OGG1 increases exercise endurance via elevated skeletal muscle FGF21

The base excision repair (BER) pathway maintains genomic integrity in the face of oxidative insult. It is initiated by DNA glycosylases such as 8-oxoguanine DNA glycosylase (OGG1) and is implicated in various pathologies such as cancers and neurodegenerative disease. BER proteins also modulate body weight and metabolic health. Mice lacking OGG1 are susceptible to obesity and its sequelae, while overexpression of human OGG1 (in OGG1-transgenic; Ogg1Tg mice) reverses these metabolic defects. We report here that OGG1 overexpression induces a remarkable over 3-fold increase in muscle endurance. This is accompanied by significant increases in muscle mitochondrial content and size and a selective increase in expression of the myokine, Fgf21, in skeletal muscle of Ogg1Tg mice. Together with elevated circulating FGF21 levels and peripheral markers of FGF21 action, these data demonstrate a novel role for skeletal muscle OGG1 in modulating mitochondrial health and muscle endurance via FGF21 secretion and signaling.