Mimicking Human Cmah Inactivation in Mice Increases Running Endurance and Muscle Respiratory Capacity: Implications for the Evolution of Genus Homo

Compared to other primates, humans are exceptional long‐distance runners, a characteristic that emerged in genus Homo ~2 million years ago (mya), and is generally attributed to anatomical and physiological adaptations such as striding bipedalism and improved heat dissipation. Deletion of a critical exon in the CMAH gene also became fixed 2–3 mya in our ancestral lineage––eliminating CMAH enzymatic activity, which generates the major cell surface sialic acid Neu5Gc, by adding one oxygen atom to the Neu5Ac precursor. Modeling Cmah loss in mice suggested a fertility‐dependent role in emergence of genus Homo and its absence exacerbates human‐like muscular dystrophy phenotypes. Considering these seemingly disparate clues, we posited a role for CMAH loss in the evolution of the hominin endurance phenotype, and evaluated exercise capacity and skeletal muscle oxygen metabolism of Cmah−/− mice. Untrained Cmah−/− mice demonstrated an increased endurance during treadmill running and ran further and faster during 15 days of voluntary running, compared to WT littermates. Time to fatigue during repeated in situ contractions of hind limb muscles was >2‐fold higher in Cmah−/− mice, and a higher capillary‐to‐myofiber ratio was noted. Maximal ex vivo oxidative phosphorylation in muscle fibers was also higher in Cmah−/− mice, and relevant differences in metabolic pathways were noted. Taken together, these data suggest that CMAH loss likely triggered multiple adaptations in the genus Homo that improved skeletal muscle capacity for oxygen delivery and/or utilization––leading to enhanced aerobic capacity, and perhaps providing a selective advantage during the transition towards persistence hunting and other features of Homo.Support or Funding InformationThis work was supported by National Institutes of Health Grants R01GM32373 and R01AR060949This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.