The role of sestrin-AMPK-mTORC11 pathway on cardiac remodeling in rats fed a high-fructose diet

Background and Aim: Previous studies have been demonstrated that AMPK activation and mTORC1 inhibition, along with sestrins, which are stress-inducible intracellular proteins, may play reducing role in cardiac hypertrophy. However, no study has been found investigating the AMPK-mTORC1 pathway together with sestrin1/2/3 expressions in fructose-rich diet (FRD)-induced cardiac remodeling. This study aimed to investigate the role of the sestrin1/2/3-AMPK-mTORC1 pathway in FRD-induced cardiac remodeling and also in the case of administration of an AMPK activator metformin, alongside FRD. Material and Methods: Sprague-Dawley female 32 adult rats were grouped as Control (F), Metformin (Met), Fructose (F), Fructose+Metformin (FMet), and fed ad libitum for ten weeks. Drinking water was given to K and Met groups, and 200gr/L fructose solution was given to F and FMet groups. In the last two weeks, intraperitoneal metformin (100mg/kg/day) injection was administered to the Met and FMet groups. Sestrin1/2/3 gene expressions in the left ventricle were analyzed by Real-Time PCR and sestrin1/2/3, AMPK, p-AMPK, P70S6K, which is a substrate of mTORC1, and p-P70S6K protein levels were determined with commercial ELISA kits. Left ventricular tissue was examined histopathologically. In statistical analysis, Kruskal-Wallis and Dunn test with Bonferroni correction were used. Results: Cardiomyocyte diameter (all p<0.05) and percentage of fibrotic areas in cardiac tissue (all p<0.01) were found to be higher in F and FMet groups compared to Met and K groups. p-P70S6K protein levels, which indicate mTORC1 activation, were higher in the F group than in the K and Met groups (p<0.05) and did not change in the FMet group. Sestrin1/2/3, AMPK, p-AMPK and P70S6K protein levels were found to be similar in all groups. Sestrin 1 gene expression was found to be higher in the FMet group than in the Met group (p<0.05). Conclusion: Fructose-rich diet increases mTORC1 activation without altering sestrin1/2/3 protein-gene expression and AMPK activation in the left ventricle and increases myocyte diameter and fibrotic area in the myocardium. Our study suggests that the increase in mTORC1 activation occurs independently of sestrins and AMPK. In addition, the increase in sestrin 1 gene expression due to metformin administration with FRD thought that sestrin 1 levels may be primarily affected by the sestrin1/2/3-AMPK-mTORC1 pathway. Keywords: AMPK, cardiac hypertrophy, fructose, metformin, mTORC1, sestrins