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Regulation of Mitochondrial Homeostasis in Response to Endurance Exercise Training in Skeletal Muscle

지구성 훈련에 반응한 골격근의 미토콘드리아 항상성 조절

  • Ju, Jeong-sun (Department of Sports Science, the University of Suwon)
  • 주정선 (수원대학교 스포츠과학부)
  • Received : 2017.02.21
  • Accepted : 2017.03.27
  • Published : 2017.03.30

Abstract

Mitochondrial homeostasis is tightly regulated by two major processes: mitochondrial biogenesis and mitochondrial degradation by autophagy (mitophagy). Research in mitochondrial biogenesis in skeletal muscle in response to endurance exercise training has been well established, while the mechanisms regulating mitophagy and the relationship between mitochondrial biogenesis and degradation following endurance exercise training are not yet well defined. Studies have demonstrated that endurance exercise training increases the expression levels of mitochondrial biogenesis-, dynamics-, mitophagy-related genes in skeletal muscle. However, the increased levels of mitochondrial biogenesis marker proteins such as Cox IV and citrate synthase, by endurance exercise training were abolished when autophagy/mitophagy was inhibited in skeletal muscle. This suggests that both autophagy/mitophagy plays an important role in mitochondrial biogenesis/homeostasis and the coordination between the opposing processes may be important for skeletal muscle adaptation to endurance exercise training to improve metabolic function and endurance exercise performance. It is considered that endurance exercise training regulates each of these processes, mitochondrial biogenesis, fusion and fission events and autophagy/mitophagy, ensuring a relatively constant mitochondrial population. Exercise training may also have contributed to mitochondrial quality control which replaces old and/or unhealthy mitochondria with new and/or healthy ones in skeletal muscle. In this review paper, the molecular mechanisms regulating mitochondrial biogenesis and mitophagy and the coordination between the opposing processes is involved in the cellular adaptation to endurance exercise training in skeletal muscle will be discussed.

미토콘드리아의 항상성은 미토콘드리아 생합성과 마이토파지(자가포식에 의한 미토콘드리아 분해)로 불리는 2가지 주요 과정들에 의해 정교하게 조절되고 있다. 지구성 운동 훈련에 반응하여 골격근에서 미토콘드리아 생합성에 관한 기전들은 잘 정립되어 있는 반면 지구성 운동 훈련 후 골격근의 마이토파지 조절 기전과 마이토파지와 미토콘드리아 생합성의 협응을 조절하는 기전은 아직 명확히 밝혀져 있지 않다. 최근 연구들에 의하면 지구성 운동 훈련은 골격근에서 미토콘드리아 생합성, 미토콘드리아 역동성, 미토콘드리아 분해와 관련된 유전인자들의 발현을 증가시킨다고 하였다. 하지만 골격근에서 자가포식이 억제되었을 경우, 지구성 운동 훈련에 의한 미토콘드리아 생합성과 관련된 지표들인 Cox IV와 citrate synthase의 증가는 상쇄되었다. 따라서 자가포식과 마이토파지는 골격근의 미토콘드리아 생합성에 중요한 역할을 하며 정반대되는 이 두 과정(이화 또는 동화작용)의 협응 과정이 지구성 운동 훈련에 반응하여 대사적 기능과 지구력 운동 수행능력을 향상시키는 것과 같은 골격근의 적응에 중요한 듯하다. 지구성 운동은 미토콘드리아의 일정한 숫자를 유지시키기 위해 미토콘드리아 생합성, 미토콘드리아의 융합과 분열, 자가포식/마이토 파지들의 각각의 과정들을 조절하는 것으로 여겨진다. 지구성 운동 훈련은 골격근에서 마이토파지를 활성화시켜 미토콘드리아 양과 질을 조절하여 늙고 건강하지 않은 미토콘드리아를 젊고 건강한 미토콘드리아로 교체시킬 수 있다. 이 총론에서 미토콘드리아 생합성과 마이토파지의 분자학적 기전과 서로 상반되는 이 두 과정간의 협응이 골격근의 지구성 훈련에 대한 세포적 적응에 관련한다는 내용이 논의될 것이다.

