Red Blood Cell Metabolic Responses to Torpor and Arousal in the Hibernator Arctic Ground Squirrel

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.