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Assessment of the final steps of insulin signaling, inflammatory pathway, oxidative stress, epigenetic mechanism by DNA methylation and GLUT4 expression in the gastrocnemius muscle of adult rats, offspring of rats with Apical Periodontitis

Grant number: 19/04182-2
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): July 01, 2019
Effective date (End): June 30, 2022
Field of knowledge:Health Sciences - Dentistry - Endodontics
Principal Investigator:Doris Hissako Sumida
Grantee:Thaís Verônica Saori Tsosura
Home Institution: Faculdade de Odontologia (FOA). Universidade Estadual Paulista (UNESP). Campus de Araçatuba. Araçatuba , SP, Brazil
Associated scholarship(s):20/10619-1 - Effect of muscle-specific ceramide depletion or induction on insulin sensitivity and muscle growth, BE.EP.DR

Abstract

Fetal programming suggests that adverse stimuli when applied during early fetal development may alter metabolism of offspring, increasing the risk of disease in adulthood. DNA methylation is one of the epigenetic mechanisms involved in this programming and regulates gene expression. Previous studies have shown that maternal Apical Periodontitis (AP) in rats promotes in their adult offspring: insulin resistance, alteration in the initial steps of the Insulin Signaling (IS) in the Gastrocnemius Muscle (GM) and increase in the plasma concentration of tumor necrosis factor-alpha (TNF-alpha). TNF-alpha can activate the nuclear transcription factor kappa B (NF-kB) that decreases the gene expression of the GLUT4 glucose transporter. In this context, more studies are needed to investigate whether changes in IS observed in adult rats, offspring of rats with AP are also present in the continuity of the insulin cascade. In addition, since oxidative stress has been implicated as a contributing factor for both the onset and progression of diabetes, it is fundamental to verify the degree of tissue oxidative stress in this adult offspring. In view of this, the objectives of this study will be to evaluate the insulin sensitivity, oxidative stress, final steps of IS and inflammatory pathway in the GM of adult rats, offspring of rats with AP. For this purpose, 21 female Wistar rats (2 months of age) will be distributed into three groups: 1) control rats (CN); 2) group with one AP induced in the upper right first molar (AP1); 3) group with four APs induced in the first and second upper and lower right molars (AP4). AP will be induced using a surgical round bur measuring 0.1 mm in diameter. After 30 days of pulp exposure, the rats of all groups will be placed for mating. Pregnant rats will be separated into individual cages. When male offspring of all rats complete 75 days of age, the following analyzes will be performed: 1) glycemia and insulinemia; 2) Akt serine/threonine phosphorylation status in GM; 3) GLUT4 content and its plasma membrane translocation index in GM; 4) gene expression of GLUT4 and TNF-alpha in GM; 5) NF-ºB p50 and p65 phosphorylation status in GM; 6) TNF-alpha and PGC-1alpha content in GM; 7) degree of oxidative stress in GM (thiobarbituric acid reactive substances and superoxide dismutase); 8) degree of DNA methylation in the promoter region of the GLUT4 gene in GM. Statistical analysis will be performed by analysis of variance, followed by the Tukey test. The level of significance adopted will be 5%. (AU)