Induction of torpor: Mimicking natural metabolic suppression for biomedical applications

Bouma, Hjalmar R.; Verhaag, Esther M.; Otis, Jessica P.; Heldmaier, Gerhard; Swoap, Steven J.; Strijkstra, Arjen M.; Henning, Robert H.; Carey, Hannah V.

doi:10.1002/jcp.22850

Cited by 91 publications

(60 citation statements)

References 77 publications

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“…Because of the remarkable abilities of torpid animals to avoid the potentially fatal consequences of hypothermia, there is great interest in determining whether a similar state could be induced in humans for medical purposes (4). The value of some forms of medically induced hypothermia is widely accepted, as it is already used successfully in cardiovascular surgery.…”

Section: Discussionmentioning

confidence: 99%

Torpor and hypothermia: reversed hysteresis of metabolic rate and body temperature

Geiser

Currie

O'Shea

et al. 2014

American Journal of Physiology-Regulatory, Integrative and Comp

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Regulated torpor and unregulated hypothermia are both characterized by substantially reduced body temperature (Tb) and metabolic rate (MR), but they differ physiologically. Although the remarkable, medically interesting adaptations accompanying torpor (e.g., tolerance for cold and ischemia, absence of reperfusion injury, and disuse atrophy) often do not apply to hypothermia in homeothermic species such as humans, the terms "torpor" and "hypothermia" are often used interchangeably in the literature. To determine how these states differ functionally and to provide a reliable diagnostic tool for differentiating between these two physiologically distinct states, we examined the interrelations between Tb and MR in a mammal (Sminthopsis macroura) undergoing a bout of torpor with those of the hypothermic response of a similar-sized juvenile rat (Rattus norvegicus). Our data show that under similar thermal conditions, 1) cooling rates differ substantially (approximately fivefold) between the two states; 2) minimum MR is approximately sevenfold higher during hypothermia than during torpor despite a similar Tb; 3) rapid, endogenously fuelled rewarming occurs in torpor but not hypothermia; and 4) the hysteresis between Tb and MR during warming and cooling proceeds in opposite directions in torpor and hypothermia. We thus demonstrate clear diagnostic physiological differences between these two states that can be used experimentally to confirm whether torpor or hypothermia has occurred. Furthermore, the data can clarify the results of studies investigating the ability of physiological or pharmacological agents to induce torpor. Consequently, we recommend using the terms "torpor" and "hypothermia" in ways that are consistent with the underlying regulatory differences between these two physiological states.

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Section: Discussionmentioning

confidence: 99%

Torpor and hypothermia: reversed hysteresis of metabolic rate and body temperature

Geiser

Currie

O'Shea

et al. 2014

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Identifying the complex molecular mechanisms orchestrating the extreme changes in hibernation could provide important contributions to the development of therapeutic strategies to improve medical outcomes in a number of conditions, including hypothermic injury, organ transplantation, stroke recovery, cardiac arrest, muscle disease, and other ischemia/reperfusion insults. Numerous studies have investigated how torpid animals tolerate cerebral ischemia following dramatic reductions of blood flow and oxygen concentration, display reversible rapid and pronounced synaptic flexibility in which synapses retract during torpor and rapidly re-emerge upon arousal, and retain skeletal muscle mass despite prolonged immobilization and lack of nutrition 77–79 . There remains much to be learned about the cellular, molecular, and systems-wide mechanisms that protect heterothermic mammals during torpor/arousal cycles, which may guide discovery of new therapeutics.…”

Section: Discussionmentioning

confidence: 99%

Gene expression profiling during hibernation in the European hamster

Gautier

Bothorel

Ciocca

et al. 2018

Sci Rep

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Hibernation is an exceptional physiological response to a hostile environment, characterized by a seasonal period of torpor cycles involving dramatic reductions of body temperature and metabolism, and arousal back to normothermia. As the mechanisms regulating hibernation are still poorly understood, here we analysed the expression of genes involved in energy homeostasis, torpor regulation, and daily or seasonal timing using digital droplet PCR in various central and peripheral tissues sampled at different stages of torpor/arousal cycles in the European hamster. During torpor, the hypothalamus exhibited strongly down-regulated gene expression, suggesting that hypothalamic functions were reduced during this period of low metabolic activity. During both torpor and arousal, many structures (notably the brown adipose tissue) exhibited altered expression of deiodinases, potentially leading to reduced tissular triiodothyronine availability. During the arousal phase, all analysed tissues showed increased expression of the core clock genes Per1 and Per2. Overall, our data indicated that the hypothalamus and brown adipose tissue were the tissues most affected during the torpor/arousal cycle, and that clock genes may play critical roles in resetting the body’s clocks at the beginning of the active period.

