Abstract 2214 Tissue specific role of OGG1 in mice skeletal muscle

The DNA glycosylase, 8-Oxoguanine glycosylase (OGG1), catalyzes the excision of oxidized guanine via the base excision DNA repair process. Previous studies have shown that Ogg1 gene deletion increased the susceptibility to tumors and neurodegenerative diseases in animals. Mice with whole body deletion of Ogg1 previously showed increased adiposity and metabolic syndrome when challenged with a high fat diet. Ogg1 transgenic mice (Ogg1Tg) with overexpressed human OGG1 are resistant to obesity and metabolic syndrome after hypercaloric diet feeding. The current study investigated the role of OGG1 in skeletal muscle energy metabolism. All in vivo experiments were carried out humanely and breeding and the care of animals were per the protocols approved by the Animal Care and Use Committee of Rutgers University, New Brunswick, NJ, USA (Protocol ID: 201900077). Unbiased transcriptomic analysis of multiple tissues revealed numerous differentially expressed genes in skeletal muscle of Ogg1Tg mice. Among these, the gene encoding for the myokine Fibroblast Growth Factor 21 (Fgf21) was one of the most highly induced genes with both RNA-Seq and qRT-PCR revealing a 1061-fold induction of Fgf21 in skeletal muscle of Ogg1Tg mice. Hepatic and cardiac expression of Fgf21 were unchanged. Conversely, Ogg1-/- mice displayed a 25% reduction in muscle Fgf21 expression. Corresponding with these changes in gene expression, plasma FGF21 levels were elevated by over 11-fold in Ogg1Tg mice, while, Ogg1-/- mice showed a 29 % reduction in plasma FGF21. Consistent with increased FGF21 activity, phosphorylation of AMP-activated protein kinase (AMPK) was increased in the muscle of Ogg1Tg mice,. Previous studies have shown that FGF21 induces PGC1α, leading to increased mitochondrial biogenesis. We discovered that Ogg1Tg mice also demonstrated increased PGC1α and a higher mitochondrial content in the skeletal muscle, concomitant with their elevated FGF21 levels. Interestingly, these elevations in FGF21 and mitochondrial content were accompanied by striking gains in exercise endurance in Ogg1Tg mice. When subjected to acute treadmill exercise, both young and old Ogg1Tg mice, showed 2.3 to 1.9 -fold increase in exercise capacity compared to age matched WT controls. To further test a tissue-sepcific role for OGG1 in modulating exercise endurance, we generated, skeletal muscle specific OGG1 knockout mice that displayed a significant 25% reduction in exercise tolerance, similar to the whole body Ogg1-/- animals. These results collectively uncover a novel role for muscle OGG1 in modulating exercise tolerance via alteration in FGF21 and mitochondrial homeostasis.