Loss of Neu5Gc during Human Evolution: Impact on Macrophage Inflammation and Muscle Metabolism

Around 2-3 million years ago, Alu-mediated deletion of a critical exon in the CMAH gene became fixed in the hominin lineage ancestral to humans and may have contributed to the speciation of Homo. Although CMAH loss has occurred independently in some other animal lineages, it is functionally intact in Old World primates, including our closest relatives, the chimpanzees. Chapter 1 is a thorough but concise review of the known consequences of Neu5Gc loss. We have speculated that hominin CMAH loss contributes to human evolution, at a time where our ancestors were using stone tools, increasing their consumption of meat, and possibly hunting. In Chapter 2, we show that when modeling Cmah loss in mice, they manifest a decreased survival in endotoxemia following bacterial lipopolysaccharide (LPS)injection. Macrophages and whole blood from Cmah-/- mice also killed E. coli K12 bacteria more effectively and this appears to be a conserved difference between humans and chimpanzees. While multiple mechanisms are likely involved, one causeis altered expression of C/EBPβ, a transcription factor affecting macrophage function that can be differentially expressed by simply feeding Neu5Gc to Cmah-/- macrophages. In Chapter 3, we show that Cmah-/- mice have a greater exercise capacity. Remarkably, the gastrocnemius complex time to fatigue measured in situ was more than 2-fold higher in non-exercise trained Cmah-/- mice when compared to WT controls. Mechanistically, the capillary to muscle fiber ratio is higher in Cmah-/- soleus, which could be contributing to a greater oxygen delivery during fatigue testing. After exercise training, metabolites in the pentose phosphate pathway and amino acid metabolism are also enriched in exercise-trained Cmah-/- soleus compared to WT, indicating a greater anabolic response. C/EBPδ, a transcription factor involved in regulation of metabolic and inflammatory pathways is also differentially expressed in Cmah-/- muscle. Therefore, we propose that the loss of CMAH in Homo likely allowed for greater bacterial killing and a greater maximum aerobic capacity. We speculate that this could have been a selective advantage when Homo transitioned towards persistence hunting and greater consumption of meat, but is likely coupled with a greater susceptibility to inflammatory pathologies and endotoxic shock