Compared to other primates, humans are exceptional long-distance runners, a feature that emerged in genusHomoapproximately 2 Ma and is classically attributed to anatomical and physiological adaptations such as an enlarged gluteus maximus and improved heat dissipation. However, no underlying genetic changes have currently been defined. Two to three million years ago, an exon deletion in the CMP-Neu5Ac hydroxylase (CMAH) gene also became fixed in our ancestral lineage.Cmahloss in mice exacerbates disease severity in multiple mouse models for muscular dystrophy, a finding only partially attributed to differences in immune reactivity. We evaluated the exercise capacity ofCmah−/−mice and observed an increased performance during forced treadmill testing and after 15 days of voluntary wheel running.Cmah−/−hindlimb muscle exhibited more capillaries and a greater fatigue resistancein situ. Maximal coupled respiration was also higher inCmahnull miceex vivoand relevant differences in metabolic pathways were also noted. Taken together, these data suggest thatCMAHloss contributes to an improved skeletal muscle capacity for oxygen use. If translatable to humans,CMAHloss could have provided a selective advantage for ancestralHomoduring the transition from forest dwelling to increased resource exploration and hunter/gatherer behaviour in the open savannah.