O‐GlcNAc Transferase Deficiency Exacerbates Metabolic Defects in the Failing Heart

Abstract

The peroxisome proliferator activated receptor gamma coactivator‐1alpha (PGC‐1α) is a transcriptional activator of many metabolic genes, especially those used in the metabolism of fatty acids. Within the failing heart, a metabolic shift occurs from utilizing mainly fatty acids to relying more on glycolysis. Concurrent with this shift is a reduction in the expression of PGC‐1α and an increase in the glucose‐derived, metabolic post‐translational modification O‐GlcNAc. We hypothesized that O‐GlcNAc signaling would play a role in the control of PGC‐1α during this metabolic change. We subjected wild‐type mice to coronary ligation (HF) or sham. After five days both PGC‐1α and PGC‐1 α levels were significantly reduced (p<0.05) and O‐GlcNAc levels significantly elevated (p<0.05). Using the MerCreMer transgene system coupled with a loxP‐flanked OGT mouse, a cardiomyocyte specific OGT 'KO' was made. After tamoxifen induction, cardiac OGT and O‐GlcNAc levels were significantly reduced (p<0.05) in the transgenic (Tg) group. NTg and Tg mice underwent HF or sham surgery and tissues were harvested after 5 days. Following HF, Tg mice exhibited a greater reduction in PGC levels (figure A, p>0.05) than their NTg counterparts. We conclude that ablation of OGT exacerbates the suppression of PGC‐1α in the failing heart.Funded by the NIH and American Heart Association.