Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Effects of insulin-like growth factor 1 on glutathione S-transferases and thioredoxin in growth hormone receptor knockout mice

  • 266 Accesses

  • 7 Citations

Abstract

Growth hormone (GH) and insulin-like growth factor 1 (IGF-1) have been shown to affect processes involved in cellular stress defense, aging, and longevity. This study was designed to identify possible mechanisms of a disrupted GH signaling pathway on stress resistance using growth hormone receptor knockout (GHRKO) mice. GHRKO mice are GH resistant due to the targeted disruption of the GH receptor/binding protein gene, thus preventing GH from binding and exerting its downstream effects. These mice have very low circulating IGF-1 levels and high GH levels, are obese yet insulin sensitive, and live longer than their wild-type controls. Wild-type or GHRKO mice were treated with saline or IGF-1 (WT saline, GHRKO saline, GHRKO IGF-1) two times daily for 7 days. Glutathione S-transferase (GST) activities, proteins, and gene expression were determined. Liver mitochondrial GSTA1, GSTA3, and GSTZ1 proteins were significantly higher in GHRKO when compared to those of WT mice. The 4-hydroxynonenal (4-HNE) GST activity was upregulated in GHRKO mice and was suppressed after IGF-1 administration. Interestingly, thioredoxin (Trx)1, Trx2, thioredoxin reductase (TrxR)1, and TrxR2 messenger RNA (mRNA) levels were significantly higher in the GHRKO as compared to WT mice, and IGF-1 treatment suppressed the expression of each. We also found that glutaredoxin (Grx)2 mRNA and cytosolic Grx activity were higher in GHRKO mice. These results suggest that the detoxification and stress response mechanisms in GHRKO mice are contributed in part by the circulating level of IGF-1.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

References

  1. Arner ES (2009) Focus on mammalian thioredoxin reductases—important selenoproteins with versatile functions. Biochim Biophys Acta 1790:495–526

  2. Aslund F, Beckwith J (1999) Bridge over troubled waters: sensing stress by disulfide bond formation. Cell 96:751–753

  3. Bartke A, Brown-Borg H (2004) Life extension in the dwarf mouse. Curr Top Dev Biol 63:189–225

  4. Bartke A, Chandrashekar V, Turyn D, Steger RW, Debeljuk L, Winters TA, Mattison JA, Danilovich NA, Croson W, Wernsing DR, Kopchick JJ (1999) Effects of growth hormone overexpression and growth hormone resistance on neuroendocrine and reproductive functions in transgenic and knock-out mice. Proc Soc Exp Biol Med 222:113–123

  5. Brown-Borg HM (2007) Hormonal regulation of longevity in mammals. Ageing Res Rev 6:28–45

  6. Brown-Borg HM, Rakoczy SG (2005) Glutathione metabolism in long-living Ames dwarf mice. Exp Gerontol 40:115–120

  7. Brown-Borg HM, Rakoczy SG, Sharma S, Bartke A (2009) Long-living growth hormone receptor knockout mice: potential mechanisms of altered stress resistance. Exp Gerontol 44:10–19

  8. Chandrashekar V, Bartke A, Coschigano KT, Kopchick JJ (1999) Pituitary and testicular function in growth hormone receptor gene knockout mice. Endocrinology 140:1082–1088

  9. Cheng JZ, Singhal SS, Sharma A, Saini M, Yang Y, Awasthi S, Zimniak P, Awasthi YC (2001) Transfection of mGSTA4 in HL-60 cells protects against 4-hydroxynonenal-induced apoptosis by inhibiting JNK-mediated signaling. Arch Biochem Biophys 392:197–207

  10. Cho CG, Kim HJ, Chung SW, Jung KJ, Shim KH, Yu BP, Yodoi J, Chung HY (2003) Modulation of glutathione and thioredoxin systems by calorie restriction during the aging process. Exp Gerontol 38:539–548

  11. Choksi KB, Roberts LJ 2nd, DeFord JH, Rabek JP, Papaconstantinou J (2007) Lower levels of F2-isoprostanes in serum and livers of long-lived Ames dwarf mice. Biochem Biophys Res Commun 364:761–764

  12. Coecke S, Vanhaecke T, Foriers A, Phillips IR, Vercruysse A, Shephard EA, Rogiers V (2000) Hormonal regulation of glutathione S-transferase expression in co-cultured adult rat hepatocytes. J Endocrinol 166:363–371

  13. Coschigano KT, Clemmons D, Bellush LL, Kopchick JJ (2000) Assessment of growth parameters and life span of GHR/BP gene-disrupted mice. Endocrinology 141:2608–2613

  14. Fernandes AP, Holmgren A (2004) Glutaredoxins: glutathione-dependent redox enzymes with functions far beyond a simple thioredoxin backup system. Antioxid Redox Signal 6:63–74

  15. Gardner JL, Gallagher EP (2001) Development of a peptide antibody specific to human glutathione S-transferase alpha 4-4 (hGSTA4-4) reveals preferential localization in human liver mitochondria. Arch Biochem Biophys 390:19–27

