Human-like Cmah inactivation in mice increases running endurance and decreases muscle fatigability: implications for human evolution

Compared to other primates, humans are exceptional long-distance runners, a feature that emerged in genus Homo ~2 million years ago (mya) 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-three mya, an exon deletion in the CMP-Neu5Ac Hydroxylase (CMAH) gene also became fixed in our ancestral lineage. Cmah loss 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 of Cmah-/- 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 resistance in situ. Maximal coupled respiration was also higher in Cmah null mice ex vivo and relevant differences in metaboli...