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“…These findings suggest that the induction of a hypometabolic state affords renal protection in nonhibernating mammals (62). For an extensive discussion of hypometabolic agents as they relate to hibernation, the reader is referred to an excellent recent review by Bouma et al (14).…”

Section: Clinical Implications Of Renal Adaptation During Hibernationmentioning

confidence: 97%

Renal adaptation during hibernation

Jani

Martin

Jain

et al. 2013

American Journal of Physiology-Renal Physiology

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Hibernators periodically undergo profound physiological changes including dramatic reductions in metabolic, heart, and respiratory rates and core body temperature. This review discusses the effect of hypoperfusion and hypothermia observed during hibernation on glomerular filtration and renal plasma flow, as well as specific adaptations in renal architecture, vasculature, the renin-angiotensin system, and upregulation of possible protective mechanisms during the extreme conditions endured by hibernating mammals. Understanding the mechanisms of protection against organ injury during hibernation may provide insights into potential therapies for organ injury during cold storage and reimplantation during transplantation.hibernation; kidney; torpor; metabolism; electrolytes MAMMALIAN HIBERNATORS EXHIBIT heterothermy during winter months, cycling through periods of low core body temperature (CBT) for days to weeks (22) during torpor, followed by periodic arousals when CBT is elevated to 37°C for ϳ12 h ( Fig. 1) (63). CBT during torpor can fall to as low as Ϫ3°C in arctic ground squirrels (7) or 2-10°C in temperate-zone hibernators (22). During torpor, hibernators undergo profound physiological changes, reducing their heart rate from a summertime level of 200 -300 to 3-5 beats/min (128), their respiratory rate from 100 -200 to 4 -6 breaths/min (33, 46) and their metabolic rate to as low as 1-5% of basal metabolic rate (47). During arousal, organs undergo rapid metabolic reactivation, reperfusion, and rewarming to near normal levels (22). After maintaining euthermia and high metabolic activity for 12-18 h, the hibernator reenters torpor (Figs. 1 and 2). This review will focus on the renal adaptations employed by hibernators that permit their kidneys to withstand extreme fluctuations in CBT and organ perfusion during winter heterothermy. Studies of hibernation have been conducted for over a century and the nomenclature used to describe the various stages of hibernation, and the criteria used to define stages of hibernation, have evolved. Earlier studies often simply compared "hibernating" with "nonhibernating," and both terms were variably used. Hibernating often meant mid-winter torpor but was also used to refer to animals that were aroused, either naturally or more often, artificially. Nonhibernating was used to denote midsummer euthermic animals or winter aroused animals (94). As a further complication in the nomenclatures used, some investigators examine monthly or seasonal changes whereas others examine changes that occur during one torpor-arousal cycle of a few days duration. More recent studies have employed specific definitions of stages, representing both seasonal and torpor-arousal cycles, based on CBT monitoring using radiotelemetry (62,63,70,83) (Fig. 1). In addition, torpor can occur daily (referred to as "daily torpor" in "daily heterotherms") or over several days to weeks typically during winter in hibernators (46,125). For the purposes of this review we will 1) focus on renal function in hibernators that e...

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Induction of torpor: Mimicking natural metabolic suppression for biomedical applications

Cited by 91 publications

References 77 publications

Torpor and hypothermia: reversed hysteresis of metabolic rate and body temperature

Torpor and hypothermia: reversed hysteresis of metabolic rate and body temperature

Gene expression profiling during hibernation in the European hamster

Renal adaptation during hibernation

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