Keywords

References

  1. Chalkiadaki, A, Igarashi, M, Nasamu, A. S, Knezevic, J. and Guarente, L. 2014. Muscle-specific SIRT1 gain-of-function increases slow-twitch fibers and ameliorates pathophysiology in a mouse model of Duchenne muscular dystrophy. PLoS Genet. 10, e1004490. https://doi.org/10.1371/journal.pgen.1004490
  2. Chan, D. C. 2012. Fusion and fission: interlinked processes critical for mitochondrial health. Annu. Rev. Genet. 46, 265-287. https://doi.org/10.1146/annurev-genet-110410-132529
  3. Davies, S. P., Helps, N. R., Cohen, P. T. and Hardie, D. G. 1995. 5'-AMPK inhibits dephosphorylation, as well as promoting phosphorylation, of the AMPK-activated protein kinase: studies using bacterially expressed human protein phosphatase-2C alpha and native bovine protein phosphatase-2AC. FEBS Lett. 377, 421-425. https://doi.org/10.1016/0014-5793(95)01368-7
  4. Drake, J. C., Wilson, R. J. and Yan, Z. 2016. Molecular mechanisms for mitochondrial adaptation to exercise training in skeletal muscle. FASEB J. 30, 13-22. https://doi.org/10.1096/fj.15-276337
  5. Geisler, S., Holmstrom, K. M., Skujat, D., Fiesel, F. C. and Rothfuss, O. C., et al. 2010. PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat. Cell Biol. 12, 119-131. https://doi.org/10.1038/ncb2012
  6. Gerhart-Hines, Z., Rodgers, J. T., Bare, O., Lerin, C. and Kim, S. H., et al. 2007. Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1alpha. EMBO J. 26, 1913-1923. https://doi.org/10.1038/sj.emboj.7601633
  7. Goldman, S. J., Taylor, R., Zhang, Y. and Jin, S. 2010. Autophagy and the degradation of mitochondria. Mitochondrion 10, 309-315. https://doi.org/10.1016/j.mito.2010.01.005
  8. Gomes, L. C., Di Benedetto, G. and Scorrano, L. 2011. During autophagy mitochondrial elongate, are spared from degradation and sustain cell viability. Nat. Cell Biol. 13, 589-598. https://doi.org/10.1038/ncb2220
  9. Hanna, R. A., Quinsay, M. N., Orogo, A. M., Giang, K. and Rikka, S., et al. 2012. Microtubule-associated protein 1 light chain 3 (LC3) interacts with Bnip3 protein to selectively remove endoplasmic reticulum and mitochondria via autophagy. J. Biol. Chem. 287, 19094-19104. https://doi.org/10.1074/jbc.M111.322933
  10. Irrcher, I., Liubicic, V. and Hood, D. A. 2009. Interactions between ROS and AMP kinase activity in the regulation of PGC-1alpha transcription in skeletal muscle cells. Am. J. Physiol. Cell Physiol. 296, C116-123. https://doi.org/10.1152/ajpcell.00267.2007
  11. Jin, S. M., Lazarou, M., Wang, C., Kane, L. A. and Narendra, D. P., et al. 2010. Mitochondrial membrane potential regulates PINK1 import and proteolytic destabilization by PARL. J. Cell Biol. 191, 933-942. https://doi.org/10.1083/jcb.201008084
  12. Ju, J. S., Jeon, S. I., Park, J. Y., Lee, J. Y. and Lee, S. C., et al. 2016. Autophagy plays a role in skeletal muscle mitochondrial biogenesis in an endurance exercise-trained condition. J. Physiol. Sci. 66, 417-430. https://doi.org/10.1007/s12576-016-0440-9
  13. Klionsky, D. J. 2007. Autophagy: from phenomenology to molecular understanding in less than a decade. Nat. Rev. Mol. Cell Biol. 8, 931-937. https://doi.org/10.1038/nrm2245
  14. Konopka, A. R., Suer, M. K., Wolff, C. A. and Harber, M. P. 2014. Markers of human skeletal muscle mitochondrial biogenesis and quality control: effects of age and aerobic exercise training. J. Gerontol. A. Biol. Sci. Med. Sci. 69, 371-378. https://doi.org/10.1093/gerona/glt107
  15. Levine, B. and Klionsky, D. J. 2004. Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev. Cell. 6, 463-477. https://doi.org/10.1016/S1534-5807(04)00099-1
  16. Lira, V. A., Okutsu, M., Zhang, M., Greene, N. P. and Laker, R. C, et al. 2013. Autophagy is required for exercise training-induced skeletal muscle adaptation and improvement of physical performance. FASEB J. 27, 4184-4193. https://doi.org/10.1096/fj.13-228486
