Humans and chimpanzees are more sensitive to endotoxin than mice or monkeys, but any underlying differences in inflammatory physiology have not been fully described or understood. We studied innate immune responses in Cmah−/− mice, emulating human loss of the gene encoding production of Neu5Gc, a major cell surface sialic acid. CMAH loss occurred ~2-3 million years ago, after the common ancestor of humans and chimpanzees, perhaps contributing to speciation of the genus Homo. Cmah−/− mice manifested a decreased survival in endotoxemia following bacterial lipopolysaccharide (LPS) injection. Macrophages from Cmah−/− mice secreted more inflammatory cytokines with LPS-stimulation and showed more phagocytic activity. Macrophages and whole blood from Cmah−/− mice also killed bacteria more effectively. Metabolic re-introduction of Neu5Gc into Cmah−/− macrophages suppressed these differences. Cmah−/− mice also showed enhanced bacterial clearance during sub-lethal lung infection. Although monocytes and monocyte-derived macrophages from humans and chimpanzees exhibited marginal differences in LPS responses, human monocyte-derived macrophages killed E. coli and ingested E. coli bioparticles better. Metabolic re-introduction of Neu5Gc into human macrophages suppressed these differences. While multiple mechanisms are likely involved, one cause is altered expression of C/EBPβ, a transcription factor affecting macrophage function. Loss of Neu5Gc in Homo likely had complex effects on immunity, providing greater capabilities to clear sub-lethal bacterial challenges, possibly at the cost of endotoxic shock risk. This trade-off may have provided a selective advantage when Homo transitioned to butchery using stone tools. The findings may also explain why the Cmah−/− state alters severity in mouse models of human disease.

Compared to other primates, humans are exceptional long-distance runners, a feature that emerged in genus approximately 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 () gene also became fixed in our ancestral lineage. 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 mice and observed an increased performance during forced treadmill testing and after 15 days of voluntary wheel running. hindlimb muscle exhibited more capillaries and a greater fatigue resistance Maximal coupled respiration was also higher in null mice and relevant differences in metabolic pathways were also noted. Taken together, these data suggest that loss contributes to an improved skeletal muscle capacity for oxygen use. If translatable to humans, loss could have provided a selective advantage for ancestral during the transition from forest dwelling to increased resource exploration and hunter/gatherer behaviour in the open savannah.

No abstract

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.