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Metabolism of stored human and macaque RBC
intertwined with the urea cycle, which is incomplete in mitochondria-devoid mature RBC. Arginine metabolism differed significantly between human and RM RBC, the latter having significantly higher RBC (and supernatant) levels of arginine, but with significantly lower levels of citrulline, ornithine, and creatine (Figure 5B). Although RM RBC had higher levels of polyamines (including sper-
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midine), these increases (10-20% by storage day 42; P<0.0025) were not sufficient to explain the >100-fold increase in arginine levels in RM RBC. However, compa- rable fold-change increases in asymmetric dimethylargi- nine (and isobaric isomers) were noted in RM RBC, as seen by untargeted metabolomics (Online Supplementary Figure S3C).
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Figure 3. Interspecies comparison of the red blood cell metabolome during refrigerated storage. (A) Comparison of the metabolome of red blood cells (RBC) from humans and Rhesus macaques (RM). (B) Partial least squares-discriminant analysis (PLS-DA) shows significant species- and time-dependent clustering of samples across principal components (PC1 and PC2, respectively). (C, D) Venn diagram (C) showing the number of significant metabolites by repeated measures two-way analysis of variance and related pathway analyses (D). (E) A heat map showing significant metabolic changes in stored RBC and supernatants as a function of stor- age duration in humans and RM. A vectorial version of this figure is provided in Online Supplementary Figure S2.
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