DOI QR코드

DOI QR Code

Ginsenoside Rg1 from Panax ginseng enhances myoblast differentiation and myotube growth

  • Go, Ga-Yeon (Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University) ;
  • Lee, Sang-Jin (Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University) ;
  • Jo, Ayoung (Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University) ;
  • Lee, Jaecheol (Division of Cardiology, Department of Medicine, Stanford University School of Medicine) ;
  • Seo, Dong-Wan (College of Pharmacy, Dankook University) ;
  • Kang, Jong-Sun (Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute) ;
  • Kim, Si-Kwan (Department of Biomedical Chemistry, College of Biomedical & Health Science, Konkuk University) ;
  • Kim, Su-Nam (Natural Products Research Institute, Korea Institute of Science and Technology) ;
  • Kim, Yong Kee (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 : 2017.05.04
  • Accepted : 2017.05.25
  • Published : 2017.10.15

Abstract

Background: Ginsenoside Rg1 belongs to protopanaxatriol-type ginsenosides and has diverse pharmacological activities. In this report, we investigated whether Rg1 could upregulate muscular stem cell differentiation and muscle growth. Methods: C2C12 myoblasts, MyoD-transfected 10T1/2 embryonic fibroblasts, and HEK293T cells were treated with Rg1 and differentiated for 2 d, subjected to immunoblotting, immunocytochemistry, or immunoprecipitation. Results: Rg1 activated promyogenic kinases, p38MAPK (mitogen-activated protein kinase) and Akt signaling, that in turn promote the heterodimerization with MyoD and E proteins, resulting in enhancing myogenic differentiation. Through the activation of Akt/mammalian target of rapamycin pathway, Rg1 induced myotube growth and prevented dexamethasone-induced myotube atrophy. Furthermore, Rg1 increased MyoD-dependent myogenic conversion of fibroblast. Conclusion: Rg1 upregulates promyogenic kinases, especially Akt, resulting in improvement of myoblast differentiation and myotube growth.

