Metabolic Processes and Physiological Parameters Involved with the Ischemia/Reperfusion Protective Phenotype in Hibernators
Authors: Bogren Lori K , D'alessandro Angelo , Nemkov Travis G , Hansen Kirk C , Martin Sandy L 
Published: November 2023

The physiology of a hibernating mammal is capable of profound plasticity. Each year hibernators cycle though summer homeothermic and winter heterothermic seasons bracketed by fall and spring transition periods in which physiological and environmental parameters are mixed. Within winter heterothermy, the animals repeatedly cycle through bouts of cold torpor that are punctuated by rapid rewarming during arousal to a brief interbout period of warm body temperature (Tb), During entrance into torpor, the animals dramatically depress their metabolic, heart, and respiratory rates, allowing Tb approach freezing. Organ blood perfusion is also decreased by ~90% during torpor (ischemia) and then rapidly re‐established during arousal (reperfusion). Thus, unlike most mammals, hibernators must be resistant to ischemia/reperfusion (I/R) injury during their winter heterothermic season. The medical applications of this resistance are numerous, including protection against tissue damage that occurs during stroke, cardiac arrest, and trauma/hemorrhagic shock. However, to be able to confer benefit from the use of a torpor‐like physiology, one must first understand the molecular mechanisms underpinning such extreme physiology. Neither the molecular drivers underlying I/R resistance nor those responsible for the physiological changes that occur during the fall transition that enable these animals to enter torpor have been elucidated. In the current study, we collected UHPLC‐MS plasma metabolomics at eleven physiologically distinct points across the hibernator's year to address these deficits in our knowledge. These metabolite data were then compared to metabolites linked to I/R damage to identify potentially protective responses in the hibernators. We then used the diverse fall transition animals to: 1) test which changing physiological and environmental factors in the fall transition period correlate to the metabolome of the protective winter phenotype; and 2) elucidate if experiencing I/R alters their metabolome. We found that during the arousal process, there were changes in succinate concentrations, consistent with its utilization during reperfusion. There were no increases in lactate, a non‐specific indicator of I/R injury, or known biomarkers of I/R organ‐specific tissue damage. However, there were increases in metabolic measures to assuage oxidative stress and decrease utilization of glucose. In the fall transition animals, Tb was the only measured physiological or environmental factor that correlated with the percent winter/protective metabolome, and there was no difference in metabolome between animals that had experienced I/R from the previous use of torpor followed by arousal and animals that had not. Results suggest that the I/R protective phenotype may be due in part to a combination of reduced glycolytic energy production and increases in oxidative stress mitigation that are independent of experiencing an initial torpor bout in the fall but are instead related to changes in Tb.Support or Funding InformationThis project was funded by University of Colorado Fund AEF CDB SIRC BRIDGE‐Martin.