  17. Little, J. P., Safdar, A., Benton, C. R. and Wright, D.C. 2011. Skeletal muscle and beyond: the role of exercise as mediator of systemic mitochondrial biogenesis. Appl. Physiol. Nutr. Metab. 36, 598-607. https://doi.org/10.1139/h11-076
  18. Masiero, E., Agatea, L., Mammucari, C., Blaauw, B. and Loro, E., et al. 2009. Autophagy is required to maintain muscle mass. Cell Metab. 10, 507-515. https://doi.org/10.1016/j.cmet.2009.10.008
  19. McConell, G. K., Ng, G. P., Phillips, M., Ruan, Z. and Macaulay, S. L., et al. 2010. Central role of nitric oxide synthase in AICAR and caffeine-induced mitochondrial biogenesis in L6 myocytes. J. App.l Physiol. 108, 589-595.
  20. Menzies, K. J., Singh, K., Saleem, A. and Hood, D. A. 2013. Sirtuin 1-mediated effects of exercise and resveratrol on mitochondrial biogenesis. J. Biol. Chem. 288, 6968-6979. https://doi.org/10.1074/jbc.M112.431155
  21. Mizushima, N., Ohsumi, Y. and Yoshimori, T. 2002. Autophagosome formation in mammalian cells. Cell Struct. Funct. 27, 421-429. https://doi.org/10.1247/csf.27.421
  22. Palikaras, K. and Tavernarakis, N. 2014. Mitochondrial homeostasis: the interplay between mitophagy and mitochondrial biogenesis. Exp. Geront. 56, 182-188. https://doi.org/10.1016/j.exger.2014.01.021
  23. Perry, C. G., Lally, J., Holloway, G. P. and Heigenhauser, G. J., et al. 2010. Repeated transient mRNA bursts precede increases in transcriptional and mitochondrial proteins during training in human skeletal muscle. J. Physiol. 588, 4795-4810. https://doi.org/10.1113/jphysiol.2010.199448
  24. Pilegaard, H., Saltin, B. and Neufer, P. D. 2003. Exercise induces transient transcriptional activation of the PGC-1 alpha gene in human skeletal muscle. J. Physiol. 546, 851-858. https://doi.org/10.1113/jphysiol.2002.034850
  25. Puigserver, P., Adelmant, G., Wu, Z., Fan, M. and Xu, J., et al. 1999. Activation of PPARgamma coactivator-1 through transcription factor docking. Science 286, 1368-1371. https://doi.org/10.1126/science.286.5443.1368
  26. Ravikumar, B., Sarkar, S., Davies, J. E., Futter, M. and Garcia-Arencibia, M., et al. 2010. Regulation of mammalian autophagy in physiology and pathophysiology. Physiol. Rev. 90, 1383-1435. https://doi.org/10.1152/physrev.00030.2009
  27. Safdar, A., Little, J. P., Stokl, A. J., Hettinga, B. P. and Akhtar, M., et al. 2011. Exercise increases mitochondrial PGC-1alpha content and promotes nuclear-mitochondrial cross-talk to coordinate mitochondrial biogenesis. J. Biol. Chem. 286, 10605-10617. https://doi.org/10.1074/jbc.M110.211466
  28. Tam, B. T., Pei, X. M., Yu, A. P., Sin, T. K. and Leung, K. K., et al. 2015. Autophagic adaptation is associated with exercise-induced fibre-type shifting in skeletal muscle. Acta. Physiol. 214, 221-236. https://doi.org/10.1111/apha.12503
  29. Twig, G., Elorza, A., Molina, A. J., Mohamed, H. and Wikstrom, J. D., et al. 2008. Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO 27, 433-446. https://doi.org/10.1038/sj.emboj.7601963
  30. Vainshtein, A. and Hood, D. A. 2016. The regulation of autophagy during exercise in skeletal muscle. J. Appl. Physiol. 120, 664-673. https://doi.org/10.1152/japplphysiol.00550.2015
  31. Warburton, D. E., Nicol, C. W. and Bredin, S. S. 2006. Health benefits of physical activity: the evidence. CM AJ. 174, 801-809.
  32. Wright, D. C., Han, D. H., Garcia-Roves, P. M., Geiger, P. C. and Jones, E. T., et al. 2007. Exercise-induced mitochondrial biogenesis begins before the increase in muscle PGC-1alpha expression. J. Biol. Chem. 282, 194-199. https://doi.org/10.1074/jbc.M606116200
  33. Xiao, B., Heath, R., Saiu, P., Leiper, F. C. and Leone, P., et al. 2007. Structural basis for AMP binding to mammalian AMP-activated protein kinase. Nature 449, 496-500. https://doi.org/10.1038/nature06161
  34. Yan, Z., Lira, V. A. and Greene, N. P. 2012. Exercise training-induced regulation of mitochondrial quality. Exerc. Sport Sci. Rev. 40, 159-164.