Journal of Ginseng Research

The Korean Society of Ginseng (고려인삼학회)
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Research article Black ginseng activates Akt signaling, thereby enhancing myoblast differentiation and myotube growth

  • Lee, Soo-Yeon (Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University) ;
  • Go, Ga-Yeon (Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University) ;
  • Vuong, Tuan Anh (Department of Molecular Cell Biology, Single Cell Network Research Center, Sungkyunkwan University School of Medicine) ;
  • Kim, Jee Won (Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University) ;
  • Lee, Sullim (Natural Products Research Institute, Korea Institute of Science and Technology) ;
  • Jo, Ayoung (Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University) ;
  • An, Jun Min (Ginseng by Pharm Co., Ltd.) ;
  • Kim, Su-Nam (Natural Products Research Institute, Korea Institute of Science and Technology) ;
  • Seo, Dong-Wan (College of Pharmacy, Dankook University) ;
  • Kim, Jin-Seok (Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University) ;
  • Kim, Yong Kee (Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University) ;
  • Kang, Jong-Sun (Department of Molecular Cell Biology, Single Cell Network Research Center, Sungkyunkwan University School of Medicine) ;
  • Lee, Sang-Jin (Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University) ;
  • Bae, Gyu-Un (Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University)
  • Received : 2017.07.21
  • Accepted : 2017.08.18
  • Published : 2018.01.15
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Abstract

Background: Black ginseng (BG) has greatly enhanced pharmacological activities relative to white or red ginseng. However, the effect and molecular mechanism of BG on muscle growth has not yet been examined. In this study, we investigated whether BG could regulate myoblast differentiation and myotube hypertrophy. Methods: BG-treated C2C12 myoblasts were differentiated, followed by immunoblotting for myogenic regulators, immunostaining for a muscle marker, myosin heavy chain or immunoprecipitation analysis for myogenic transcription factors. Results: BG treatment of C2C12 cells resulted in the activation of Akt, thereby enhancing hetero-dimerization of MyoD and E proteins, which in turn promoted muscle-specific gene expression and myoblast differentiation. BG-treated myoblasts formed larger multinucleated myotubes with increased diameter and thickness, accompanied by enhanced Akt/mTOR/p70S6K activation. Furthermore, the BG treatment of human rhabdomyosarcoma cells restored myogenic differentiation. Conclusion: BG enhances myoblast differentiation and myotube hypertrophy by activating Akt/mTOR/p70S6k axis. Thus, our study demonstrates that BG has promising potential to treat or prevent muscle loss related to aging or other pathological conditions, such as diabetes.

