Comfortably Numb and Back: Plasma Metabolomics Reveals Biochemical Adaptations in the Hibernating 13-Lined Ground Squirrel

Hibernation is an evolutionary adaptation
that affords some mammals
the ability to exploit the cold to achieve extreme metabolic depression
(torpor) while avoiding ischemia/reperfusion or hemorrhagic shock
injuries. Hibernators cycle periodically out of torpor, restoring
high metabolic activity. If understood at the molecular level, the
adaptations underlying torpor-arousal cycles may be leveraged for
translational applications in critical fields such as intensive care
medicine. Here, we monitored 266 metabolites to investigate the metabolic
adaptations to hibernation in plasma from 13-lined ground squirrels
(57 animals, 9 time points). Results indicate that the periodic arousals
foster the removal of potentially toxic oxidative stress-related metabolites,
which accumulate in plasma during torpor while replenishing reservoirs
of circulating catabolic substrates (free fatty acids and amino acids).
Specifically, we identified metabolic fluctuations of basic amino
acids lysine and arginine, one-carbon metabolism intermediates, and
sulfur-containing metabolites methionine, cysteine, and cystathionine.
Conversely, reperfusion injury markers such as succinate/fumarate
remained relatively stable across cycles. Considering the cycles of
these metabolites with the hibernator’s cycling metabolic activity
together with their well-established role as substrates for the production
of hydrogen sulfide (H2S), we hypothesize that these metabolic
fluctuations function as a biological clock regulating torpor to arousal
transitions and resistance to reperfusion during arousal.