Journal of the Korean Applied Science and Technology (한국응용과학기술학회지)

The Korean Society of Applied Science and Technology (한국응용과학기술학회)
권호 표지
DOI QR코드

DOI QR Code

The effect of endurance exercise and MitoQ intake on pathological characteristics in MPTP-induced animal model of Parkinson's disease

지구성 운동과 MitoQ 섭취가 MPTP로 유도된 파킨슨 질환 생쥐의 병리학적 특징에 미치는 영향

  • Kim, Dong-Cheol (Exercise biochemistry Laboratory, Korea National Sport University) ;
  • Um, Hyun Seob (Department of Sports Medicine, Konyang University) ;
  • Oh, Eun-Tak (Department of Sports Science & Rehabilitation, Woosong University) ;
  • Cho, Joon-Yong (Department of Health and Exercise Science, Korea National Sport University) ;
  • Jang, Yongchul (Exercise biochemistry Laboratory, Korea National Sport University)
  • 김동철 (한국체육대학교 운동생화학실) ;
  • 엄현섭 (건양대학교 스포츠의학과) ;
  • 오은택 (우송대학교 스포츠건강재활학과) ;
  • 조준용 (한국체육대학교 운동건강관리학과) ;
  • 장용철 (한국체육대학교 운동생화학실)
  • Received : 2020.07.28
  • Accepted : 2020.08.19
  • Published : 2020.08.31
Download PDF
⟨ Previous Next ⟩

Abstract

We investigated the whether endurance exercise and MitoQ intake mediated neuroprotection are associated with mitochondrial function in 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine(MPTP) -induced mice model of Parkinson's disease. C57BL/6 male mice were randomly assigned to five groups: Normal Conrol(NC, n=10), MPTP Control(MC, n=10), MPTP +MitoQ(MQ, n=10), MPTP + Exercise(ME, n=10) and MPTP + MitoQ + Exercise(MQE, n=10). Exercise intervention groups performed the treadmill exercise for 5days/week for 5 weeks with gradual increase of intensity. MitoQ intake groups consumed the MitoQ at a concentration of 250μmol by dissolving with water during experiment period. Our data demonstrated that ME and MQE group restored MPTP-induced motor dysfunction. In addition, treatment groups(MQ, ME and MQE) increased tyrosine hydroxylase levels, and suppressed the accumulation of α-synuclein levels. Futhermore, treatment groups modulated the mitochondrial function such as upregulated mitochondrial biogenesis, increased antioxidant enzyme, enhanced a anti-apoptotic protein(e.g., BCL2), and reduced a pro-apoptotic protein(e.g., BAX). Taken together, these results suggested that endurance exercise and MitoQ intake-mediated increase in mitochondrial function contributes to improvement of aggravated dopaminergic neuronal, resulting in attenuation of motor function of Parkinson's disease.

본 연구는 파킨슨 질환(Parkinson's disease) 마우스 모델을 대상으로 지구성 운동과 MitoQ 섭취가 뇌의 흑질의 미토콘드리아 기능에 미치는 영향을 확인하는데 목적이 있다. 파킨슨 질환을 유도하기 위해 C57BL/6 수컷 마우스를 대상으로 복강 내 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) 25mg/kg과 흡수를 돕기 위한 probenecid 250mg/kg을 이용하여 주 2회 5주간 총 10회 투여하였다. 실험 집단은 생리식염수를 투여하는 집단(Normal Conrol (NC), n=10), MPTP 투여집단(MPTP Control (MC), n=10), MPTP 투여 + MitoQ 투여집단(MPTP + MitoQ (MQ), n=10), MPTP 투여 + 운동집단(MPTP + Exercise (ME), n=10), MPTP 투여 + MitoQ 투여 + 운동집단(MPTP + MitoQ + Exercise (MQE), n=10) 총 5 집단으로 구성하였으며, 운동집단은 지구성 운동을 실시하였고 MitoQ집단은 점진적으로 250μmol로 늘리면서 5주간 섭취하였다. 연구결과 Rotarod-test에서 MC 집단에 비해 처치 집단은 운동 기능 저하의 개선을 보였다. 또한 MC 집단에 비해 처치 집단은 tyrosine hydroxylase의 수준의 증가와 알파시누클린(α-synuclein) 단백질 축적을 감소시켰다. 그리고 미토콘드리아 생합성에 주요조절 인자인 PGC-1α와 항산화 효소인 Catalase 발현이 MC 집단에 비해 처치 집단에서 증가해 미토콘드리아 기능을 개선했으며, 세포사멸 조절인자인 Bcl-2의 증가와 Bax의 감소를 통해 세포사멸을 완화했다. 따라서 5주간의 지구성 운동과 MitoQ 섭취는 파킨슨 질환에서 나타나는 병리학적 특징을 완화하고 운동기능을 향상시키는데 효과적인 것으로 나타났다.

