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Circadian transcription factor HSF1 regulates differential HSP70 gene transcription during the arousal-torpor cycle in mammalian hibernation.

ABSTRACT: Mammalian hibernation is a seasonal phenomenon. The hibernation season consists of torpor periods with a reduced body temperature (Tb), interrupted by euthermic arousal periods (interbout arousal, IBA). The physiological changes associated with hibernation are assumed to be under genetic control. However, the molecular mechanisms that govern hibernation-associated gene regulation are still unclear. We found that HSP70 transcription is upregulated in the liver of nonhibernating (summer-active) chipmunks compared with hibernating (winter-torpid) ones. In parallel, HSF1, the major transcription factor for HSP70 expression, is abundant in the liver-cell nuclei of nonhibernating chipmunks, and disappears from the nuclei of hibernating ones. Moreover, during IBA, HSF1 reappears in the nuclei and drives HSP70 transcription. In mouse liver, HSF1 is regulated by the daily Tb rhythm, and acts as a circadian transcription factor. Taken together, chipmunks similarly use the Tb rhythm to regulate gene expression via HSF1 during the torpor-arousal cycle in the hibernation season.

SUBMITTER: Tsukamoto D

PROVIDER: S-EPMC6351659 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Circadian transcription factor HSF1 regulates differential HSP70 gene transcription during the arousal-torpor cycle in mammalian hibernation.

Tsukamoto Daisuke D Hasegawa Tomoko T Hirose Shin-Ichi SI Sakurai Yukina Y Ito Michihiko M Takamatsu Nobuhiko N

Scientific reports 20190129 1

Mammalian hibernation is a seasonal phenomenon. The hibernation season consists of torpor periods with a reduced body temperature (Tb), interrupted by euthermic arousal periods (interbout arousal, IBA). The physiological changes associated with hibernation are assumed to be under genetic control. However, the molecular mechanisms that govern hibernation-associated gene regulation are still unclear. We found that HSP70 transcription is upregulated in the liver of nonhibernating (summer-active) ch ...[more]

PMID: 30696859

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Project description:The physiology of small mammalian hibernators shifts profoundly over a year, from summer homeothermy to winter heterothermy. Torpor-arousal cycles define high-amplitude tissue activity fluctuations in winter, particularly for skeletal muscle, which contributes to the energetically demanding rewarming process via shivering. To better understand the biochemistry underlying summer-winter and torpor-arousal transitions, we applied two-dimensional gel electrophoresis coupled with liquid chromatography/mass spectrometry/mas spectrometry to the soluble proteins from hindlimb muscle of 13-lined ground squirrels (Ictidomys tridecemlineatus) in two summer and six winter states. Two hundred sixteen protein spots differed by sampled state. Significantly, intrawinter protein adjustment was a minor component of the dataset despite large discrepancies in muscle activity level among winter states; rather, the bulk of differences (127/138 unequivocally identified proteins spots) occurred between summer and winter. We did not detect any proteomic signatures of skeletal muscle atrophy in this hibernator nor any differential seasonal regulation of protein metabolism. Instead, adjustments to metabolic substrate preferences dominated the detected proteomic differences. Pathways of carbohydrate metabolism (glycolysis and gluconeogenesis) were summer enriched, whereas the winter proteome was enriched for fatty acid β-oxidation. Nevertheless, our data suggest that some reliance on carbohydrate reserves is maintained during winter. Phosphoglucomutase (PGM1), which reversibly prepares glucose subunits for either glycolysis or glycogenesis, showed apparent winter state-specific phosphorylation. PGM1 was phosphorylated during rewarming and dephosphorylated by interbout arousal, implying that glucose supplements lipid fuels during rewarming. This, along with winter elevation of TCA cycle enzymes, suggests that hindlimb muscles are primed for rapid energy production and that carbohydrates are an important fuel for shivering thermogenesis.