Keywords

References

  1. Sun BS, Gu LJ, Fang ZM, Wang CY, Wang Z, Lee MR, Li Z, Li JJ, Sung CK. Simultaneous quantification of 19 ginsenosides in black ginseng developed from Panax ginseng by HPLC-ELSD. J Pharm Biomed Anal 2009;50:15-22. https://doi.org/10.1016/j.jpba.2009.03.025
  2. Jin Y, Piao J, Lee SM. Evaluating the validity of the Braden scale using longitudinal electronic medical records. Res Nurs Health 2015;38:152-61. https://doi.org/10.1002/nur.21642
  3. Liu L, Zhu XM, Wang QJ, Zhang DL, Fang ZM, Wang CY, Wang Z, Sun BS, Wu H, Sung CK. Enzymatic preparation of 20(S, R)-protopanaxadiol by transformation of 20(S, R)-Rg3 from black ginseng. Phytochemistry 2010;71: 1514-20. https://doi.org/10.1016/j.phytochem.2010.05.007
  4. Jung K, An JM, Eom DW, Kang KS, Kim SN. Preventive effect of fermented black ginseng against cisplatin-induced nephrotoxicity in rats. J Ginseng Res 2017;41:188-94. https://doi.org/10.1016/j.jgr.2016.03.001
  5. Hu JN, Liu Z, Wang Z, Li XD, Zhang LX, Li W, Wang YP. Ameliorative effects and possible molecular mechanism of action of black ginseng (Panax ginseng) on acetaminophen-mediated liver injury. Molecules 2017;22.
  6. Seo YS, Shon MY, Kong R, Kang OH, Zhou T, Kim DY, Kwon DY. Black ginseng extract exerts anti-hyperglycemic effect via modulation of glucose metabolism in liver and muscle. J Ethnopharmacol 2016;190:231-40. https://doi.org/10.1016/j.jep.2016.05.060
  7. Pownall ME, Gustafsson MK, Emerson Jr CP. Myogenic regulatory factors and the specification of muscle progenitors in vertebrate embryos. Annu Rev Cell Dev Biol 2002;18:747-83. https://doi.org/10.1146/annurev.cellbio.18.012502.105758
  8. Charge SB, Rudnicki MA. Cellular and molecular regulation of muscle regeneration. Physiol Rev 2004;84:209-38. https://doi.org/10.1152/physrev.00019.2003
  9. Lee SJ, Yoo M, Go GY, Kim DH, Choi H, Leem YE, Kim YK, Seo DW, Ryu JH, Kang JS, et al. Bakuchiol augments MyoD activation leading to enhanced myoblast differentiation. Chem Biol Interact 2016;248:60-7. https://doi.org/10.1016/j.cbi.2016.02.008
  10. Bae GU, Kim BG, Lee HJ, Oh JE, Lee SJ, Zhang W, Krauss RS, Kang JS. Cdo binds Abl to promote p38alpha/beta mitogen-activated protein kinase activity and myogenic differentiation. Mol Cell Biol 2009;29:4130-43. https://doi.org/10.1128/MCB.00199-09
  11. Rommel C, Bodine SC, Clarke BA, Rossman R, Nunez L, Stitt TN, Yancopoulos GD, Glass DJ. Mediation of IGF-1-induced skeletal myotube hypertrophy by PI(3)K/Akt/mTOR and PI(3)K/Akt/GSK3 pathways. Nat Cell Biol 2001;3:1009-13. https://doi.org/10.1038/ncb1101-1009
  12. Bae GU, Lee JR, Kim BG, Han JW, Leem YE, Lee HJ, Ho SM, Hahn MJ, Kang JS. Cdo interacts with APPL1 and activates Akt in myoblast differentiation. Mol Biol Cell 2010;21:2399-411. https://doi.org/10.1091/mbc.E09-12-1011
  13. Lee SJ, Hwang J, Jeong HJ, Yoo M, Go GY, Lee JR, Leem YE, Park JW, Seo DW, Kim YK, et al. PKN2 and Cdo interact to activate AKT and promote myoblast differentiation. Cell Death Dis 2016;7:e2431.
  14. Bak MJ, Jeong WS, Kim KB. Detoxifying effect of fermented black ginseng on H2O2-induced oxidative stress in HepG2 cells. Int J MolMed 2014;34:1516-22.
  15. Serra C, Palacios D, Mozzetta C, Forcales SV, Morantte I, Ripani M, Jones DR, Du K, Jhala US, Simone C, et al. Functional interdependence at the chromatin level between the MKK6/p38 and IGF1/PI3K/AKT pathways during muscle differentiation. Mol Cell 2007;28:200-13. https://doi.org/10.1016/j.molcel.2007.08.021
  16. Milasincic DJ, Dhawan J, Farmer SR. Anchorage-dependent control of musclespecific gene expression in C2C12 mouse myoblasts. In Vitro Cell Dev Biol Anim 1996;32:90-9. https://doi.org/10.1007/BF02723040
  17. Neuhold LA, Wold B. HLH forced dimers: tethering MyoD to E47 generates a dominant positive myogenic factor insulated from negative regulation by Id. Cell 1993;74:1033-42. https://doi.org/10.1016/0092-8674(93)90725-6
  18. Lluis F, Ballestar E, Suelves M, Esteller M, Munoz-Canoves P. E47 phosphorylation by p38 MAPK promotes MyoD/E47 association and muscle-specific gene transcription. EMBO J 2005;24:974-84. https://doi.org/10.1038/sj.emboj.7600528
  19. Forcales SV, Albini S, Giordani L, Malecova B, Cignolo L, Chernov A, Coutinho P, Saccone V, Consalvi S, Williams R, et al. Signal-dependent incorporation of MyoD-BAF60c into Brg1-based SWI/SNF chromatin-remodelling complex. EMBO J 2012;31:301-16. https://doi.org/10.1038/emboj.2011.391
  20. Tapscott SJ. The circuitry of a master switch: Myod and the regulation of skeletal muscle gene transcription. Development 2005;132:2685-95. https://doi.org/10.1242/dev.01874
  21. Wilson EM, Rotwein P. Selective control of skeletal muscle differentiation by Akt1. J Biol Chem 2007;282:5106-10. https://doi.org/10.1074/jbc.C600315200
  22. Stitt TN, Drujan D, Clarke BA, Panaro F, Timofeyva Y, Kline WO, Gonzalez M, Yancopoulos GD, Glass DJ. The IGF-1/PI3K/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors. Mol Cell 2004;14:395-403. https://doi.org/10.1016/S1097-2765(04)00211-4
  23. Sandri M, Barberi L, Bijlsma AY, Blaauw B, Dyar KA, Milan G, Mammucari C, Meskers CG, Pallafacchina G, Paoli A, et al. Signalling pathways regulating muscle mass in ageing skeletal muscle: the role of the IGF1-Akt-mTOR-FoxO pathway. Biogerontology 2013;14:303-23. https://doi.org/10.1007/s10522-013-9432-9
  24. Hauerslev S, Vissing J, Krag TO. Muscle atrophy reversed by growth factor activation of satellite cells in a mouse muscle atrophy model. PLoS One 2014;9:e100594. https://doi.org/10.1371/journal.pone.0100594
  25. Coda DM, Lingua MF, Morena D, Foglizzo V, Bersani F, Ala U, Ponzetto C, Taulli R. SMYD1 and G6PD modulation are critical events for miR-206-mediated differentiation of rhabdomyosarcoma. Cell Cycle 2015;14:1389-402. https://doi.org/10.1080/15384101.2015.1005993

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