DOI QR코드

DOI QR Code

Rapamycin Rescues the Poor Developmental Capacity of Aged Porcine Oocytes

  • Received : 2013.12.13
  • Accepted : 2014.02.21
  • Published : 2014.05.01

Abstract

Unfertilized oocytes age inevitably after ovulation, which limits their fertilizable life span and embryonic development. Rapamycin affects mammalian target of rapamycin (mTOR) expression and cytoskeleton reorganization during oocyte meiotic maturation. The goal of this study was to examine the effects of rapamycin treatment on aged porcine oocytes and their in vitro development. Rapamycin treatment of aged oocytes for 24 h (68 h in vitro maturation [IVM]; $44h+10{\mu}M$ rapamycin/24 h, $47.52{\pm}5.68$) or control oocytes (44 h IVM; $42.14{\pm}4.40$) significantly increased the development rate and total cell number compared with untreated aged oocytes (68 h IVM, $22.04{\pm}5.68$) (p<0.05). Rapamycin treatment of aged IVM oocytes for 24 h also rescued aberrant spindle organization and chromosomal misalignment, blocked the decrease in the level of phosphorylated-p44/42 mitogen-activated protein kinase (MAPK), and increased the mRNA expression of cytoplasmic maturation factor genes (MOS, BMP15, GDF9, and CCNB1) compared with untreated, 24 h-aged IVM oocytes (p<0.05). Furthermore, rapamycin treatment of aged oocytes decreased reactive oxygen species (ROS) activity and DNA fragmentation (p<0.05), and downregulated the mRNA expression of mTOR compared with control or untreated aged oocytes. By contrast, rapamycin treatment of aged oocytes increased mitochondrial localization (p<0.05) and upregulated the mRNA expression of autophagy (BECN1, ATG7, MAP1LC3B, ATG12, GABARAP, and GABARAPL1), anti-apoptosis (BCL2L1 and BIRC5; p<0.05), and development (NANOG and SOX2; p<0.05) genes, but it did not affect the mRNA expression of pro-apoptosis genes (FAS and CASP3) compared with the control. This study demonstrates that rapamycin treatment can rescue the poor developmental capacity of aged porcine oocytes.

