Advertisement

Journal of Comparative Physiology B

, Volume 180, Issue 6, pp 927–934 | Cite as

Regulation of Akt during torpor in the hibernating ground squirrel, Ictidomys tridecemlineatus

  • David C. McMullen
  • John M. Hallenbeck
Original Paper

Abstract

The 13-lined ground squirrel (Ictidomys tridecemlineatus) is capable of entering into extended periods of torpor during winter hibernation. The state of torpor represents a hypometabolic shift wherein the rate of oxygen consuming processes are strongly repressed in an effort to maintain cellular homeostasis as the availability of food energy becomes limited. We are interested in studying hibernation/torpor because of the robust state of tolerance to constrained oxygen delivery, oligemia, and hypothermia achieved by the tissues of hibernating mammals. The role of the serine/threonine kinase Akt (also known as PKB) has been examined in torpor in previous studies. However, this is the first study that examines the level of Akt phosphorylation in the liver during the two transition phases of the hibernation cycle: entrance into torpor, and the subsequent arousal from torpor. Our results indicate that Akt is activated in the squirrel liver by phosphorylation of two key residues (Thr308 and Ser473) during entrance into torpor and arousal from torpor. Moreover, we observed increased phosphorylation of key substrates of Akt during the two transition stages of torpor. Finally, this study reports the novel finding that PRAS40, a component of the TORC1 multi-protein complex and a potentially important modulator of metabolism, is regulated during torpor.

Keywords

Ictidomys tridecemlineatus Hibernation Metabolic rate depression Akt PRAS40 mTOR 

Notes

Acknowledgments

The authors would like to thank Jan Storey and Dr. Maria Spatz for critical review of this manuscript. This research was supported (in part) by the Intramural Research Program of the NIH, NINDS.