Keywords

References

  1. J.A. Obeso, M.C. Rodriguez-Oroz, C.G. Goetz, C. Marin, J.H. Kordower, M.Rodriguez, E.C. Hirsch, M. Farrer, A.H. Schapira, G. Halliday, "Missing piecesin the Parkinson's disease puzzle", Nature Medicine, Vol.16, No.6 pp. 653-661, (2010). https://doi.org/10.1038/nm.2165
  2. L.V. Kalia,A.E. Lang, "Parkinson's disease", The Lancet, Vol.386, No.9996 pp. 896-912, (2015). https://doi.org/10.1016/S0140-6736(14)61393-3
  3. A.B. Singleton,M. Farrer, J. Johnson, A. Singleton, S. Hague, J. Kachergus, M. Hulihan, T.Peuralinna, A. Dutra, R. Nussbaum, S. Lincoln, A. Crawley, M. Hanson, D.Maraganore, C. Adler, M.R. Cookson, M. Muenter, M. Baptista, D. Miller, J.Blancato, J. Hardy, K. Gwinn-Hardy, "alpha-Synuclein locus triplication causesParkinson's disease", Science, Vol.302, No5646 pp. 841, (2003). https://doi.org/10.1126/science.1090278
  4. S.W. Tait, D.R.Green, "Mitochondrial regulation of cell death", Cold Spring Harbor Perspectives in Biology, Vol.15, No.9 a008706, (2013).
  5. C. Ciron, L.Zheng, W. Bobela, G.W. Knott, T.C. Leone, D.P. Kelly, B.L. Schneider, "PGC-$1{\alpha}$ activity in nigral dopamine neurons determines vulnerability to $\alpha$-synuclein", Acta Neuropathologica Communications, Vol.3, No.16 s40478-015-0200-8, (2015).
  6. G.M. Petzinger,B.E. Fisher, S. McEwen, J.A. Beeler, J.P. Walsh, M.W. Jakowec, "Exercise-enhanced neuroplasticity targeting motor and cognitive circuitry in Parkinson's disease", The Lancet Neurology, Vol.12, No7 pp. 716-726, (2013). https://doi.org/10.1016/S1474-4422(13)70123-6
  7. J.H. Koo, Y.C.Jang, D.J. Hwang, H.S. Um, N.H. Lee, J.H. Jung, J.Y. Cho, "Treadmill exercise produces neuroprotective effects in a murine model of Parkinson's disease by regulating the TLR2/MyD88/NF-${\kappa}B$ signaling pathway", Neuroscience, Vol.356, pp. 102-113, (2017). https://doi.org/10.1016/j.neuroscience.2017.05.016
  8. Y. Jang, J.H. Koo, I. Kwon, E.B. Kang, H.S. Um, H. Soya, Y. Lee, J.Y. Cho, "Neuroprotective effects of endurance exercise against neuroinflammation in MPTP-induced Parkinson's disease mice", Brain Research, Vol.1655, pp. 186-193, (2017). https://doi.org/10.1016/j.brainres.2016.10.029
  9. Y. Jang, I.Kwon, W. Song, L.M. Cosio-Lima, S. Taylor, Y. Lee, "Modulation of mitochondrial phenotypes by endurance exercise contributes to neuroprotection against a MPTP-induced animal model of PD", Life Science, Vol.209, pp. 455-465, (2018). https://doi.org/10.1016/j.lfs.2018.08.045
  10. A.O. Oyewole, M.A. Birch-Machin, "Mitochondria-targeted antioxidants", The FASEB Journal, Vol.29, No.12 pp. 4766-4771, (2015). https://doi.org/10.1096/fj.15-275404
  11. M.J. McManus, M.P. Murphy, J.L. Franklin, "The mitochondria-targeted antioxidant MitoQprevents loss of spatial memory retention and early neuropathology in atransgenic mouse model of Alzheimer's disease", Journal of Neuroscience, Vol.31, No.44 pp. 15703-15715, (2011). https://doi.org/10.1523/JNEUROSCI.0552-11.2011
