Comparative expression analysis of the phosphocreatine circuit in extant primates: Implications for human brain evolution

Abstract

While the hominid fossil record clearly shows that brain size has rapidly expanded over the last ~2.5 M.yr. the forces driving this change remain unclear. One popular hypothesis proposes that metabolic adaptations in response to dietary shifts supported greater encephalization in humans. An increase in meat consumption distinguishes the human diet from that of other great apes. Creatine, an essential metabolite for energy homeostasis in muscle and brain tissue, is abundant in meat and was likely ingested in higher quantities during human origins. Five phosphocreatine circuit proteins help regulate creatine utilization within energy demanding cells. We compared the expression of all five phosphocreatine circuit genes in cerebral cortex, cerebellum, and skeletal muscle tissue for humans, chimpanzees, and rhesus macaques. Strikingly, SLC6A8 and CKB transcript levels are higher in the human brain, which should increase energy availability and turnover compared to non-human primates. Combined with other well-documented differences between humans and non-human primates, this allocation of energy to the cerebral cortex and cerebellum may be important in supporting the increased metabolic demands of the human brain.

Figure 1. Schematic representation of the phosphocreatine circuit

A. Creatine enters cells through the membrane transporter SLC6A8. B. Creatine moves across the outer mitochondrial membrane through porin. C. Creatine is phosphorylated within the outer mitochondrial space by CKMT1 or CKMT2. D. Phosphocreatine moves through porin back into the cytosol where it can diffuse to site with high ATPase activity. E. Phosphocreatine interacts with either CKB or CKM to generate ATP. F. The resulting ATP is then available as a source of energy for cytoplasmic ATPases and creatine returns to the mitochondria. ATPases, such as the sodium-potassium pump, are proteins that typically utilize energy from ATP to perform a specific cellular function. SLC6A8: creatine transporter, CKMT1: creatine kinase mitochondrial 1, CKMT2: creatine kinase mitochondrial 2, CKM: creatine kinase muscle, CKB: creatine kinase brain

Figure 2. Phosphocreatine circuit gene expression comparisons among species

Quantitative PCR measurements for the creatine transporter and kinases in humans, chimpanzees, and rhesus macaques. Individuals are each represented by a point, the horizontal bar is the mean, and the spread of the bar from the mean represents one standard deviation. SLC6A8: creatine transporter, CKMT1: creatine kinase mitochondrial 1, CKMT2: creatine kinase mitochondrial 2, CKM: creatine kinase muscle, CKB: creatine kinase brain, Hsap: Homo sapiens, Ptro: Pan troglodytes, Mmul: Macaca mulatta