The tissue-specific role of 8-oxoguanine dna glycosylase in skeletal muscle and adipose tissue in energy metabolism
Creators: name: Blaze, Bhavya
Publisher: name: No Publisher Supplied
Year: 2024

description: 8-oxoguanine DNA glycosylase 1(OGG1) is a DNA glycosylase enzyme localized in mitochondria and nucleus. The primary function of OGG1 is to initiate the base excision repair process to repair oxidized guanine. OGG1 function contributes to the maintenance of genomic integrity and thus protects animals from pathological conditions such as cancer, progressive neurological disorders, and metabolic syndrome. Mitochondrial DNA is prone to oxidative damage due to its proximity to proteins involved in oxidative phosphorylation. Guanine has the least oxidation potential among DNA bases, and it gets easily oxidized. The oxidized guanine product, 8-oxo-7,8-dihydrogunanine (8-oxoG) can pair with adenine. Unrepaired oxidized guanine products can cause G·C→T·A transversion. Prior studies have shown that OGG1 deletion in mice can disrupt metabolic homeostasis and decrease skeletal muscle function. Previous studies have also shown that human-OGG1(h-OGG1) overexpression in mice (Ogg1Tg) can protect them from diet-induced obesity and show improved glucose tolerance. All these metabolic studies have been done on whole-body knockout mice or on whole-body transgenic mice. We still did not know the tissue-specific role OGG1 plays in the metabolism of mice. To elucidate the OGG1 role in major metabolic organs, RNA-Seq analyses in the liver, skeletal muscle (SM), and adipose tissue (AT) were performed. The AT and SM of Ogg1Tg mice showed significant differential expression of genes. The liver of Ogg1Tg, however, showed a minimal difference. We used Ogg1Tg mice to study the role of OGG1 in skeletal muscle function. Our study shows that when OGG1 is overexpressed mice have improved skeletal muscle function. Ogg1Tg mice showed more than two times exercise endurance enabled by a higher skeletal muscle glycogen content. Ogg1Tg mice also showed increased muscle lipid and a higher mitochondrial content in the muscle. The skeletal muscle of Ogg1Tg mice showed more than a thousand-fold increase in the myokine Fgf21 expression. Together, these results show that OGG1 in the skeletal muscle of Ogg1Tg mice is better functioning due to improved mitochondrial functioning and FGF21 action. Two novel conditional knockout mice were developed and used to study the tissue-specific contribution of OGG1 in modulating whole body energy metabolism. In the adipocyte OGG1 knockout mice (AKO) mice, OGG1 in the adipocyte was deleted under adiponectin CRE promoter and was used to study the role of adipocyte OGG1 in the modulation of whole-body energy metabolism. The skeletal muscle OGG1 conditional knockout mice (MKO) was developed under human--actin promoter to study the role skeletal muscle OGG1 plays in whole-body energy metabolism. The AKO mice were prone to diet- induced obesity with a decrease in glucose clearance after 12 weeks of 60% high-fat-diet (HFD). AKO mice showed delayed glucose clearance and dyslipidemia, as shown through higher plasma triglyceride (TAG). MKO mice showed a better glucose clearance after the 12-week HFD and showed no evidence of dyslipidemia and diet-induced obesity. The exercise endurance of MKO mice was lower compared to the control mice. This thesis proves that OGG1 plays a tissue-specific role in modulating metabolism under different conditions, such as acute exercise and a hypercaloric diet in which 60% of the total calories are derived from fat.