References

  1. Abnous K, Dieni CA, Storey KB (2008) Regulation of Akt during hibernation in Richardson’s ground squirrels. Biochim Biophys Acta 1780(2):185–193PubMedGoogle Scholar
  2. Alexia C, Bras M, Fallot G, Vadrot N, Daniel F, Lasfer M, Tamouza H, Grover A (2006) Pleiotropic effects of PI-3′ kinase/Akt signaling in human hepatoma cell proliferation and drug-induced apoptosis. Ann N Y Acad Sci 1090:1–17CrossRefPubMedGoogle Scholar
  3. Cai D, McCarron RM, Yu EZ, Li Y, Hallenbeck J (2004) Akt phosphorylation and kinase activity are down-regulated during hibernation in the 13-lined ground squirrel. Brain Res 1014(1–2):14–21CrossRefPubMedGoogle Scholar
  4. Chong ZZ, Li F, Maiese K (2007) The pro-survival pathways of mTOR and protein kinase B target glycogen synthase kinase-3beta and nuclear factor-kappaB to foster endogenous microglial cell protection. Int J Mol Med 19(2):263–272PubMedGoogle Scholar
  5. Drew KL, Tǿien Ǿ, Rivera PM, Smith MA, Perry G, Rice ME (2002) Role of the antioxidant ascorbate in hibernation and warming from hibernation. Comp Biochem Physiol C Toxicol Pharmacol 133(4):483–492CrossRefPubMedGoogle Scholar
  6. Duronio V (2008) The life of a cell: apoptosis regulation by the PI3K/PKB pathway. Biochem J 415(3):333–344CrossRefPubMedGoogle Scholar
  7. Eddy SF, Storey KB (2003) Differential expression of Akt, PPARgamma, and PGC-1 during hibernation in bats. Biochem Cell Biol 81(4):269–274CrossRefPubMedGoogle Scholar
  8. Eddy SF, McNally JD, Storey KB (2005) Up-regulation of a thioredoxin peroxidase-like protein, proliferation-associated gene, in hibernating bats. Arch Biochem Biophys 435(1):103–111CrossRefPubMedGoogle Scholar
  9. Fleck CC, Carey HV (2005) Modulation of apoptotic pathways in intestinal mucosa during hibernation. Am J Physiol Regul Integr Comp Physiol 289(2):586–595Google Scholar
  10. Franke TF (2008) Intracellular signaling by Akt: bound to be specific. Sci Signal 1(24):pe29CrossRefPubMedGoogle Scholar
  11. Frerichs KU, Hallenbeck JM (1998) Hibernation in ground squirrels induces state and species-specific tolerance to hypoxia and aglycemia: an in vitro study in hippocampal slices. J Cereb Blood Flow Metab 18(2):168–175CrossRefPubMedGoogle Scholar
  12. Frerichs KU, Kennedy C, Sokoloff L, Hallenbeck JM (1994) Local cerebral blood flow during hibernation, a model of natural tolerance to “cerebral ischemia”. J Cereb Blood Flow Metab 14(2):193–205PubMedGoogle Scholar
  13. Frerichs KU, Smith CB, Brenner M, DeGracia DJ, Krause GS, Marrone L, Dever TE, Hallenbeck JM (1998) Suppression of protein synthesis in brain during hibernation involves inhibition of protein initiation and elongation. Proc Natl Acad Sci USA 95(24):14511–14516CrossRefPubMedGoogle Scholar
  14. Geiser F (1988) Reduction of metabolism during hibernation and daily torpor in mammals and birds: temperature effect or physiological inhibition? J Comp Physiol B 158(1):25–37CrossRefPubMedGoogle Scholar
  15. Guertin DA, Sabatini DM (2007) Defining the role of mTOR in cancer. Cancer Cell 12(1):9–22CrossRefPubMedGoogle Scholar
  16. Helgen KM, Cole FR, Helgen LE, Wilson DE (2009) Genetic revision of in the holarctic ground squirrel genus Spermophilus. J Mammal 90:270–305CrossRefGoogle Scholar
  17. Hittel D, Storey KB (2002) The translation state of differentially expressed mRNAs in the hibernating 13-lined ground squirrel (Ictidomys tridecemlineatus). Arch Biochem Biophys 401(2):244–254CrossRefPubMedGoogle Scholar
  18. Hoehn KL, Hudachek SF, Summers SA, Florant GL (2004) Seasonal, tissue-specific regulation of Akt/protein kinase B and glycogen synthase in hibernators. Am J Physiol Regul Integr Comp Physiol 286:R498–R504PubMedGoogle Scholar
  19. Huang J, Manning BD (2009) A complex interplay between Akt, TSC2 and the two mTOR complexes. Biochem Soc Trans 37(Pt 1):217–222CrossRefPubMedGoogle Scholar
  20. Jacinto E, Facchinetti V, Liu D, Soto N, Wei S, Jung SY, Huang Q, Qin J, Su B (2006) SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell 127(1):125–137CrossRefPubMedGoogle Scholar
  21. Kaper F, Dornhoefer N, Giaccia AJ (2006) Mutations in the PI3K/PTEN/TSC2 pathway contribute to mammalian target of rapamycin activity and increased translation under hypoxic conditions. Cancer Res 66(3):1561–1569CrossRefPubMedGoogle Scholar
  22. Kops GJ, Dansen TB, Polderman PE, Sarloos I, Wertz KW, Coffey PJ, Huang TT, Bos JL, Medema RH, Bergering BM (2002) Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress. Nature 419(6904):316–321CrossRefPubMedGoogle Scholar
  23. Kovacina KS, Park GY, Bae SS, Guzzetta EW, Schaeffer E, Birnbaum MJ, Roth RA (2003) Identification of a proline-rich Akt substrate as a 14-3-3 binding partner. J Biol Chem 278(12):10189–10194CrossRefPubMedGoogle Scholar
  24. Lee M, Choi I, Park K (2002) Activation of stress signaling molecules in bat brain during arousal from hibernation. J Neurochem 82(4):867–873CrossRefPubMedGoogle Scholar
  25. Mamady H, Storey KB (2006) Up-regulation of the endoplasmic reticulum molecular chaperone GRP78 during hibernation in thirteen-lined ground squirrels. Mol Cell Biochem 292(1–2):89–98CrossRefPubMedGoogle Scholar
  26. Morin P Jr, Storey KB (2006) Evidence for a reduced transcriptional state during hibernation in ground squirrels. Cryobiology 53(3):310–318CrossRefPubMedGoogle Scholar
  27. Morin P Jr, Storey KB (2007) Antioxidant defense in hibernation: cloning and expression of peroxiredoxins from hibernating ground squirrels, Spermophilus tridecemlineatus. Arch Biochem Biophys 461(1):59–65CrossRefPubMedGoogle Scholar
