Cardiac hypertrophy drives PGC-1α suppression associated with enhanced O-glycosylation.

The peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) regulates metabolism and is essential for normal cardiac function. Its activity is suppressed during pressure overload induced cardiac hypertrophy and such suppression at least partially contributes to the associated morbidity. The O-linked β-N-acetylglucosamine post-translational modification (O-GlcNAc) of proteins is a glucose-derived metabolic signal. The relationship between O-GlcNAc, and PGC-1α activity in cardiac hypertrophy is unknown. We hypothesized that hypertrophy-induced suppression of PGC-1α was at least partially regulated by O-GlcNAc signaling. Treatment of neonatal rat cardiac myocytes with phenylephrine (an inducer of cardiomyocyte hypertrophy) significantly enhanced global O-GlcNAc signaling. Quantitative real-time PCR analysis revealed a downregulation of PGC-1α with concomitant suppression of fatty acid oxidation/mitochondrial genes. Transverse aortic constriction in mice decreased the basal expression of PGC-1α and its downstream genes. Reduction of O-GlcNAc signaling alleviated suppression of PGC-1α and most of its downstream genes. Interestingly, augmentation of O-GlcNAc signaling with glucosamine or PUGNAC (a O-GlcNAcase inhibitor) reduced glucose starvation-induced PGC-1α upregulation even in the absence of hypertrophy. Finally, we found that PGC-1α itself is O-GlcNAcylated. 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 O-GlcNAc signaling and also may have some implications for metabolic dysregulation during cardiac diseases.