Project description:Many birds and mammals drastically reduce their energy expenditure during times of cold exposure, food shortage, or drought, by temporarily abandoning euthermia, i.e. the maintenance of high body temperatures. Traditionally, two different types of heterothermy, i.e. hypometabolic states associated with low body temperature (torpor), have been distinguished: daily torpor, which lasts less than 24 h and is accompanied by continued foraging, versus hibernation, with torpor bouts lasting consecutive days to several weeks in animals that usually do not forage but rely on energy stores, either food caches or body energy reserves. This classification of torpor types has been challenged, suggesting that these phenotypes may merely represent extremes in a continuum of traits. Here, we investigate whether variables of torpor in 214 species (43 birds and 171 mammals) form a continuum or a bimodal distribution. We use Gaussian-mixture cluster analysis as well as phylogenetically informed regressions to quantitatively assess the distinction between hibernation and daily torpor and to evaluate the impact of body mass and geographical distribution of species on torpor traits. Cluster analysis clearly confirmed the classical distinction between daily torpor and hibernation. Overall, heterothermic endotherms tend to be small; hibernators are significantly heavier than daily heterotherms and also are distributed at higher average latitudes (∼35°) than daily heterotherms (∼25°). Variables of torpor for an average 30 g heterotherm differed significantly between daily heterotherms and hibernators. Average maximum torpor bout duration was >30-fold longer, and mean torpor bout duration >25-fold longer in hibernators. Mean minimum body temperature differed by ∼13°C, and the mean minimum torpor metabolic rate was ∼35% of the basal metabolic rate (BMR) in daily heterotherms but only 6% of BMR in hibernators. Consequently, our analysis strongly supports the view that hibernators and daily heterotherms are functionally distinct groups that probably have been subject to disruptive selection. Arguably, the primary physiological difference between daily torpor and hibernation, which leads to a variety of derived further distinct characteristics, is the temporal control of entry into and arousal from torpor, which is governed by the circadian clock in daily heterotherms, but apparently not in hibernators.

Project description:Mammalian hibernators experience repeated hypoxic ischaemia and reperfusion during the torpor-arousal cycle. We investigated levels of oxidative stress, antioxidant capacity, and the underlying mechanism in heart, liver, brain and kidney tissue as well as plasma during different periods of hibernation in Daurian ground squirrels (Spermophilus dauricus). Our data showed that the levels of hydrogen peroxide significantly increased in the heart and brain during late torpor (LT) compared with levels during the summer active (SA) state. The content of malondialdehyde (MDA) was significantly lower during interbout arousal (IBA) and early torpor (ET) than that during SA or pre-hibernation (PRE), and MDA levels in the LT brain were significantly higher than the levels in other states. Superoxide dismutase 2 protein levels increased markedly in the heart throughout the entire torpor-arousal cycle. Catalase expression remained at an elevated level in the liver during the hibernation cycle. Superoxide dismutase 1 and glutathione peroxidase 1 (GPx1) expression increased considerably in all tissues during the IBA and ET states. In addition, the activities of the various antioxidant enzymes were higher in all tissues during IBA and ET than during LT; however, GPx activity in plasma decreased significantly during the hibernation season. The expression of p-Nrf2 decreased in all tissue types during IBA, but significantly increased during LT, especially in liver tissue. Interestingly, most changed indicators recovered to SA or PRE levels in post-hibernation (POST). These results suggest that increased reactive oxygen species during LT may activate the Nrf2/Keap1 antioxidant pathway and may contribute to the decreased MDA levels found during the IBA and ET states, thereby protecting organisms from oxidative damage over the torpor-arousal cycle of hibernation. This is the first report on the remarkable controllability of oxidative stress and tissue specificity in major oxidative tissues of a hibernator.

Dataset Information

Circadian transcription factor HSF1 regulates differential HSP70 gene transcription during the arousal-torpor cycle in mammalian hibernation.

Publications

Circadian transcription factor HSF1 regulates differential HSP70 gene transcription during the arousal-torpor cycle in mammalian hibernation.

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