A proposed mechanism for exercise attenuated methylglyoxal accumulation: Activation of the ARE-Nrf pathway and increased glutathione biosynthesis

Abstract

The dicarbonyl methylglyoxal (MGO) is an endogenous metabolite and a known intracellular precursor of advanced glycation endproducts (AGEs). High serum levels of MGO have been correlated with MGO-derived AGEs in individuals with type 2 diabetes (T2DM). Furthermore, there is human and animal evidence to suggest that MGO is causal in copious pathologies related to AGE accumulation including heart disease, hypertension, nephropathy and insulin resistance. MGO is detoxified through the glutathione (GSH) dependent glyoxalase system and diminished glutathione status results in impaired MGO detoxification. Individuals with uncontrolled T2DM have diminished GSH status, suggesting the increase in serum MGO can be partially attributed to impaired MGO detoxification. GSH biosynthesis is heavily dependent upon the antioxidant response element-nuclear respiratory factor pathway (ARE-Nrf) and pharmacological and dietary intervention studies have demonstrated that activation of the ARE-Nrf pathway increases intracellular GSH and glyoxalase enzymes and reduces MGO levels. Acute and chronic exercise has also been shown to increase activation of the ARE-Nrf pathway and GSH biosynthesis, and to improve GSH status. Therefore, we propose that exercise improves MGO detoxification and attenuates MGO accumulation by increasing GSH biosynthesis and improving GSH status through activation of the ARE-Nrf pathway. © 2013 Elsevier Ltd.