Factors limiting the duration of artificially induced torpor in mice

The possibility of artificial induction of a torpid state in animals that do not naturally do so, as well as in humans, offers a great potential in biomedicine and in human spaceflight. However, the mechanisms of action that provide a coordinated and concomitant downregulation with a safe recovery from this state are poorly understood. In our previous study, we demonstrated that the metabolic rate of mice can be reduced by nearly 94% and can remain stable under hypothermic conditions for a prolonged period of up to 11 h. The present study was carried out in order to test the limitations and identify potential factors that can enable the safe and reversible arousal of non-hibernating mice from deep artificially-induced torpor to an active state. Results demonstrate that the energy budget may be a limiting factor for the prolongation and safe recovery from the hypometabolic state. While the continuation of torpor may be possible for additional hours, we found that a reduction of 40% or more in the plasma glucose level increases the risk of heart fibrillation, which results in death during arousal. Therefore, the plasma glucose level could be a component of the criteria indicating the reversibility of torpor. Another important factor complementing the energetic necessity that may limit the duration of torpor in mice is a gradual reduction in body mass during torpor. Under the conditions of our experiment, body mass declines by nearly 15% after 16 h from the initiation of torpor and may continue to decline if the mice are allowed to remain in torpor longer. Extrapolation of this data suggests that there may be a critical mass relating to animal mortality and thus limiting the duration of torpor. Control and maintenance of the body mass and glucose level in a torpid animal may extend the longevity of torpor and mitigate the risk of cardiac failure during rewarming to the metabolically active state. The cardiac complications that occur during arousal from torpor in many cases could be mitigated and even avoided by applying appropriate temperature-arising kinetics and providing a sufficient dynamic range to maintain cardiac output.