Genes Whose Gain or Loss-of-Function Increases Endurance Performance in Mice: A Systematic Literature Review.

Endurance is not only a key factor in many sports but endurance-related variables are also associated with good health and low mortality. Twin and family studies suggest that several endurance-associated traits are ≈50% inherited. However, we still poorly understand what DNA sequence variants contribute to endurance heritability. To address this issue, we conducted a systematic review to identify genes whose experimental loss or gain-of-function increases endurance capacity in mice. We found 31 genes including two isoforms of whose manipulation increases running or swimming endurance performance by up to 1800%. Genes whose gain-of-function increases endurance are , (Pepck) (both the a and b isoforms of the protein Pgc-1α), (calcineurin) & . Genes whose loss-of-function increases endurance in mice are . Of these genes, human DNA sequence variants of , , , , , , , , and are also associated with endurance capacity and/or VOmax trainability suggesting evolutionary conservation between mice and humans. Bioinformatical analyses show that there are numerous amino acid or copy number-changing DNA variants of endurance genes in humans, suggesting that genetic variation of endurance genes contributes to the variation of human endurance capacity, too. Moreover, several of these genes/proteins change their expression or phosphorylation in skeletal muscle or the heart after endurance exercise, suggesting a role in the adaptation to endurance exercise.