THE EFFECT OF EXERCISE ON PGC1 EPIGENETIC CHANGES: ITS IMPACT ON TYPE 2 DIABETES MELLITUS

Coordinator: SANDRA APARECIDA BENITE RIBEIRO
The worldwide prevalence of type 2 diabetes is increasing and the intramuscular accumulation of fatty acid metabolites is gradually recognized as a central feature of this condition, since lipotoxicity induces insulin resistance. Emerging evidence suggests that defects in mitochondria, key organelles in lipid metabolism, play a central role in insulin resistance. Mitochondrial homeostasis is tightly regulated by a nucleus-mitochondria signaling pathway and peroxisome proliferator-activated receptor γ coactivator-1α (PGC1) is the main regulator of important mitochondrial processes. PGC1 is downregulated in insulin-resistant skeletal muscle, and abnormal post-translational histone modification, epigenetic modifications, are becoming an important factor. Studies have shown the benefits of regular exercise in improving insulin sensitivity, but the mechanism for this result is not fully identified. Therefore, the submitted project aims to verify the effect of aerobic exercise on the epigenetic modification of PGC1 and mitochondrial function in type 2 diabetic animals. For this, Wistar rats will be induced to type 2 diabetes by the combination of a low dose of streptozotocin and a high-calorie diet. Non-diabetics of the same age will be used as controls. After the diabetic induction protocol, half of the animals will perform 6 weeks of aerobic exercise and swimming, and the other half will be kept at rest. Finally, blood and gastrocnemius muscle will be collected and insulin resistance by HOMA, histone modification at the PGC1 promoter, number and function of mitochondrial biogenesis and glucose transporter (GLUT4) will be evaluated. We expect that animals with type 2 diabetes will show decreased histone acetylation (Ac-H3K9) and increased histone methylation (H3K9-3me) at the PGC1 promoter, representing the repression of this gene. In addition, we believe that diabetes will induce subnormal biogenesis, function and number of mitochondria and GLUT4 expression. Furthermore, we expect that physical exercise will attenuate the effect of diabetes on the PGC1 promoter and that this may reverse the effect of diabetes on mitochondria and GLUT4, in addition to improving insulin resistance. This project will be carried out at the Department of Physiology of the Federal University of Goiás during 2014 and 2015. We are confident that the results will contribute to the understanding of the mechanism underlying the development of diabetes and the beneficial effects of aerobic exercise as a treatment for this alarming disease.