  12. H. Jin, A. Kanthasamy, A. Ghosh, V. Anantharam, B. Kalyanaraman, A.G. Kanthasamy, "Mitochondria-targeted antioxidants for treatment of Parkinson's disease:preclinical and clinical outcomes", Biochimica et Biophysica Acta, Vol.1842, No.8 pp. 1282-1294, (2014). https://doi.org/10.1016/j.bbadis.2013.09.007
  13. B.J. Snow,F.L. Rolfe, M.M. Lockhart, C.M. Frampton, J.D. O'Sullivan, V. Fung, R.A. Smith,M.P. Murphy, K.M. Taylor, "A double-blind, placebo-controlled study to assessthe mitochondria-targeted antioxidant MitoQ as a disease-modifying therapy in Parkinson's disease", Movement Disorders, Vol.25, No.11 pp. 1670-1674, (2014). https://doi.org/10.1002/mds.23148
  14. Y.S. Lau, G. Patki, K. Das-Panja, W.D. Le, S.O. Ahmad, "Neuroprotective effects and mechanisms of exercise in a chronic mouse model of Parkinson's disease with moderate neurodegeneration", European Journal of Neuroscience, Vol.33, No.7 pp. 1264-1274, (2011). https://doi.org/10.1111/j.1460-9568.2011.07626.x
  15. S.Rodriguez-Cuenca, H.M. Cocheme, A. Logan, I. Abakumova, T.A. Prime, C. Rose, A.Vidal-Puig, A.C. Smith, D.C. Rubinsztein, I.M. Fearnley, B.A. Jones, S. Pope,S.J. Heales, B.Y. Lam, S.G. Neogi, I. McFarlane, A.M. James, R.A. Smith, M.P.Murphy, "Consequences of long-term oral administration of the mitochondriatargeted antioxidant MitoQ to wild-type mice", Free Radical Biology & Medicine, Vol.48, No.1 pp. 161-72, (2010). https://doi.org/10.1016/j.freeradbiomed.2009.10.039
  16. M.M Bradford, "A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding", Analytical Biochemistry, Vol.72, No.1-2 pp. 248-254, (1976). https://doi.org/10.1016/0003-2697(76)90527-3
  17. G.E. Meredith,D.J. Rademacher, "MPTP mouse models of Parkinson's disease: an update", Journal of Parkinson's Disease, Vol.1, No.1 pp. 19-33, (2011). https://doi.org/10.3233/JPD-2011-11023
  18. G.M.Petzinger, J.P. Walsh, G. Akopian, E. Hogg, A. Abernathy, P. Arevalo, P.Turnquist, M. Vuckovic, B.E. Fisher, D.M. Togasaki, M.W. Jakowec, "Effects of treadmill exercise on dopaminergic transmission in the1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine-lesioned mouse model of basal ganglia injury", Journal of Neuroscience, Vol.27, No.20 pp. 5291- 5300, (2007). https://doi.org/10.1523/JNEUROSCI.1069-07.2007
  19. H.F. Shu, T.Yang, S.X. Yu, H.D. Huang, L.L. Jiang, J.W. Gu, Y.Q. Kuang, "Aerobic exercisefor Parkinson's disease: a systematic review and meta-analysis of randomized controlled trials", PLoS One, Vol.9, No.7 pp. e100503, (2014). https://doi.org/10.1371/journal.pone.0100503
