Methylglyoxal and Glyoxalase 1 Metabolism in Skeletal Muscle: Effect of Type 2 Diabetes and Exercise

Dicarbonyl stress and the glyoxalase system are emerging factors related to the development and progression of type 2 diabetes and associated complications. However, despite the essential role that skeletal muscle health plays in maintaining glucose homeostasis and preventing the onset of type 2 diabetes, dicarbonyl stress and the glyoxalase system have not been well investigated in this highly metabolic tissue. Thus, the purpose of this research was to characterize skeletal muscle dicarbonyl stress, the glyoxalase system and their respective regulatory mechanisms in the context of type 2 diabetes and to further elucidate their role in skeletal muscle specific mechanisms by utilizing a clinical-translation approach. The results of this research describe increased dicarbonyl stress and aberrant glyoxalase system regulation in the skeletal muscle of individuals with type 2 diabetes, while a chronic, intense lifestyle intervention rescued major components of dicarbonyl stress and the glyoxalase system. These clinical results were supplemented by cell culture studies which described skeletal muscle specific mechanisms of dicarbonyl stress and glyoxalase system regulation in the context of type 2 diabetes pathology and preventative treatments. In conclusion, this research depicts a dysregulation of dycarbonyl stress and the glyoxalase system in insulin resistant skeletal muscle and illustrates a role for exercise and metformin, the first line pharmacological therapy for insulin resistance, on dicarbonyl and glyoxalase biology. Further investigation is warranted to understand the therapeutic potential of targeting these pathways in skeletal muscle.