References

  1. Pellestor, F., B. Andreo, F. Arnal, C. Humeau, and J. Demaille. 2003. Maternal aging and chromosomal abnormalities: new data drawn from in vitro unfertilized human oocytes. Hum. Genet. 112:195-203.
  2. Sun, Q. Y., G. M. Wu, L. Lai, A. Bonk, R. Cabot, K. W. Park, B. N. Day, R. S. Prather, and H. Schatten. 2002. Regulation of mitogen-activated protein kinase phosphorylation, microtubule organization, chromatin behavior, and cell cycle progression by protein phosphatases during pig oocyte maturation and fertilization in vitro. Biol. Reprod. 66:580-588. https://doi.org/10.1095/biolreprod66.3.580
  3. Shigenaga, M. K., T. M. Hagen, and B. N. Ames. 1994. Oxidative damage and mitochondrial decay in aging. Proceedings of the National Academy of Sciences of the United States of America 91:10771-10778. https://doi.org/10.1073/pnas.91.23.10771
  4. Somfai, T., K. Kikuchi, M. Kaneda, S. Akagi, S. Watanabe, E. Mizutani, S. Haraguchi, T. Q. Dang-Nguyen, Y. Inaba, M. Geshi, and T. Nagai. 2011. Cytoskeletal abnormalities in relation with meiotic competence and ageing in porcine and bovine oocytes during in vitro maturation. Anat. Histol. Ebryol. 40:335-344. https://doi.org/10.1111/j.1439-0264.2011.01079.x
  5. Steuerwald, N. M., M. D. Steuerwald, and J. B. Mailhes. 2005. Post-ovulatory aging of mouse oocytes leads to decreased MAD2 transcripts and increased frequencies of premature centromere separation and anaphase. Mol. Hum. Reprod. 11:623-630. https://doi.org/10.1093/molehr/gah231
  6. Tarin, J.J. 1996. Potential effects of age-associated oxidative stress on mammalian oocytes/embryos. Mol. Hum. Reprod. 2:717-724. https://doi.org/10.1093/molehr/2.10.717
  7. Toth, M. L., T. Sigmond, E. Borsos, J. Barna, P. Erdelyi, K. Takacs-Vellai, L. Orosz, A. L. Kovacs, G. Csikos, M. Sass, and T. Vellai. 2008. Longevity pathways converge on autophagy genes to regulate life span in Caenorhabditis elegans. Autophagy 4:330-338. https://doi.org/10.4161/auto.5618
  8. Tripathi, A., S. Khatun, A. N. Pandey, S. K. Mishra, R. Chaube, T. G. Shrivastav, and S. K. Chaube. 2009. Intracellular levels of hydrogen peroxide and nitric oxide in oocytes at various stages of meiotic cell cycle and apoptosis. Free Radic. Res. 43(3):287-294. https://doi.org/10.1080/10715760802695985
  9. Vellai, T., K. Takacs-Vellai, Y. Zhang, A. L. Kovacs, L. Orosz, and F. Muller. 2003. Genetics: influence of TOR kinase on lifespan in C. elegans. Nature 426(6967):620.
  10. Blagosklonny, M. V. 2008. Aging: ROS or TOR. Cell Cycle 7(21):3344-3354. https://doi.org/10.4161/cc.7.21.6965
  11. Wullschleger, S., R. Loewith, and M.N. Hall. 2006. TOR signaling in growth and metabolism. Cell 124:471-484. https://doi.org/10.1016/j.cell.2006.01.016
  12. Xu, Z., A. Abbott, G. S. Kopf, R. M. Schultz, and T. Ducibella. 1997. Spontaneous activation of ovulated mouse eggs: time-dependent effects on M-phase exit, cortical granule exocytosis, maternal messenger ribonucleic acid recruitment, and inositol 1,4,5-trisphosphate sensitivity. Biol. Reprod. 57:743-750. https://doi.org/10.1095/biolreprod57.4.743
  13. Bjedov, I., J. M. Toivonen, F. Kerr, C. Slack, J. Jacobson, A. Foley, and L. Partridge. 2010. Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metab. 11:35-46. https://doi.org/10.1016/j.cmet.2009.11.010
  14. Chambers, I., D. Colby, M. Robertson, J. Nichols, S. Lee, S. Tweedie, and A. Smith. 2003. Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell 113:643-655. https://doi.org/10.1016/S0092-8674(03)00392-1
  15. Agarwal, A., S. Gupta, and R. Sharma. 2005. Oxidative stress and its implications in female infertility - A clinician's perspective. Reprod. Biomed. Online 11(5):641-650. https://doi.org/10.1016/S1472-6483(10)61174-1
  16. Baird, D. T., J. Collins, J. Egozcue, L. H. Evers, L. Gianaroli, H. Leridon, A. Sunde, A. Templeton, A. Van Steirteghem, J. Cohen, P. G. Crosignani, P. Devroey, K. Diedrich, B. C. Fauser, L. Fraser, A. Glasier, I. Liebaers, G. Mautone, G. Penney, and B. Tarlatzis. 2005. Fertility and ageing. Hum. Reprod. Update 11(3):261-276. https://doi.org/10.1093/humupd/dmi006
  17. Dodson, M. G., B. S. Minhas, S. K. Curtis, T. V. Palmer, and J. L. Robertson. 1989. Spontaneous zona reaction in the mouse as a limiting factor for the time in which an oocyte may be fertilized. J. In Vitro Fert. Embryo Transf. 6:101-106. https://doi.org/10.1007/BF01130735
  18. Dumont, F. J., M. J. Staruch, S. L. Koprak, M. R. Melino, and N. H. Sigal. 1990. Distinct mechanisms of suppression of murine T cell activation by the related macrolides FK-506 and rapamycin. J. Immunol. 144:251-258.
  19. Harman, D. 1956. Aging: A theory based on free radical and radiation chemistry. J. Gerontol. 11:298-300. https://doi.org/10.1093/geronj/11.3.298
