Abstract
The torpor–arousal cycle of mammalian hibernation is characterized by drastic changes in physiological state that are supported by reprogramming of metabolic functions. The entrance and arousal phases of the cycle function as transitional stages, where major changes in oxygen metabolism take place. Acute changes in oxygen delivery can lead to either ischemia-related injuries during torpor induction or reperfusion damage during arousal. This study examines the regulation of the forkhead box O3 (FoxO3) transcription factor, which functions to increase cellular cytoprotection in response to oxidative stress stimuli. Immunoblots show that total expression of FoxO3a was elevated during early torpor (ET) and late torpor by 3.6- and 4.5-fold, respectively, compared to euthermic control. However, enhanced phosphorylation of FoxO3a at Thr-32 was only evident during ET by 1.5-fold, accompanied by increased phosphorylation of c-Jun N-terminal kinases by 1.2-fold. During ET, increased nuclear inclusion of FoxO3a was evident along with its transcriptional co-activator β-catenin by 1.9- and 2.7-fold, respectively. As well, FoxO3a DNA binding was elevated by 1.8-fold during ET, along with increased expression of FoxO3a downstream genes catalase, p27, and cyclin G 2 , by 1.4-, 1.6-, and 1.3-fold, respectively. Overall, the results indicate activation of FoxO3a during ET, suggesting a role of FoxO3a in response to cellular stress during hibernation.
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Acknowledgments
Thanks to J. M. Storey for editorial review of the manuscript. We are also grateful to Dr. J. M. Hallenbeck for providing the ground squirrel tissues used in this study. Research in the Storey Laboratory is supported by a Discovery Grant from NSERC Canada. Kenneth B. Storey holds the Canada Research Chair in Molecular Physiology; Cheng-Wei Wu holds a NSERC PGS-D postgraduate fellowship.
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Wu, CW., Storey, K.B. FoxO3a-mediated activation of stress responsive genes during early torpor in a mammalian hibernator. Mol Cell Biochem 390, 185–195 (2014). https://doi.org/10.1007/s11010-014-1969-7
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DOI: https://doi.org/10.1007/s11010-014-1969-7