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C2C12 골격근 세포에서 히스톤 탈 아세틸 효소의 억제가 인슐린 유사성장인자(IGF-I)에 의한 BDNF 발현 조절에 미치는 영향

Insulin-like Growth Factor-I Modulates BDNF Expression by Inhibition of Histone Deacetylase in C2C12 Skeletal Muscle Cells

  • 김혜진 (이화여자대학교 신산업융합대학 체육과학과) ;
  • 이원준 (이화여자대학교 신산업융합대학 체육과학과)
  • Kim, Hye Jin (Department of Kinesiology and Sports Studies, College of Science and Industry Convergence, Ewha Womans University) ;
  • Lee, Won Jun (Department of Kinesiology and Sports Studies, College of Science and Industry Convergence, Ewha Womans University)
  • 투고 : 2017.07.24
  • 심사 : 2017.08.09
  • 발행 : 2017.08.30

초록

히스톤 탈 아세틸 효소(HDAC)와 인슐린유사성장인자(IGF-I)는 근육 관련 유전자들의 활성 및 발현을 조절하여 골격근의 성장 및 발달을 조절하지만 이들이 근신경계 발달 및 대사 기능에 중요한 역할을 담당하는 뇌신경성장인자(BDNF)의 발현에 미치는 영향에 관한 연구는 거의 이루어지지 않았다. 따라서 본 연구에서는 IGF-I과 HDAC의 억제제인 SAHA가 C2C12 골격근 세포에서 BDNF 발현에 미치는 영향을 알아보고자 하였다. 그 결과 IGF-I은 농도와 시간 의존적으로 BDNF의 mRNA 및 단백질 발현을 감소시켰지만 HDAC을 억제하자 IGF-I에 의해 감소되었던 BDNF의 발현이 증가하는 경향을 관찰할 수 있었다. 따라서 IGF-I은 BDNF의 발현을 억제하며, HDAC의 억제는 IGF-I에 의한 BDNF의 발현 억제를 감소시킬 수 있다는 사실을 확인할 수 있었다.

It is well established that brain-derived neurotrophic factor (BDNF) is expressed not only in the brain but also in skeletal muscle, and is required for normal neuromuscular system function. Histone deacetylases (HDACs) and insulin-like growth factor-I (IGF-I) are potent regulators of skeletal muscle myogenesis and muscle gene expression, but the mechanisms of HDAC and IGF-I in skeletal muscle-derived BDNF expression have not been examined. In this study, we examined the effect of IGF-I and suberoylanilide hydroxamic acid (SAHA), a pan-HDAC inhibitor, on BDNF induction. Proliferating or differentiating C2C12 skeletal muscle cells were treated with increasing concentrations (0-50 ng/ml) of IGF-I in the absence or presence of $5{\mu}M$ SAHA for various time periods (3-24 hr). Treatment of C2C12 cells with IGF-I resulted in a dose- and time-dependent decrease in BDNF mRNA expression. However, inhibition of HDAC led to a significant increase in the expression of BDNF mRNA levels. In addition, immunocytochemistry revealed high BDNF protein levels in undifferentiated C2C12 skeletal muscle cells, whether untreated, IGF-I-treated, or exposed to SAHA. These results represent the first evidence that IGF-I can suppress the mRNA and protein expression of BDNF; conversely, SAHA attenuates the effects of IGF-I. Consequently, SAHA upregulates BDNF expression in C2C12 skeletal muscle cells.