  16. Gladyshev VN, Liu A, Novoselov SV, Krysan K, Sun QA, Kryukov VM, Kryukov GV, Lou MF (2001) Identification and characterization of a new mammalian glutaredoxin (thioltransferase), Grx2. J Biol Chem 276:30374–30380

  17. Habig WH, Jakoby WB (1981) Assays for differentiation of glutathione S-transferases. Methods Enzymol 77:398–405

  18. Hauck SJ, Bartke A (2000) Effects of growth hormone on hypothalamic catalase and Cu/Zn superoxide dismutase. Free Radic Biol Med 28:970–978

  19. Hauck SJ, Aaron JM, Wright C, Kopchick JJ, Bartke A (2002) Antioxidant enzymes, free-radical damage, and response to paraquat in liver and kidney of long-living growth hormone receptor/binding protein gene-disrupted mice. Horm Metab Res 34:481–486

  20. Hayes JD, Strange RC (1995) Potential contribution of the glutathione S-transferase supergene family to resistance to oxidative stress. Free Radic Res 22:193–207

  21. Hayes JD, Flanagan JU, Jowsey IR (2005) Glutathione transferases. Annu Rev Pharmacol Toxicol 45:51–88

  22. Heid CA, Stevens J, Livak KJ, Williams PM (1996) Real time quantitative PCR. Genome Res 6:986–994

  23. Holmgren A (1979) Glutathione-dependent synthesis of deoxyribonucleotides. Characterization of the enzymatic mechanism of Escherichia coli glutaredoxin. J Biol Chem 254:3672–3678

  24. Holmgren A (1985) Thioredoxin. Annu Rev Biochem 54:237–271

  25. Holmgren A (1989) Thioredoxin and glutaredoxin systems. J Biol Chem 264:13963–13966

  26. Holmgren A, Bjornstedt M (1995) Thioredoxin and thioredoxin reductase. Methods Enzymol 252:199–208

  27. Holmgren A, Lu J (2010) Thioredoxin and thioredoxin reductase: current research with special reference to human disease. Biochem Biophys Res Commun 396:120–124

  28. Jowsey IR, Thomson RE, Orton TC, Elcombe CR, Hayes JD (2003) Biochemical and genetic characterization of a murine class Kappa glutathione S-transferase. Biochem J 373:559–569

  29. Kops GJ, Dansen TB, Polderman PE, Saarloos I, Wirtz KW, Coffer PJ, Huang TT, Bos JL, Medema RH, Burgering BM (2002) Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress. Nature 419:316–321

  30. Lee S, Kim SM, Lee RT (2013) Thioredoxin and thioredoxin target proteins: from molecular mechanisms to functional significance. Antioxid Redox Signal 18:1165–1207

  31. Lillig CH, Holmgren A (2007) Thioredoxin and related molecules—from biology to health and disease. Antioxid Redox Signal 9:25–47

  32. Lundberg M, Johansson C, Chandra J, Enoksson M, Jacobsson G, Ljung J, Johansson M, Holmgren A (2001) Cloning and expression of a novel human glutaredoxin (Grx2) with mitochondrial and nuclear isoforms. J Biol Chem 276:26269–26275

  33. Luthman M, Holmgren A (1982) Rat liver thioredoxin and thioredoxin reductase: purification and characterization. Biochemistry 21:6628–6633

  34. Mannervik B, Castro VM, Danielson UH, Tahir MK, Hansson J, Ringborg U (1987) Expression of class Pi glutathione transferase in human malignant melanoma cells. Carcinogenesis 8:1929–1932

  35. Mitsui A, Hamuro J, Nakamura H, Kondo N, Hirabayashi Y, Ishizaki-Koizumi S, Hirakawa T, Inoue T, Yodoi J (2002) Overexpression of human thioredoxin in transgenic mice controls oxidative stress and life span. Antioxid Redox Signal 4:693–696

  36. Panici JA, Wang F, Bonkowski MS, Spong A, Bartke A, Pawlikowska L, Kwok PY, Masternak MM (2009) Is altered expression of hepatic insulin-related genes in growth hormone receptor knockout mice due to GH resistance or a difference in biological life spans? J Gerontol A Biol Sci Med Sci 64:1126–1133

  37. Perez VI, Cortez LA, Lew CM, Rodriguez M, Webb CR, Van Remmen H, Chaudhuri A, Qi W, Lee S, Bokov A, Fok W, Jones D, Richardson A, Yodoi J, Zhang Y, Tominaga K, Hubbard GB, Ikeno Y (2011) Thioredoxin 1 overexpression extends mainly the earlier part of life span in mice. J Gerontol A Biol Sci Med Sci 66:1286–1299

  38. Powis G, Montfort WR (2001) Properties and biological activities of thioredoxins. Annu Rev Biophys Biomol Struct 41:261–295

