Arctic ground squirrels provide a unique model to investigate metabolic responses to hibernation in mammals. During winter months these rodents are exposed to severe
hypothermia, prolonged fasting, and
hypoxemia. In the light of their role in
oxygen transport/off-loading and owing to the absence of nuclei and organelles (and thus de novo
protein synthesis capacity), mature red blood cells have evolved metabolic programs to counteract physiological or pathological
hypoxemia. However, red blood cell metabolism in hibernation has not yet been investigated. Here we employed targeted and untargeted metabolomics approaches to investigate erythrocyte metabolism during entrance to torpor to arousal, with a high resolution of the intermediate time points. We report that torpor and arousal promote metabolism through glycolysis and pentose phosphate pathway, respectively, consistent with previous models of
oxygen-dependent metabolic modulation in mature erythrocytes. Erythrocytes from hibernating squirrels showed up to 100-fold lower levels of
biomarkers of
reperfusion injury, such as the pro-inflammatory dicarboxylate
succinate. Altered
tryptophan metabolism during torpor was here correlated to the accumulation of potentially neurotoxic catabolites
kynurenine,
quinolinate, and
picolinate. Arousal was accompanied by alterations of
sulfur metabolism, including sudden spikes in a metabolite putatively identified as
thiorphan (level 1 confidence)-a potent inhibitor of several
metalloproteases that play a crucial role in nociception and inflammatory complication to reperfusion secondary to
ischemia or
hemorrhage. Preliminary studies in rats showed that
intravenous injection of
thiorphan prior to
resuscitation mitigates metabolic and
cytokine markers of
reperfusion injury, etiological contributors to inflammatory complications after
shock.