromatography-mass spectrometry. AG supplementation increased total plasmalogens in DCM hearts and attenuated lung congestion of both sexes, but only prevented cardiac dysfunction in males. This was associated with attenuated cardiac and renal enlargement, a more favorable pro-cardiac gene expression profile, and a trend for lower cardiac fibrosis. By lipidomics, specific d18:1 ceramide species associated with cardiac pathology were lower in the DCM hearts from mice on the AG diet, and tetralinoleoyl cardiolipins, a lipid crucial for mitochondrial function was restored with AG supplementation. Proteomic analysis of hearts from male DCM mice receiving AG supplementation revealed enrichment in mitochondrial protein network, as well as upregulation of extracellular matrix binding proteins including agrin, a protein associated with cardiac regeneration. In summary, AG supplementation restored plasmalogens in DCM hearts but showed greater therapeutic potential in males than females.