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AMPK와 자식작용의 미토콘드리아 생합성 조절 기전

Control Mechanism of AMPK and Autophagy for Mitochondrial Biogenesis

  • 발행 : 2009.04.28

초록

비정상적인 미토콘드리아에 의해 산화 스트레스가 증가하면 세포내 신호전달 및 유전자 발현에 손상을 일으켜 인슐린 저항성이나 당뇨병 등의 여러 질환들을 유발한다. 그런데 자식작용은 산화 스트레스로 기능이 저하된 미토콘드리아를 제거하여 인슐린 저항성 등을 억제해준다. 한편 운동도 미토콘드리아 생합성을 강화시켜 조직의 기능저하나 퇴행을 회복시켜준다. 따라서 운동과 자식작용이 서로 연관되어 미토콘드리아 생합성을 유도하는 신호체계로 작용할 가능성이 있고, 이 연구를 통해 운동 혹은 AICAR (aminoimidazole-4-carboxamide-1-${\beta}$-D-ribofuranoside)처치로 활성 화된 AMPK(5'-AMP- activated protein kinase) 신호전달체계가 미토콘드리아 생합성을 증가시키는 경로에 자식작용이 관여하는지의 여부를 확인하고자 하였다. 연구결과에 따르면, 6시간의 급성운동으로 쥐의 골격근에서 PGC-1(peroxisome proliferator-activated receptor gamma coactivator 1)과 mtTFA (mitochondrial transcription factor A)의 mRNA 발현이 유의하게 증가하였다. 하지만 자식작용 표지제인 LC3(microtubule-associated proteinl light chain 3)의 mRNA 발현은 증가경향을 나타냈지만 유의하지 않았다. 한편 C2C12 근세포에서도 AICAR 처치에 의해 PGC-1, mtTFA mRNA 발현이 모두 증가하였지만, 이러한 증가는 LC3 SiRNA에 의해서 억제되지 않는 것으로 나타났다. 이러한 결과들을 통해 자식작용은 AMPK에 의해 조절되는 신호전달 전달체계와는 다른 경로로 미토콘드리아 생합성에 영향을 미칠 것으로 사료된다.

Increased oxidative stress by abnormal mitochondrial function can damage cell signal transduction and gene expression, and induce insulin resistance or diabetes. Autophagy, however, improve insulin resistance by clearance of malfunctioning mitochondria. Exercise also recovers the muscle dysfunction and degeneration by activating mitochondrial biogenesis. As it seems that exercise and autophagy might act as an orchestrated network to induce mitochondrial biogenesis, we investigated whether autophagy is involved in AMPK signal pathway stimulated by exercise or AICAR to increase mitochondrial biogenesis. And it showed that PGC-1 and mtTFA, but not autophagy marker LC3 mRNA expression were significantly increased by 6 hr of acute exercise. On the other hand, PGC-1 and mtTFA mRNA expression were upregulated by AICAR treatment to C2C12 myotube. However these genes were not inhibited by LC3 siRNA transfection. These results provide the evidence that autopahgy affects on mitochondrial biogenesis through different signal pathway from AMPK signal transduction.