  20. George, M. A., S. J. Pickering, P. R. Braude, and M. H. Johnson. 1996. The distribution of alpha- and gamma-tubulin in fresh and aged human and mouse oocytes exposed to cryoprotectant. Mol. Hum. Reprod. 2:445-456. https://doi.org/10.1093/molehr/2.6.445
  21. Guertin, D. A. and D. M. Sabatini. 2007. Defining the role of mTOR in cancer. Cancer Cell 12:9-22. https://doi.org/10.1016/j.ccr.2007.05.008
  22. Gupta, M. K., S. J. Uhm, and H. T. Lee. 2010. Effect of vitrification and beta-mercaptoethanol on reactive oxygen species activity and in vitro development of oocytes vitrified before or after in vitro fertilization. Fertil. Steril. 93:2602-2607. https://doi.org/10.1016/j.fertnstert.2010.01.043
  23. Harris, T. E. and J. C. JrLawrence. 2003. TOR signaling. Science's STKE: signal transduction knowledge environment 2003(212):re15.
  24. Harrison, D. E., R. Strong, Z. D. Sharp, J. F. Nelson, C. M. Astle, K. Flurkey, N. L. Nadon, J. E. Wilkinson, K. Frenkel, C. S. Carter, M. Pahor, M. A. Javors, E. Fernandez, and R. A. Miller. 2009. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460:392-395.
  25. Jacinto, E. and M. N. Hall. 2003. Tor signalling in bugs, brain and brawn. Nat. Rev. Mol. Cell Biol. 4:117-126. https://doi.org/10.1038/nrm1018
  26. Kaeberlein, M., R. W. 3rd Powers, K. K. Steffen, E. A. Westman, D. Hu, N. Dang, E. O. Kerr, K. T. Kirkland, S. Fields, and B. K. Kennedy. 2005. Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science 310(5751):1193-1196. https://doi.org/10.1126/science.1115535
  27. Kapahi, P., B. M. Zid, T. Harper, D. Koslover, V. Sapin, and S. Benzer. 2004. Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. Curr. Biol. 14:885-890. https://doi.org/10.1016/j.cub.2004.03.059
  28. Kenyon, C. J. 2010. The genetics of ageing. Nature 464:504-512. https://doi.org/10.1038/nature08980
  29. Lee, S. E., J. H. Kim, and N. H. Kim. 2007. Inactivation of MAPK affects centrosome assembly, but not actin filament assembly, in mouse oocytes maturing in vitro. Mol. Reprod. Dev. 74:904-911. https://doi.org/10.1002/mrd.20695
  30. Khurana, N.K. and H. Niemann. 2000. Energy metabolism in preimplantation bovine embryos derived in vitro or in vivo. Biology of reproduction 62(4):847-856. https://doi.org/10.1095/biolreprod62.4.847
  31. Kikuchi, K., K. Naito, J. Noguchi, A. Shimada, H. Kaneko, M. Yamashita, F. Aoki, H. Tojo, and Y. Toyoda. 2000. Maturation/M-phase promoting factor: a regulator of aging in porcine oocytes. Biol. Reprod. 63:715-722. https://doi.org/10.1095/biolreprod63.3.715
  32. Lee, S. E., K. C. Hwang, S. C. Sun, Y. N. Xu, and N. H. Kim. 2011. Modulation of autophagy influences development and apoptosis in mouse embryos developing in vitro. Mol. Reprod. Dev. 78:498-509. https://doi.org/10.1002/mrd.21331
  33. Lee, S. E., S. C. Sun, H. Y. Choi, S. J. Uhm, and N. H. Kim. 2012. mTOR is required for asymmetric division through small GTPases in mouse oocytes. Mol. Reprod. Dev. 79:356-366. https://doi.org/10.1002/mrd.22035
  34. Livak, K. J. and T. D. Schmittgen. 2001. Analysis of relative gene expression data using real-time quantitative PCR and the $2-^{\Delta{\Delta}CT}$ method. Methods 25:402-408. https://doi.org/10.1006/meth.2001.1262
  35. Luo, S. and D. C. Rubinsztein. 2007. Atg5 and Bcl-2 provide novel insights into the interplay between apoptosis and autophagy. Cell Death Differ. 14:1247-1250. https://doi.org/10.1038/sj.cdd.4402149
  36. Ma, W., D. Zhang, Y. Hou, Y. H. Li, Q.Y. Sun, X. F. Sun, and W. H. Wang. 2005. Reduced expression of MAD2, BCL2, and MAP kinase activity in pig oocytes after in vitro aging are associated with defects in sister chromatid segregation during meiosis II and embryo fragmentation after activation. Biol. Reprod. 72:373-383. https://doi.org/10.1095/biolreprod.104.030999
  37. Mammucari, C. and R. Rizzuto. 2010. Signaling pathways in mitochondrial dysfunction and aging. Mech. Ageing Dev. 131:536-543. https://doi.org/10.1016/j.mad.2010.07.003
  38. Miao, Y. L., K. Kikuchi, Q. Y. Sun, and H. Schatten. 2009. Oocyte aging: cellular and molecular changes, developmental potential and reversal possibility. Human Reprod. Update 15:573-585. https://doi.org/10.1093/humupd/dmp014
  39. Mitsui, K., Y. Tokuzawa, H. Itoh, K. Segawa, M. Murakami, K. Takahashi, M. Maruyama, M. Maeda, and S. Yamanaka. 2003. The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Cell 113:631-642. https://doi.org/10.1016/S0092-8674(03)00393-3
  40. Nichols, J., B. Zevnik, K. Anastassiadis, H. Niwa, D. Klewe-Nebenius, I. Chambers, H. Scholer, and A. Smith. 1998. Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell 95:379-391. https://doi.org/10.1016/S0092-8674(00)81769-9
  41. Ono, T., E. Mizutani, C. Li, K. Yamagata, and T. Wakayama. 2011. Offspring from intracytoplasmic sperm injection of aged mouse oocytes treated with caffeine or MG132. Genesis 49:460-471. https://doi.org/10.1002/dvg.20756

