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

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Raw images with lead ATPase staining used to determine capillary densit

Metabolomics data

Metabolomics of the soleus (~20mg) from WT vs Cmah null mice with or without 15 days of voluntary exercise training. This data was generated by the West Coast Metabolomics Center at UC Davis

Data from: 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 metabolic pathways were also noted. Taken together, these data suggest that CMAH loss contributes to an improved skeletal muscle capacity for oxygen utilization. If translatable to humans, CMAH loss could have provided a selective advantage for ancestral Homo during the transition from forest dwelling to increased resource exploration and hunter/gatherer behavior in the open savannah