키워드

참고문헌

  1. 정혜승, "생쥐의 노화과정에서 동반되는 미토콘 드리아의 변화와 인슐린 저항성과의 상관관계에 대한 분석", 서울대학교 박사학위논문, 2007.
  2. T. Akimoto, S. C. Pohnert, P. Li, M. Zhang, C. Gumbs, P. B. Rosenberg, R. S. Williams, and Z. Yan, "Exercise stimulates Pgc-1alpha transcription in skeletal muscle through activation of the p38 MAPK pathway," J. Biol. Chem., Vol.280, No.20, pp.19587-19593, 2005. https://doi.org/10.1074/jbc.M408862200
  3. K. Almind and C. R. Kahn, "Genetic determinants of energy expenditure and insulin resistance in diet-induced obesity in mice," Diabetes, Vol.53, No.12, pp.3274-3285, 2004. https://doi.org/10.2337/diabetes.53.12.3274
  4. P. M. Barger, A. C. Browning, A. N. Garner, and D. P. Kelly, "p38 mitogen-activated protein kinase activates peroxisome proliferator-activated receptor ${\alpha}," J. Biol. Chem., Vol.276, pp.44495-44501, 2001. https://doi.org/10.1074/jbc.M105945200
  5. Z. P. Chen, T. J. Stephens, S. Murthy, B. J. Canny, M. Hargreaves, L. A. Witters, B. E. Kemp, and G. K. McConell, "Effect of exercise intensity on skeletal muscle AMPK signaling in humans," Diabetes, Vol.52, No.9, pp.2205-2212, 2003. https://doi.org/10.2337/diabetes.52.9.2205
  6. J. L. Evans, I. D. Goldfine, B. A. Maddux, and G. M. Grodsky, "Oxidative stress and stress-activated signaling pathways: a unifying hypothesis of type 2 diabetes," Endocr. Rev., Vol.23, No.5, pp.599-622, 2002. https://doi.org/10.1210/er.2001-0039
  7. J. L. Evans, B. A. Maddux, and I. D. Goldfine, "The molecular basis for oxidative stress-induced insulin resistance," Antioxid. Redox. Signal.., Vol.7, No.7-8, pp.1040-1052, 2005. https://doi.org/10.1089/ars.2005.7.1040
  8. R. C. Ho, N. Fujii, L. A. Witters, M. F. Hirshman, and L. J. Goodyear, "Dissociation of AMP-activated protein kinase and p38 mitogen-activated protein kinase signaling in skeletal muscle," Biochem. Biophys. Res. Commun., Vol.362, No.2, pp.354-359, 2007. https://doi.org/10.1016/j.bbrc.2007.07.154
  9. D. A. Hood and A. Saleem, "Exercise-induced mitochondrial biogenesis in skeletal muscle," Nutr. Metab. Cardiovasc. Dis., Vol.17, No.5, pp.332-337, 2007. https://doi.org/10.1016/j.numecd.2007.02.009
  10. D. J. Klionsky and S. D. Emr, "Autophagy as a regulated pathway of cellular degradation," Science, Vol.290, No.5497, pp.1717-1721, 2000. https://doi.org/10.1126/science.290.5497.1717
  11. B. Levine and J. Yuan, "Autophagy in cell death: an innocent convict?," J. Clin. Invest., Vol.115, No.10, pp.2679-2688, 2005. https://doi.org/10.1172/JCI26390
  12. T. Masuyama, Y. Katsuda, and M. Shinohara, "A novel model of obesity-related diabetes: introgression of the Lepr(fa) allele of the Zucker fatty rat into nonobese Spontaneously Diabetic Torii (SDT) rats," Exp. Anim.., Vol.54, No.1, pp.13-20, 2005. https://doi.org/10.1538/expanim.54.13
  13. E. O. Ojuka, T. E. Jones, L. A. Nolte, M. Chen, B. R. Wamhoff, M. Sturek, and J. O. Holloszy, "Regulation of GLUT4 biogenesis in muscle: evidence for involvement of AMPK and Ca(2+)," Am. J. Physiol. Endocrinol. Metab., Vol.282, No.5, pp.E1008-1013, 2002. https://doi.org/10.1152/ajpendo.00512.2001
  14. P. Puigserver, J. Rhee, J. Lin, Z. Wu, J. C. Yoon, C. Y. Zhang, S. Krauss, V. K. Mootha, B. B. Lowell, and B. M. Spiegelman, "Cytokine stimulation of energy expenditure through p38 MAP kinase activation of PPARγ coactivator-1," Molecular Cell., Vol.8, pp.971-982, 2001. https://doi.org/10.1016/S1097-2765(01)00390-2
  15. G. M. Reaven, "Pathophysiology of insulin resistance in human disease," Physiol. Rev., Vol.75, No.3, pp.473-486, 1995.
  16. I. Trounce, E. Byrne, and S. Marzuki, "Decline in skeletal muscle mitochondrial respiratory chain function: possible factor in ageing," Lancet, Vol.1, No.8639, pp.637-639, 1989.
  17. D. C. Wright, P. C. Geiger, D. H. Han, T. E. Jones, and J. O. Holloszy, "Calcium induces increases in peroxisome proliferator-activated receptor gamma coactivator-1alpha and mitochondrial biogenesis by a pathway leading to p38 mitogen-activated protein kinase activation," J. Biol. Chem., Vol.282, No.26, pp.18793-18799, 2007. https://doi.org/10.1074/jbc.M611252200
  18. D. C. Wright, D. H. Han, P. M. Garcia-Roves, P. C. Geiger, T. E. Jones, and J. O. Holloszy, "Exercise-induced mitochondrial biogenesis begins before the increase in muscle PGC-1alpha expression," J. Biol. Chem., Vol.282, No.1, pp.194-199, 2007. https://doi.org/10.1074/jbc.M606116200
  19. X. Xi, J. Han and J. Z. Zhang, "Stimulation of glucose transport by AMP-activated protein kinase via activation of p38 mitogen-activated protein kinase," J. Biol. Chem., Vol.276, No.44, pp.41029-41034, 2001. https://doi.org/10.1074/jbc.M102824200