Keywords

References

  1. Sanchez AM, Csibi A, Raibon A, Docquier A, Lagirand-Cantaloube J, Leibovitch MP, Leibovitch SA, Bernardi H. eIF3f: a central regulator of the antagonism atrophy/hypertrophy in skeletal muscle. Int J Biochem Cell Biol 2013;45:2158-62. https://doi.org/10.1016/j.biocel.2013.06.001
  2. von Maltzahn J, Chang NC, Bentzinger CF, Rudnicki MA. Wnt signaling in myogenesis. Trends Cell Biol 2012;22:602-9. https://doi.org/10.1016/j.tcb.2012.07.008
  3. Horsley V, Pavlath GK. Forming a multinucleated cell: molecules that regulate myoblast fusion. Cells Tissues Organs 2004;176:67-78. https://doi.org/10.1159/000075028
  4. Krauss RS. Regulation of promyogenic signal transduction by cell-cell contact and adhesion. Exp Cell Res 2010;316:3042-9. https://doi.org/10.1016/j.yexcr.2010.05.008
  5. Tapscott SJ, Davis RL, Thayer MJ, Cheng PF, Weintraub H, Lassar AB. MyoD1: a nuclear phosphoprotein requiring a Myc homology region to convert fibroblasts to myoblasts. Science 1988;242:405-11. https://doi.org/10.1126/science.3175662
  6. Simone C, Forcales SV, Hill DA, Imbalzano AN, Latella L, Puri PL. p38 pathway targets SWI-SNF chromatin-remodeling complex to muscle-specific loci. Nat Genet 2004;36:738-43. https://doi.org/10.1038/ng1378
  7. 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
  8. Lawlor MA, Rotwein P. Insulin-like growth factor-mediated muscle cell survival: central roles for Akt and cyclin-dependent kinase inhibitor p21. Mol Cell Biol 2000;20:8983-95. https://doi.org/10.1128/MCB.20.23.8983-8995.2000
  9. 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
  10. 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
  11. Takaesu G, Kang JS, Bae GU, Yi MJ, Lee CM, Reddy EP, Krauss RS. Activation of p38alpha/beta MAPK in myogenesis via binding of the scaffold protein JLP to the cell surface protein Cdo. J Cell Biol 2006;175:383-8. https://doi.org/10.1083/jcb.200608031
  12. Gonzalez I, Tripathi G, Carter EJ, Cobb LJ, Salih DA, Lovett FA, Holding C, Pell JM. Akt2, a novel functional link between p38 mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways in myogenesis. Mol Cell Biol 2004;24:3607-22. https://doi.org/10.1128/MCB.24.9.3607-3622.2004
  13. Bodine SC, Stitt TN, Gonzalez M, Kline WO, Stover GL, Bauerlein R, Zlotchenko E, Scrimgeour A, Lawrence JC, Glass DJ, et al. Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo. Nat Cell Biol 2001;3:1014-9. https://doi.org/10.1038/ncb1101-1014
  14. 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
  15. 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
  16. Kim JH. Cardiovascular diseases and Panax ginseng: a review on molecular mechanisms and medical applications. J Ginseng Res 2012;36:16-26. https://doi.org/10.5142/jgr.2012.36.1.16
  17. Kim TH, Lee SM. The effects of ginseng total saponin, panaxadiol and panaxatriol on ischemia/reperfusion injury in isolated rat heart. Food Chem Toxicol 2010;48:1516-20. https://doi.org/10.1016/j.fct.2010.03.018
  18. Yu T, Yang Y, Kwak YS, Song GG, Kim MY, Rhee MH, Cho JY. Ginsenoside Rc from Panax ginseng exerts anti-inflammatory activity by targeting TANK-binding kinase 1/interferon regulatory factor-3 and p38/ATF-2. J Ginseng Res 2017;41:127-33. https://doi.org/10.1016/j.jgr.2016.02.001
  19. Hwang CR, Lee SH, Jang GY, Hwang IG, Kim HY, Woo KS, Lee J, Jeong JS. Changes in ginsenoside compositions and antioxidant activities of hydroponic-cultured ginseng roots and leaves with heating temperature. J Ginseng Res 2014;38:180-6. https://doi.org/10.1016/j.jgr.2014.02.002
  20. Gui QF, Xu ZR, Xu KY, Yang YM. The efficacy of ginseng-related therapies in type 2 diabetes mellitus: an updated systematic review and meta-analysis. Medicine 2016;95, e2584. https://doi.org/10.1097/MD.0000000000002584
  21. Shin JY, Lee JM, Shin HS, Park SY, Yang JE, Cho SK, Yi TH. Anti-cancer effect of ginsenoside F2 against glioblastoma multiforme in xenograft model in SD rats. J Ginseng Res 2012;36:86-92. https://doi.org/10.5142/jgr.2012.36.1.86
  22. Jiang B, Xiong Z, Yang J, Wang W, Wang Y, Hu ZL, Wang F, Chen JG. Antidepressant-like effects of ginsenoside Rg1 are due to activation of the BDNF signalling pathway and neurogenesis in the hippocampus. Br J Pharmacol 2012;166:1872-87. https://doi.org/10.1111/j.1476-5381.2012.01902.x
  23. Lee HM, Lee OH, Kim KJ, Lee BY. Ginsenoside Rg1 promotes glucose uptake through activated AMPK pathway in insulin-resistant muscle cells. Phytother Res 2012;26:1017-22. https://doi.org/10.1002/ptr.3686
  24. Lee SJ, Leem YE, Go GY, Choi Y, Song YJ, Kim I, Kim YK, Seo DW, Kang JS, Bae GU. Epicatechin elicits MyoD-dependent myoblast differentiation and myogenic conversion of fibroblasts. PLoS One 2017;12, e0175271. https://doi.org/10.1371/journal.pone.0175271
  25. 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.
  26. 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
  27. 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
  28. Takamura Y, Makanae Y, Ato S, Yoshii N, Kido K, Nomura M, Uchiyama A, Shiozawa N, Fujita S. Panaxatriol derived from ginseng augments resistance exercised-induced protein synthesis via mTORC1 signaling in rat skeletal muscle. Nutr Res 2016;36:1193-201. https://doi.org/10.1016/j.nutres.2016.09.002
  29. Marabita M, Baraldo M, Solagna F, Ceelen JJ, Sartori R, Nolte H, Nemazanyy I, Pyronnet S, Kruger M, Pende M, et al. S6K1 Is required for increasing skeletal muscle force during hypertrophy. Cell Rep 2016;17:501-13. https://doi.org/10.1016/j.celrep.2016.09.020
  30. Hasselgren PO. Glucocorticoids and muscle catabolism. Curr Opin Clin Nutr Metab Care 1999;2:201-5. https://doi.org/10.1097/00075197-199905000-00002
  31. Kimura K, Cheng XW, Inoue A, Hu L, Koike T, Kuzuya M. Beta-hydroxy-beta-methylbutyrate facilitates PI3K/Akt-dependent mammalian target of rapamycin and FoxO1/3a phosphorylations and alleviates tumor necrosis factor alpha/interferon gamma-induced MuRF-1 expression in C2C12 cells. Nutr Res 2014;34:368-74. https://doi.org/10.1016/j.nutres.2014.02.003
  32. Sandri M, Sandri C, Gilbert A, Skurk C, Calabria E, Picard A, Walsh K, Schiaffino S, Lecker SH, Goldberg AL. Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. Cell 2004;117:399-412. https://doi.org/10.1016/S0092-8674(04)00400-3
  33. Zetser A, Gredinger E, Bengal E. p38 mitogen-activated protein kinase pathway promotes skeletal muscle differentiation. Participation of the Mef2c transcription factor. J Biol Chem 1999;274:5193-200. https://doi.org/10.1074/jbc.274.8.5193
  34. Meregalli M, Farini A, Colleoni F, Cassinelli L, Torrente Y. The role of stem cells in muscular dystrophies. Curr Gene Ther 2012;12:192-205. https://doi.org/10.2174/156652312800840559