  20. H.S. Cho, M.S.Shin, W. Song, T.W. Jun, B.V. Lim, Y.P. Kim, C.J. Kim, "Treadmill exercise alleviates short-term memory impairment in 6-hydroxydopamineinduced Parkinson's rats", Journal of Exercise Rehabilitation, Vol.9, No.3 pp. 354-364, (2013). https://doi.org/10.12965/jer.130048
  21. A. Ghosh, K.Chandran, S.V. Kalivendi, J. Joseph, W.E. Antholine, C.J. Hillard, A.Kanthasamy, A. Kanthasamy, B. Kalyanaraman, Neuroprotection by amitochondria-targeted drug in a Parkinson's disease model, Free Radical Biology & Medicine, Vol.49, No.11 pp. 1674-1684, (2010). https://doi.org/10.1016/j.freeradbiomed.2010.08.028
  22. L. Xu, J. Pu, "Alpha-Synuclein in Parkinson's Disease: From Pathogenetic Dysfunction to Potential Clinical Application", Parkinson's Disease, Vol.2016, 1720621, (2016).
  23. W. Zhou, J.C.Barkow, C.R. Freed, "Running wheel exercise reduces $\alpha$ -synuclein aggregation and improves motor and cognitive function in a transgenic mouse model of Parkinson's disease", PLoS One, Vol.12, No.12 e0190160, (2017). https://doi.org/10.1371/journal.pone.0190160
  24. L. Yang, N.Y.Calingasan, E.J. Wille, K. Cormier, K. Smith, R.J. Ferrante, M.F. Beal, "Combination therapy with coenzyme Q10 and creatine produces additiveneuroprotective effects in models of Parkinson's and Huntington's diseases", Journal of Neurochemistry, Vol.105, No.5 pp. 1427-1439, (2009).
  25. M.R. Cookson, "Parkinsonism due to mutations in PINK1, parkin, and DJ-1 and oxidative stress and mitochondrial pathways", Cold Spring Harbor Perspectives in Medicine, Vol.2, No.9 a009415, (2012). https://doi.org/10.1101/cshperspect.a009415
  26. J.H. Park,J.D. Burgess, A.H. Faroqi, N.N. DeMeo, F.C. Fiesel, W. Springer, M. Delenclos, P.J. McLean, "Alpha-synucleininduced mitochondrial dysfunction is mediated via a sirtuin 3-dependent pathway", Molecular Neurodegeneration, Vol.15, No.1 s13024-019-0349, (2020).
  27. J.H. Koo, J.Y.Cho, "Treadmill Exercise Attenuates $\alpha$-Synuclein Levels by Promoting Mitochondrial Function and Autophagy Possibly via SIRT1 in the Chronic MPTP/P-Induced Mouse Model of Parkinson's Disease", Neurotoxicity Research, Vol.32, No.3 pp. 473-486, (2017). https://doi.org/10.1007/s12640-017-9770-5
  28. Y. Xi, D.Feng, K. Tao, R. Wang, Y. Shi, H. Qin, M.P. Murphy, Q. Yang, G. Zhao, "MitoQ protects dopaminergic neurons in a 6-OHDA induced PD model by enhancing Mfn2-dependent mitochondrial fusion via activation of PGC-$1{\alpha}$", Biochimica et Biophysica Acta-Molecular Basis of Disease, Vol.2864, No.9 pp. 2859-2870, (2018).
  29. Y.C. Jang ,D.J. Hwang, J.H. Koo, H.S. Um, N.H. Lee, D.C. Yeom, Y. Lee, J.Y. Cho, "Association of exercise-induced autophagy upregulation and apoptosiss uppression with neuroprotection against pharmacologically induced Parkinson's disease", J Exerc Nutrition Biochem, Vol.22, No.1 pp. 1-8, (2018). https://doi.org/10.20463/jenb.2018.0001