Browse > Article
http://dx.doi.org/10.1016/j.jgr.2019.01.007

Ginsenoside Rb1 and Rb2 upregulate Akt/mTOR signaling-mediated muscular hypertrophy and myoblast differentiation  

Go, Ga-Yeon (Research Institute of Pharmaceutical Science, College of Pharmacy, Sookmyung Women's University)
Jo, Ayoung (Research Institute of Pharmaceutical Science, College of Pharmacy, Sookmyung Women's University)
Seo, Dong-Wan (College of Pharmacy, Dankook University)
Kim, Woo-Young (Research Institute of Pharmaceutical Science, College of Pharmacy, Sookmyung Women's University)
Kim, Yong Kee (Research Institute of Pharmaceutical Science, College of Pharmacy, Sookmyung Women's University)
So, Eui-Young (Division of Hematology/Oncology, Department of Medicine, Alpert Medical School of Brown University, Rhode Island Hospital)
Chen, Qian (Department of Orthopaedics, Alpert Medical School of Brown University/Rhode Island Hospital)
Kang, Jong-Sun (Department of Molecular Cell Biology, Single Cell Network Research Center, Sungkyunkwan University School of Medicine)
Bae, Gyu-Un (Research Institute of Pharmaceutical Science, College of Pharmacy, Sookmyung Women's University)
Lee, Sang-Jin (Research Institute of Pharmaceutical Science, College of Pharmacy, Sookmyung Women's University)
Publication Information
Journal of Ginseng Research / v.44, no.3, 2020 , pp. 435-441 More about this Journal
Abstract
Background: As a process of aging, skeletal muscle mass and function gradually decrease. It is reported that ginsenoside Rb1 and Rb2 play a role as AMP-activated protein kinase activator, resulting in regulating glucose homeostasis, and Rb1 reduces oxidative stress in aged skeletal muscles through activating the phosphatidylinositol 3-kinase/Akt/Nrf2 pathway. We examined the effects of Rb1 and Rb2 on differentiation of the muscle stem cells and myotube formation. Methods: C2C12 myoblasts treated with Rb1 and/or Rb2 were differentiated and induced to myotube formation, followed by immunoblotting for myogenic marker proteins, such as myosin heavy chain, MyoD, and myogenin, or immunostaining for myosin heavy chain or immunoprecipitation analysis for heterodimerization of MyoD/E-proteins. Results: Rb1 and Rb2 enhanced myoblast differentiation through accelerating MyoD/E-protein heterodimerization and increased myotube hypertrophy, accompanied by activation of Akt/mammalian target of rapamycin signaling. In addition, Rb1 and Rb2 induced the MyoD-mediated transdifferentiation of the rhabdomyosarcoma cells into myoblasts. Furthermore, co-treatment with Rb1 and Rb2 had synergistically enhanced myoblast differentiation through Akt activation. Conclusion: Rb1 and Rb2 upregulate myotube growth and myogenic differentiation through activating Akt/mammalian target of rapamycin signaling and inducing myogenic conversion of fibroblasts. Thus, our first finding indicates that Rb1 and Rb2 have strong potential as a helpful remedy to prevent and treat muscle atrophy, such as age-related muscular dystrophy.
Keywords
Akt/mTOR signaling; Hypertrophy; Myoblast differentiation; Rb1; Rb2;
Citations & Related Records
Times Cited By KSCI : 3  (Citation Analysis)
연도 인용수 순위
1 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.   DOI
2 Lee SY, Go GY, Vuong TA, Kim JW, Lee S, Jo A, An JM, Kim SN, Seo DW, Kim JS, et al. Black ginseng activates Akt signaling, thereby enhancing myoblast differentiation and myotube growth. J Ginseng Res 2018;42:116-21.   DOI
3 Domingues-Faria C, Vasson MP, Goncalves-Mendes N, Boirie Y, Walrand S. Skeletal muscle regeneration and impact of aging and nutrition. Ageing Res Rev 2016;26:22-36.   DOI
4 Molkentin JD, Olson EN. Defining the regulatory networks for muscle development. Curr Opin Genet Dev 1996;6:445-53.   DOI
5 Sartorelli V, Caretti G. Mechanisms underlying the transcriptional regulation of skeletal myogenesis. Curr Opin Genet Dev 2005;15:528-35.   DOI
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.   DOI
7 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.   DOI
8 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.   DOI
9 Glass DJ. Signalling pathways that mediate skeletal muscle hypertrophy and atrophy. Nat Cell Biol 2003;5:87-90.   DOI
10 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.   DOI
11 Zhuang CL, Mao XY, Liu S, Chen WZ, Huang DD, Zhang CJ, Chen BC, Shen X, Yu Z. Ginsenoside Rb1 improves postoperative fatigue syndrome by reducing skeletal muscle oxidative stress through activation of the PI3K/Akt/Nrf2 pathway in aged rats. Eur J Pharmacol 2014;740:480-7.   DOI
12 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.   DOI
13 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.   DOI
14 Attele AS, Wu JA, Yuan CS. Ginseng pharmacology: multiple constituents and multiple actions. Biochem Pharmacol 1999;58:1685-93.   DOI
15 Lee KT, Jung TW, Lee HJ, Kim SG, Shin YS, Whang WK. The antidiabetic effect of ginsenoside Rb2 via activation of AMPK. Arch Pharm Res 2011;34:1201-8.   DOI
16 Shen L, Haas M, Wang DQ, May A, Lo CC, Obici S, Tso P, Woods SC, Liu M. Ginsenoside Rb1 increases insulin sensitivity by activating AMP-activated protein kinase in male rats. Physiol Rep 2015;3.
17 Go GY, Lee SJ, Jo A, Lee J, Seo DW, Kang JS, Kim SK, Kim SN, Kim YK, Bae GU. Ginsenoside Rg1 from Panax ginseng enhances myoblast differentiation and myotube growth. J Ginseng Res 2017;41:608-14.   DOI
18 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.
19 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.   DOI
20 Sousa-Victor P, Gutarra S, Garcia-Prat L, Rodriguez-Ubreva J, Ortet L, Ruiz-Bonilla V, Jardi M, Ballestar E, Gonzalez S, Serrano AL, et al. Geriatric muscle stem cells switch reversible quiescence into senescence. Nature 2014;506:316-21.   DOI
21 Krauss RS, Cole F, Gaio U, Takaesu G, Zhang W, Kang JS. Close encounters: regulation of vertebrate skeletal myogenesis by cell-cell contact. J Cell Sci 2005;118:2355-62.   DOI
22 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.   DOI
23 Berkes CA, Tapscott SJ. MyoD and the transcriptional control of myogenesis. Semin Cell Dev Biol 2005;16:585-95.   DOI
24 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.   DOI
25 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.   DOI
26 Keller C, Guttridge DC. Mechanisms of impaired differentiation in rhabdomyosarcoma. FEBS J 2013;280:4323-34.   DOI
27 Weintraub H, Tapscott SJ, Davis RL, Thayer MJ, Adam MA, Lassar AB, Miller AD. Activation of muscle-specific genes in pigment, nerve, fat, liver, and fibroblast cell lines by forced expression of MyoD. Proc Natl Acad Sci U S A 1989;86:5434-8.   DOI