Hexosamine Signaling Mediates Peroxisome Proliferator‐Activated Receptor‐gamma Coactivator (PGC)‐1alpha Suppression During Cardiac Hypertrophy

The peroxisome proliferator‐activated receptor‐gamma coactivator‐1α (PGC‐1α) is essential for normal cardiac function. The O‐linked β‐N‐acetylglucosamine post‐translational modification (O‐GlcNAc) of proteins is a glucose‐derived metabolic signal. The relationship between O‐GlcNAc modification and PGC‐1α activity in hypertrophy is unknown. We hypothesized that the metabolic switch from fatty acids to glycolysis during hypertrophy would involve augmented O‐GlcNAc signaling. Transverse aortic constriction in mice in vivo or treatment of neonatal rat cardiac myocytes with phenylephrine significantly enhanced (p<0.05) global O‐GlcNAc signaling and augmented O‐GlcNAc transferase (OGT: adds O‐GlcNAc to proteins) expression. Quantitative real‐time PCR analysis revealed a downregulation of PGC‐1α with concomitant suppression of fatty acid oxidation and mitochondrial biogenesis genes. Reduction of O‐GlcNAc signaling partially rescued the cells from hypertrophic changes (i.e. ANP mRNA elevation), and, reversed the effect of in vitro hypertrophy on PGC‐1α levels and on most of its regulated downstream genes. Interestingly, augmentation of O‐GlcNAc signaling with glucosamine markedly reduced PGC‐1α activity, in the absence of hypertrophy. Similarly, basal expression of PGC‐1α and its downstream genes was elevated in cardiac specific OGT knockout mice. Together, these results reveal the recruitment of O‐GlcNAc signaling as a potentially novel regulator of PGC‐1α activity during cardiac hypertrophy. Furthermore, O‐GlcNAc signaling may mediate constitutive suppression of PGC‐1α activity in the heart. Such findings illuminate new possibilities regarding the inter‐regulation of glycolytic and fatty acid metabolism. Financial support: NIH, American Heart Association