키워드

참고문헌

  1. Adams, G. R. 2002. Autocrine/paracrine IGF-I and skeletal muscle adaptation. J. Appl. Physiol. 93, 1159-1167. https://doi.org/10.1152/japplphysiol.01264.2001
  2. Anderson, B. C., Christiansen, S. P., Grandt, S., Grange, R. W. and McLoon, L. K. 2006. Increased extraocular muscle strength with direct injection of insulin-like growth factor-I. Invest. Ophthalmol. Vis. Sci. 47, 2461-2467. https://doi.org/10.1167/iovs.05-1416
  3. Bharathy, N., Ling, B. M. and Taneja, R. 2013. Epigenetic regulation of skeletal muscle development and differentiation. Subcell. Biochem. 61, 139-150.
  4. Chen, P. S., Peng, G. S., Li, G., Yang, S., Wu, X., Wang, C. C., Wilson, B., Lu, R. B., Gean, P. W., Chuang, D. M. and Hong, J. S. 2006. Valproate protects dopaminergic neurons in midbrain neuron/glia cultures by stimulating the release of neurotrophic factors from astrocytes. Mol. Psychiatry 11, 1116-1125. https://doi.org/10.1038/sj.mp.4001893
  5. Clemmons, D. R. 2009. Role of IGF-I in skeletal muscle mass maintenance. Trends Endocrinol. Metab. 20, 349-356. https://doi.org/10.1016/j.tem.2009.04.002
  6. Clow, C. and Jasmin, B. J. 2010. Brain-derived neurotrophic factor regulates satellite cell differentiation and skeletal muscle regeneration. Mol. Biol. Cell. 21, 2182-2190. https://doi.org/10.1091/mbc.E10-02-0154
  7. Cohen, T. J., Barrientos, T., Hartman, Z. C., Garvey, S. M., Cox, G. A. and Yao, T. P. 2009. The deacetylase HDAC4 controls myocyte enhancing factor-2-dependent structural gene expression in response to neural activity. FASEB. J. 23, 99-106. https://doi.org/10.1096/fj.08-115931
  8. Colombo, E., Bedogni, F., Lorenzetti, I., Landsberger, N., Previtali, S. C. and Farina, C. 2013. Autocrine and immune cell-derived BDNF in human skeletal muscle: implications for myogenesis and tissue regeneration. J. Pathol. 231, 190-198. https://doi.org/10.1002/path.4228
  9. Cotman, C. W. and Berchtold, N. C. 2002. Exercise: a behavioral intervention to enhance brain health and plasticity. Trends Neurosci. 25, 295-301. https://doi.org/10.1016/S0166-2236(02)02143-4
  10. Cotman, C. W., Berchtold, N. C. and Christie, L. A. 2007. Exercise builds brain health: key roles of growth factor cascades and inflammation. Trends Neurosci. 30, 464-472. https://doi.org/10.1016/j.tins.2007.06.011
  11. Dey, B. R., Furlanetto, R. W. and Nissley, P. 2000. Suppressor of cytokine signaling (SOCS)-3 protein interacts with the insulin-like growth factor-I receptor. Biochem. Biophys. Res. Commun. 278, 38-43. https://doi.org/10.1006/bbrc.2000.3762
  12. Fu, X., Zhao, J. X., Liang, J., Zhu, M. J., Foretz, M., Viollet, B. and Du, M. 2013. AMP-activated protein kinase mediates myogenin expression and myogenesis via histone deacetylase 5. Am. J. Physiol. 305, C887-895. https://doi.org/10.1152/ajpcell.00124.2013
  13. Galvin, C. D., Hardiman, O. and Nolan, C. M. 2003. IGF-I receptor mediates differentiation of primary cultures of mouse skeletal myoblasts. Mol. Cell. Endocrinol. 200, 19-29. https://doi.org/10.1016/S0303-7207(02)00420-3
  14. Glass, D. J. 2003. Signalling pathways that mediate skeletal muscle hypertrophy and atrophy. Nat. Cell. Biol. 5, 87-90. https://doi.org/10.1038/ncb0203-87
  15. Griesbeck, O., Parsadanian, A. S., Sendtner, M. and Thoenen, H. 1995. Expression of neurotrophins in skeletal muscle: quantitative comparison and significance for motoneuron survival and maintenance of function. J. Neurosci. Res. 42, 21-33. https://doi.org/10.1002/jnr.490420104
  16. Iezzi, S., Cossu, G., Nervi, C., Sartorelli, V. and Puri, P. L. 2002. Stage-specific modulation of skeletal myogenesis by inhibitors of nuclear deacetylases. Proc. Natl. Acad. Sci. USA 99, 7757-7762. https://doi.org/10.1073/pnas.112218599
