OGG1 increases exercise endurance via elevated skeletal muscle FGF21

The base excision repair 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 diseases. Base excision repair proteins also modulate body weight and metabolic health. Mice lacking OGG1 are susceptible to obesity and its sequelae, whereas overexpression of human OGG1 (in OGG1-transgenic mice; Ogg1^Tg mice) reverses these metabolic defects. We report here that OGG1 overexpression induces a remarkable over threefold 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, fibroblast growth factor 21 (Fgf21), in skeletal muscle of Ogg1^Tg 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.