Cited by

  1. 12,23-Dione dammarane triterpenes from Gynostemma longipes and their muscle cell proliferation activities via activation of the AMPK pathway vol.9, pp.None, 2017, https://doi.org/10.1038/s41598-018-37808-9
  2. Panax ginseng Total Protein Facilitates Recovery from Dexamethasone-Induced Muscle Atrophy through the Activation of Glucose Consumption in C2C12 Myotubes vol.2019, pp.None, 2017, https://doi.org/10.1155/2019/3719643
  3. Natural constituents from food sources: potential therapeutic agents against muscle wasting vol.10, pp.11, 2017, https://doi.org/10.1039/c9fo00912d
  4. BST204, a Rg3 and Rh2 Enriched Ginseng Extract, Upregulates Myotube Formation and Mitochondrial Function in TNF-α-Induced Atrophic Myotubes vol.48, pp.3, 2017, https://doi.org/10.1142/s0192415x20500329
  5. Ginsenoside Rg1 Improves Differentiation by Inhibiting Senescence of Human Bone Marrow Mesenchymal Stem Cell via GSK-3 β and β -Catenin vol.2020, pp.None, 2020, https://doi.org/10.1155/2020/2365814
  6. Red Ginseng Improves Exercise Endurance by Promoting Mitochondrial Biogenesis and Myoblast Differentiation vol.25, pp.4, 2020, https://doi.org/10.3390/molecules25040865
  7. Myogenesis 촉진에 관여하는 최근 천연물의 동향 vol.30, pp.2, 2017, https://doi.org/10.5352/jls.2020.30.2.202