A Human Genetic Mechanism for Endurance Running

Humans are unusual among primates in being capable of sustained long-distance running, a key phenotype that emerged in genus Homo about 2 million years ago (Mya). The underlying genetic changes that defined this exercise phenotype are not well understood. About 2-3 mya, an exon deletion in the CMP-Neu5Ac hydroxylase (CMAH) gene became fixed in our ancestral lineage, completely eliminating the hydroxylase activity required to add an oxygen atom to the sialic acid Neu5Ac to form Neu5Gc. Thus unlike the case in other old world primates, human cells do not express Neu5Gc, and instead have an excess of Neu5Ac on cell surfaces and secreted glycoconjugates. Modeling Cmah loss in mice allows us to explore potential mechanisms involved in the evolution of this hominin endurance phenotype. Untrained Cmah-/- mice demonstrate a remarkable increase in endurance during treadmill running exercise and voluntarily run further and faster when housed with a running wheel. Cmah-/- mice also exhibit skeletal muscle adaptations that are known to occur in exercise training, including more capillaries, enhanced mitochondrial respiration and greater fatigue resistance, despite remaining sedentary. Metabolic pathway analysis of sedentary and exercise trained Cmah-/- mice reveal increased and decreased patterns in Cmah-/- mice that augment those that occur with exercise training. In particular, elevations in amino acid and pentosphosphate pathways were identified. Taking a closer look at the final steps of the oxygen transport in peripheral skeletal muscle, our data suggest that loss of Camh-/- may allow for more efficient transfer of oxygen from Hb in red blood cells to deoxy-Mb, increased endothelial cell permeability and, enhanced mitochondrial activation in Cmah-/- myofibers at very low, near limiting extracellular oxygen levels for mitochondrial respiration. Taken together, these data suggest that CMAH loss may have contributed to multiple adaptations in genus Homo that improved skeletal muscle capacity for oxygen delivery and/or utilization, and perhaps provided a selective advantage during the transition towards persistence hunting and other features of Homo, such as increased foraging range and resource exploration.