Cardiac O-GlcNAc levels variation with age: Impact of suckling to weaning transition

Abstract

O-GlcNAcylation is a well-preserved, ubiquitous, post-translational modification, involved in the reprogramming of cardiac metabolism to enhance stress adaptation and acute cardiac O-GlcNAc stimulation is associated with beneficial effects. Two enzymes regulate O-GlcNAc levels: (i) O-GlcNAc Transferase (OGT) and (ii) O-GlcNAcAse (OGA) which adds and removes the GlcNAc residue respectively. GFAT, the rate-limiting enzyme of the hexosamines biosynthesis pathway (HBP), modulates O-GlcNAc levels through cellular metabolism. Cardiac metabolism varies during the first days of life with an important transition after birth, from carbohydrate in utero, to fatty acid in adults. Interestingly, hearts are less sensitive to ischemic stress during the first day of life. Study the variations in O-GlcNAc level and regulator during aging. Hearts were harvested from Wistar rats before and after birth (D-1 and D0), before and after weaning (D12 and D28) with a carbohydrate free diet (CHO-F) (D28F) to avoid metabolic transition and adult (D84). O-GlcNAc levels, GFAT, OGT and OGA protein and gene expression were evaluated. A Click-iT technique was used to identify O-GlcNAcylated proteins at D0 and/or D28. Cardiac O-GlcNAc levels decrease from D-1 to D84 (13 fold), along with GFAT1 (50 fold) and GFAT2 (10 fold) and OGT (6 fold) while OGA is nearly undetectable at D-1 and increases over development. Interestingly, metabolism had no impact on cardiac O-GlcNAc levels however CHO-F diet reduces OGA expression (5 fold). The mass spectrometry analysis allows to identify potential protein of interest as they can play an important role in stress response, transcription and metabolism. O-GlcNAcylation levels decrease throughout aging and are independent of metabolism. Proteins identified in mass spectrometry need to be explored more specifically now to evaluate the potential involvement of O-GlcNAc levels in stress response in young.