  39. Prabhu KS, Reddy PV, Gumpricht E, Hildenbrandt GR, Scholz RW, Sordillo LM, Reddy CC (2001) Microsomal glutathione S-transferase A1-1 with glutathione peroxidase activity from sheep liver: molecular cloning, expression and characterization. Biochem J 360:345–354

  40. Raza H, Robin MA, Fang JK, Avadhani NG (2002) Multiple isoforms of mitochondrial glutathione S-transferases and their differential induction under oxidative stress. Biochem J 366:45–55

  41. Richie JP Jr, Lang CA, Chen TS (1992) Acetaminophen-induced depletion of glutathione and cysteine in the aging mouse kidney. Biochem Pharmacol 44:129–135

  42. Robin MA, Prabu SK, Raza H, Anandatheerthavarada HK, Avadhani NG (2003) Phosphorylation enhances mitochondrial targeting of GSTA4-4 through increased affinity for binding to cytoplasmic Hsp70. J Biol Chem 278:18960–18970

  43. Rojanathammanee L, Rakoczy S, Brown-Borg HM (2013) Growth hormone alters the glutathione S-transferase and mitochondrial thioredoxin system in long-living Ames dwarf mice. J Gerontol A Biol Sci Mes Sci (in press)

  44. Russell SJ, Kahn CR (2007) Endocrine regulation of ageing. Nat Rev Mol Cell Biol 8:681–691

  45. Salmon AB, Murakami S, Bartke A, Kopchick J, Yasumura K, Miller RA (2005) Fibroblast cell lines from young adult mice of long-lived mutant strains are resistant to multiple forms of stress. Am J Physiol Endocrinol Metab 289:E23–29

  46. Singh SP, Janecki AJ, Srivastava SK, Awasthi S, Awasthi YC, Xia SJ, Zimniak P (2002) Membrane association of glutathione S-transferase mGSTA4-4, an enzyme that metabolizes lipid peroxidation products. J Biol Chem 277:4232–4239

  47. Spyrou G, Enmark E, Miranda-Vizuete A, Gustafsson J (1997) Cloning and expression of a novel mammalian thioredoxin. J Biol Chem 272:2936–2941

  48. Srivastava PK, Waxman DJ (1993) Sex-dependent expression and growth hormone regulation of class alpha and class mu glutathione S-transferase mRNAs in adult rat liver. Biochem J 294(Pt 1):159–165

  49. Staffas L, Mankowitz L, Soderstrom M, Blanck A, Porsch-Hallstrom I, Sundberg C, Mannervik B, Olin B, Rydstrom J, DePierre JW (1992) Further characterization of hormonal regulation of glutathione transferase in rat liver and adrenal glands. Sex differences and demonstration that growth hormone regulates the hepatic levels. Biochem J 286(Pt 1):65–72

  50. Stone RC, Kim S, Barnes BJ, Aviv A (2012) Diverging antioxidative responses to IGF-1 in cultured human skin fibroblasts versus vascular endothelial cells. J Gerontol A Biol Sci Med Sci 67:939–946

  51. Toba G, Aigaki T (2000) Disruption of the microsomal glutathione S-transferase-like gene reduces life span of Drosophila melanogaster. Gene 253:179–187

  52. Tsuda M, Ootaka R, Ohkura C, Kishita Y, Seong KH, Matsuo T, Aigaki T (2010) Loss of Trx-2 enhances oxidative stress-dependent phenotypes in Drosophila. FEBS Lett 584:3398–3401

  53. Yoshitake S, Nanri H, Fernando MR, Minakami S (1994) Possible differences in the regenerative roles played by thioltransferase and thioredoxin for oxidatively damaged proteins. J Biochem 116:42–46

  54. Zhou Y, Xu BC, Maheshwari HG, He L, Reed M, Lozykowski M, Okada S, Cataldo L, Coschigamo K, Wagner TE, Baumann G, Kopchick JJ (1997) A mammalian model for Laron syndrome produced by targeted disruption of the mouse growth hormone receptor/binding protein gene (the Laron mouse). Proc Natl Acad Sci U S A 94:13215–13220

Download references

Acknowledgments

This work was supported by the NIH [RO1-AG034206 (HMBB); KO2 AG038509 (HMBB)], the Ellison Medical Foundation [AG-SS-2376-09 (HMBB)], and the Glenn Foundation for Medical Research (HMBB).

Author information

Correspondence to Holly M. Brown-Borg.

About this article

Verify currency and authenticity via CrossMark

Cite this article

Rojanathammanee, L., Rakoczy, S., Kopchick, J. et al. Effects of insulin-like growth factor 1 on glutathione S-transferases and thioredoxin in growth hormone receptor knockout mice. AGE 36, 9687 (2014). https://doi.org/10.1007/s11357-014-9687-3

Download citation

Keywords

  • Growth hormone
  • Glutathione S-transferase
  • Growth hormone receptor knockout mice
  • Thioredoxin
  • Glutaredoxin