  28. Morin P Jr, Ni J, McMullen DC, Storey KB (2008) Expression of Nrf2 and its downstream gene targets in hibernating 13-lined ground squirrels, Spermophilus tridecemlineatus. Mol Cell Biochem 312(1–2):121–129CrossRefPubMedGoogle Scholar
  29. Noshita N, Lewén A, Sugawara T, Chan PH (2001) Evidence of phosphorylation of Akt and neuronal survival after transient focal cerebral ischemia in mice. J Cereb Blood Flow Metab 21:1442–1450CrossRefPubMedGoogle Scholar
  30. Orr AL, Lohse LA, Drew KL, Hermes-Lima M (2009) Physiological oxidative stress after arousal from hibernation in Arctic ground squirrel. Comp Biochem Physiol A Mol Integr Physiol 153(2):213–221CrossRefPubMedGoogle Scholar
  31. Oshiro N, Takahashi R, Yoshino K, Tanimura K, Nakashima A, Egushi S, Miyamoto T, Hara K, Takehana K, Avruch J, Kikkawa U, Yonezawa K (2007) The proline-rich Akt substrate of 40 kDa (PRAS40) is a physiological substrate of mammalian target of rapamycin complex 1. J Biol Chem 282(28):20329–20339CrossRefPubMedGoogle Scholar
  32. Paradis S, Ruvkun G (1998) Caenorhabditis elegans Akt/PKB transduces insulin receptor-like signals from AGE-1 PI3 kinase to the DAF-16 transcription factor. Genes Dev 12(16):2488–2498CrossRefPubMedGoogle Scholar
  33. Rayasam GV, Tulasi VK, Soghi R, Davis JA, Ray A (2009) Glycogen Synthase Kinase 3: more than a namesake. Br J Pharmacol 156:885–898CrossRefPubMedGoogle Scholar
  34. Reiling JH, Sabitini DM (2006) Stress and mTORture signaling. Oncogene 25(48):6373–6383CrossRefPubMedGoogle Scholar
  35. Sancak Y, Thoreen CC, Peterson TR, Lindquist RA, Kang SA, Spooner E, Carr SA, Sabatini DM (2007) PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol Cell 25(6):903–915CrossRefPubMedGoogle Scholar
  36. Sarbassov DD, Ali SM, Sabatini DM (2005) Growing roles for the mTOR pathway. Curr Opin Cell Biol 17(6):596–603CrossRefPubMedGoogle Scholar
  37. Seol DW (2008) Up-regulation of IAPs by PI-3K: a cell survival signal-mediated anti-apoptotic mechanism. Biochem Biophys Res Commun 377(2):508–511CrossRefPubMedGoogle Scholar
  38. Shah OJ, Kimball SR, Jefferson LS (2000) Among translational effectors, p70S6k is uniquely sensitive to inhibition by glucocorticoids. Biochem J 347(Pt 2):389–397CrossRefPubMedGoogle Scholar
  39. Storey KB (2003) Mammalian hibernation transcriptional and translational controls. Adv Exp Med Biol 543:21–38PubMedGoogle Scholar
  40. Storey KB, Storey JM (1990) Metabolic rate depression and biochemical adaptation in anaerobiosis, hibernation and estivation. Q Rev Biol 65(2):145–174CrossRefPubMedGoogle Scholar
  41. Storey KB, Storey JM (2004) Metabolic rate depression in animals: transcriptional and translational controls. Biol Rev Camb Philos Soc 79(1):207–233CrossRefPubMedGoogle Scholar
  42. Thedieck K, Polak P, Kim ML, Molle KD, Cohen A, Jeno P, Arrieumerlou C, Hall MN (2007) PRAS40 and PRR5-like protein are new mTOR interactors that regulate apoptosis. PLoS ONE 2(11):e1217CrossRefPubMedGoogle Scholar
  43. Toschi A, Lee E, Gadir N, Ohh M, Foster DA (2008) Differential dependence of hypoxia-inducible factors 1 alpha and 2 alpha on mTORC1 and mTORC2. J Biol Chem 283(50):34495–34499CrossRefPubMedGoogle Scholar
  44. Tran H, Brunet A, Grenier JM, Datta SR, Fornace AJ Jr, DiStefano PS, Chiang LW, Greenberg ME (2002) DNA repair pathway stimulated by the forkhead transcription factor FOXO3a through the Gadd45 protein. Science 296(5567):530–534CrossRefPubMedGoogle Scholar
  45. Van Breukelen F, Martin SL (2001) Translational initiation is uncoupled from elongation at 18 degrees C during mammalian hibernation. Am J Physiol Regul Integr Comp Physiol 281:R1374–R1379PubMedGoogle Scholar
  46. Van Breukelen F, Martin SL (2002) Reversible depression of transcription during hibernation. J Comp Physiol B 172:355–361CrossRefPubMedGoogle Scholar
  47. Van Breukelen F, Sonenberg N, Martin SL (2004) Seasonal and state-dependent changes of eIF4E and 4E-BP1 during mammalian hibernation: implications for the control of translation during torpor. Am J Physiol Regul Integr Comp Physiol 287(2):R349–R353PubMedGoogle Scholar
  48. Vander Haar E, Lee SE, Bandhakavi S, Griffin TJ, Kim DH (2007) Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nat Cell Biol 9(3):316–323CrossRefPubMedGoogle Scholar
  49. Wang LCH, Lee TF (1996) Torpor and hibernation in mammals: metabolic, physiological, and biochemical adaptations. In: Fregley MJ, Blatteis CM (eds) Handbook of physiology: environmental physiology, section 4, vol 1. Oxford University Press, New York, pp 507–532Google Scholar
  50. Wang L, Harris TE, Roth RA, Laurence JC Jr (2007) PRAS40 regulates mTORC1 kinase activity by functioning as a direct inhibitor of substrate binding. J Biol Chem 282(27):20036–20044CrossRefPubMedGoogle Scholar
  51. Whiteman EL, Cho H, Birnbaum MJ (2002) Role of Akt/protein kinase B in metabolism. Trends Endocrinol Metab 13(10):444–451CrossRefPubMedGoogle Scholar
  52. Zhang F, Beharry ZM, Harris TE, Lilly MB, Smith CD, Mahajan S, Kraft AS (2009) PIM1 protein kinase regulates PRAS40 phosphorylation and mTOR activity in FDCP1 cells. Cancer Biol Ther 8(9):846–853PubMedGoogle Scholar

Copyright information

© US Government 2010

Authors and Affiliations

  1. 1.Stroke Branch, National Institute of Neurological Disorders and StrokeNational Institutes of HealthBethesdaUSA

Personalised recommendations