Hibernation in mammals is characterized by drastic decreases in body temperature, heart rate, respiration and other factors that greatly decrease metabolic rate and yield energy savings during the long, cold months of winter. However, hibernation is not a constant state; in such animals as ground squirrels and marmots, hibernation is regularly interrupted by periods of normal body temperature, in addition to the final arousal at winter's end. While a great deal is known about the enzymatic and cardiovascular changes that permit hibernation bouts and arousal periods, far less attention has been paid to the physiological consequences of the massive metabolic upregulation required during the return to normal body temperature and activity levels. It would seem, for example, that the increased metabolic demands of arousal could result in tissue hypoxia (low oxygenation) or, conversely, induce cellular stress from the sudden increases in blood flow and oxygen supply.
Cellular stress could be induced both by inflammatory responses and by reactive oxygen species (ROS). ROS are produced by a variety of mechanisms,including oxidative phosphorylation in mitochondria. Thus, the reduced metabolism of hibernation and/or the high oxygen demands of arousal could prime the tissues for a mismatch between oxygen supply and mitochondrial activity, followed by a massive release of ROS. When normal cellular antioxidant defenses are overwhelmed, ROS interact with cellular lipids,proteins and DNA, resulting in cellular damage and death. The question, then,is whether or not hibernating animals become hypoxic during torpor or arousal,and, if so, are they able to prevent ROS damage during periods of increased blood flow and respiration?
To tackle this question, Kelly Drew's group at the University of Alaska Fairbanks studied hypoxia and cellular stress in Arctic ground squirrels. To examine hypoxia, the team compared arterial oxygen levels and hemoglobin saturation in hibernating Arctic ground squirrels (torpid, cold),non-hibernating winter animals (normal body temperature) and animals that had entered an arousal period (core temperature returned to at least 34°C). They also examined the animals' brain histology for evidence of cellular damage; they compared brain levels of hypoxia inducible factor (HIF-1α)as a marker of hypoxia and the accumulation of inducible nitric oxide synthase(iNOS) as a marker of inflammation.
Drew's team reports that hibernating Arctic ground squirrels show no evidence of hypoxia, cellular stress or inflammatory responses in the brain;their reduced metabolism allows these animals to avoid hypoxic stress. The enormous metabolic demands of arousal from hibernation, however, do decrease oxygen levels and lead to the accumulation of HIF-1α in the brain, but the authors found no evidence of neuronal pathology, oxidative stress or inflammation in the brain following the return to basal metabolism. By contrast, non-hibernating winter animals are apparently the most highly stressed physiologically, experiencing chronic mild hypoxia, low hemoglobin saturation and the accumulation of both HIF-1α and iNOS.
So, like us, Arctic ground squirrels are apparently most stressed by real life! But their ability to avoid oxidative damage following hibernation and arousal presents an interesting natural model providing insights on how to survive periods of low oxygen and the sudden restoration of blood flow to tissues after these periods.