  17. Koppel, I. and Timmusk, T. 2013. Differential regulation of BDNF expression in cortical neurons by class-selective histone deacetylase inhibitors. Neuropharmacology 75, 106-115. https://doi.org/10.1016/j.neuropharm.2013.07.015
  18. McKinsey, T. A., Zhang, C. L. and Olson, E. N. 2001. Control of muscle development by dueling HATs and HDACs. Curr. Opin. Genet. Dev. 11, 497-504. https://doi.org/10.1016/S0959-437X(00)00224-0
  19. Mitsiades, C. S., Mitsiades, N. S., McMullan, C. J., Poulaki, V., Shringarpure, R., Hideshima, T., Akiyama, M., Chauhan, D., Munshi, N., Gu, X., Bailey, C., Joseph, M., Libermann, T. A., Richon, V. M., Marks, P. A. and Anderson, K. C. 2004. Transcriptional signature of histone deacetylase inhibition in multiple myeloma: biological and clinical implications. Proc. Natl. Acad. Sci. USA 101, 540-545. https://doi.org/10.1073/pnas.2536759100
  20. Miura, P., Amirouche, A., Clow, C., Belanger, G. and Jasmin, B. J. 2012. Brain-derived neurotrophic factor expression is repressed during myogenic differentiation by miR-206. J. Neurochem. 120, 230-238. https://doi.org/10.1111/j.1471-4159.2011.07583.x
  21. Mousavi, K. and Jasmin, B. J. 2006. BDNF is expressed in skeletal muscle satellite cells and inhibits myogenic differentiation. J. Neurosci. 26, 5739-5749. https://doi.org/10.1523/JNEUROSCI.5398-05.2006
  22. Mousavi, K., Parry, D. J. and Jasmin, B. J. 2004. BDNF rescues myosin heavy chain IIB muscle fibers after neonatal nerve injury. Am. J. Physiol. 287, C22-29. https://doi.org/10.1152/ajpcell.00583.2003
  23. Ntanasis-Stathopoulos, J., Tzanninis, J. G., Philippou, A. and Koutsilieris, M. 2013. Epigenetic regulation on gene expression induced by physical exercise. J. Musculoskelet. Neuronal. Interact. 13, 133-146.
  24. Pandorf, C. E., Haddad, F., Wright, C., Bodell, P. W. and Baldwin, K. M. 2009. Differential epigenetic modifications of histones at the myosin heavy chain genes in fast and slow skeletal muscle fibers and in response to muscle unloading. Am. J. Physiol. 297, C6-16. https://doi.org/10.1152/ajpcell.00075.2009
  25. Park, H. and Poo, M. M. 2013. Neurotrophin regulation of neural circuit development and function. Nat. Rev. Neurosci. 14, 7-23. https://doi.org/10.1038/nrc3653
  26. Pedersen, B. K. and Febbraio, M. A. 2008. Muscle as an endocrine organ: focus on muscle-derived interleukin-6. Physiol. Rev. 88, 1379-1406. https://doi.org/10.1152/physrev.90100.2007
  27. Pedersen, B. K. 2009. Muscle as an endocrine organ: IL-6 and other myokines. J. Appl. Physiol. 107, 1006-1014. https://doi.org/10.1152/japplphysiol.00734.2009
  28. Pedersen, B. K. and Febbraio, M. A. 2012. Muscles, exercise and obesity: skeletal muscle as a secretory organ. Nat. Rev. Endocrinol. 8, 457-465. https://doi.org/10.1038/nrendo.2012.49
  29. Sacheck, J. M., Ohtsuka, A., McLary, S. C. and Goldberg, A. L. 2004. IGF-I stimulates muscle growth by suppressing protein breakdown and expression of atrophy-related ubiquitin ligases, atrogin-1 and MuRF1. Am. J. Physiol. 287, E591-601.
  30. Wrann, C. D., White, J. P., Salogiannnis, J., Laznik-Bogoslavski, D., Wu, J., Ma, D., Lin, J. D., Greenberg, M. E. and Spiegelman, B. M. 2013. Exercise induces hippocampal BDNF through a PGC-$1{\alpha}$/FNDC5 pathway. Cell. Metab. 18, 649-659. https://doi.org/10.1016/j.cmet.2013.09.008
  31. Xu, B. 2013. BDNF (I)rising from exercise. Cell. Metab. 18, 612-614. https://doi.org/10.1016/j.cmet.2013.10.008
  32. Zwetsloot, K. A., Laye, M. J. and Booth, F. W. 2009. Novel epigenetic regulation of skeletal muscle myosin heavy chain genes. Focus on "Differential epigenetic modifications of histones at the myosin heavy chain genes in fast and slow skeletal muscle fibers and in response to muscle unloading". Am. J. Physiol. 297, C1-3. https://doi.org/10.1152/ajpcell.00176.2009