Cited by

  1. Effect of L-carnitine supplementation on maturation and early embryo development of immature mouse oocytes selected by brilliant cresyle blue staining vol.32, pp.4, 2015, https://doi.org/10.1007/s10815-015-0430-5
  2. Cell Synchronization by Rapamycin Improves the Developmental Competence of Porcine SCNT Embryos vol.18, pp.3, 2016, https://doi.org/10.1089/cell.2015.0090
  3. Ovarian ageing: the role of mitochondria in oocytes and follicles vol.22, pp.6, 2016, https://doi.org/10.1093/humupd/dmw028
  4. Short-term rapamycin treatment increases ovarian lifespan in young and middle-aged female mice vol.16, pp.4, 2017, https://doi.org/10.1111/acel.12617
  5. Treatment of allicin improves maturation of immature oocytes and subsequent developmental ability of preimplantation embryos vol.25, pp.04, 2017, https://doi.org/10.1017/S0967199417000302
  6. Effect and possible mechanisms of melatonin treatment on the quality and developmental potential of aged bovine oocytes vol.29, pp.9, 2017, https://doi.org/10.1071/RD16223
  7. Mitochondrial dysfunction and ovarian aging vol.77, pp.5, 2017, https://doi.org/10.1111/aji.12651
  8. Fibroblast growth factor 10 markedly improves in vitro maturation of porcine cumulus-oocyte complexes vol.84, pp.1, 2017, https://doi.org/10.1002/mrd.22756
  9. Parental age and gene expression profiles in individual human blastocysts vol.8, pp.1, 2018, https://doi.org/10.1038/s41598-018-20614-8
  10. The role of mitochondria in the female germline: Implications to fertility and inheritance of mitochondrial diseases vol.42, pp.6, 2018, https://doi.org/10.1002/cbin.10947