ROLE OF SIRT1 IN THE OVARIAN ADAPTIVE RESPONSE TO METHYLGLYOXAL-INDUCED DICARBONYL STRESS

Dicarbonyl stress is caused by an imbalance of the formation of dicarbonyl metabolites such as methylglyoxal (MG), a major precursor of advanced glycation end products (AGEs). In the ovary, dicarbonyl stress is associated with reproductive aging and polycystic ovarian syndrome (PCOS) [1]. In the present study we have investigated the possible role of the NAD(+)-dependent Class III- deacetylase SIRT1, a sensor of the redox state in oocytes and ovary [2], in the ovarian adaptive response to MG. We observed that MG-induced upregulation of glyoxalases 2 gene, a component of the MG detoxification enzymatic system, was prevented by oocyte exposure to the SIRT1 inhibitor EX527. Moreover, the inhibition of SIRT1 worsened the effects of MG on oocyte maturation rates. In order to study the ovarian response to MG in an in vivo model, female CD1 mice received 100 mg/kg MG by gastric administration for 28-days [3]. Western blotting analysis revealed that MG intake increased SIRT1 ovarian levels along with over-expression of catalase, superoxide dismutase 2, SIRT3, and PGC1α. Protein expression of glyoxalase 1, the main MG detoxifying enzyme, enhanced in MG mice whereas MG-AGEs remained unchanged. Although control and MG mice showed similar ovarian reserve and ovulation rate, oocytes ovulated by MG mice exhibited abnormal meiotic spindles, a condition predisposing to embryo aneuploidy. Our results suggest that MG triggers in oocytes and ovary an ovarian adaptive response involving a SIRT1 signalling and anti-glycation defence, which prevents MG-AGE accumulation, but negatively affects oocyte development.