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Korean red ginseng suppresses mitochondrial apoptotic pathway in denervation-induced skeletal muscle atrophy

  • Ji-Soo Jeong (College of Veterinary Medicine (BK21 FOUR Program), Chungnam National University) ;
  • Jeong-Won Kim (College of Veterinary Medicine (BK21 FOUR Program), Chungnam National University) ;
  • Jin-Hwa Kim (College of Veterinary Medicine (BK21 FOUR Program), Chungnam National University) ;
  • Chang-Yeop Kim (College of Veterinary Medicine (BK21 FOUR Program), Chungnam National University) ;
  • Je-Won Ko (College of Veterinary Medicine (BK21 FOUR Program), Chungnam National University) ;
  • Tae-Won Kim (College of Veterinary Medicine (BK21 FOUR Program), Chungnam National University)
  • Received : 2022.12.13
  • Accepted : 2023.07.01
  • Published : 2024.01.01

Abstract

Background: Skeletal muscle denervation leads to motor neuron degeneration, which in turn reduces muscle fiber volumes. Recent studies have revealed that apoptosis plays a role in regulating denervation-associated pathologic muscle wasting. Korean red ginseng (KRG) has various biological activities and is currently widely consumed as a medicinal product worldwide. Among them, ginseng has protective effects against muscle atrophy in in vivo and in vitro. However, the effects of KRG on denervation-induced muscle damage have not been fully elucidated. Methods: We induced skeletal muscle atrophy in mice by dissecting the sciatic nerves, administered KRG, and then analyzed the muscles. KRG was administered to the mice once daily for 3 weeks at 100 and 400 mg/kg/day doses after operation. Results: KRG treatment significantly increased skeletal muscle weight and tibialis anterior (TA) muscle fiber volume in injured areas and reduced histological alterations in TA muscle. In addition, KRG treatment reduced denervation-induced apoptotic changes in TA muscle. KRG attenuated p53/Bax/cytochrome c/Caspase 3 signaling induced by nerve injury in a dose-dependent manner. Also, KRG decreases protein kinase B/mammalian target of rapamycin pathway, reducing restorative myogenesis. Conclusion: Thus, KRG has potential protective role against denervation-induced muscle atrophy. The effect of KRG treatment was accompanied by reduced levels of mitochondria-associated apoptosis.

Keywords

Acknowledgement

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (2021R1A4A1033078) and the Basic Science Research Program through the NRF funded by the Ministry of Education (2021R1A6A1A03045495).

References

  1. Shirakawa T, Miyawaki A, Kawamoto T, Kokabu S. Natural compounds attenuate denervation-induced skeletal muscle atrophy. Int J Mol Sci 2021;22(15):8310. 
  2. Eisenberg HA, Hood DA. Blood flow, mitochondria, and performance in skeletal muscle after denervation and reinnervation. J Appl Physiol 1994;76(2):859-66. 1985.  https://doi.org/10.1152/jappl.1994.76.2.859
  3. Wicks KL, Hood DA. Mitochondrial adaptations in denervated muscle: relationship to muscle performance. Am J Physiol 1991;260(4 Pt 1):C841-50.  https://doi.org/10.1152/ajpcell.1991.260.4.C841
  4. Jackman RW, Kandarian SC. The molecular basis of skeletal muscle atrophy. Am J Physiol Cell Physiol 2004;287(4):C834-43.  https://doi.org/10.1152/ajpcell.00579.2003
  5. Primeau AJ, Adhihetty PJ, Hood DA. Apoptosis in heart and skeletal muscle. Can J Appl Physiol 2002;27(4):349-95.  https://doi.org/10.1139/h02-020
  6. Dirks AJ, Leeuwenburgh C. The role of apoptosis in age-related skeletal muscle atrophy. Sports Med 2005;35(6):473-83.  https://doi.org/10.2165/00007256-200535060-00002
  7. Adhihetty PJ, O'Leary MF, Chabi B, Wicks KL, Hood DA. Effect of denervation on mitochondrially mediated apoptosis in skeletal muscle. J Appl Physiol 1985;102(3):1143-51. 2007.  https://doi.org/10.1152/japplphysiol.00768.2006
  8. Memme JM, Oliveira AN, Hood DA. p53 regulates skeletal muscle mitophagy and mitochondrial quality control following denervation-induced muscle disuse. J Biol Chem 2022;298(2):101540. 
  9. Siu PM, Alway SE. Mitochondria-associated apoptotic signalling in denervated rat skeletal muscle. J Physiol 2005;565(Pt 1):309-23.  https://doi.org/10.1113/jphysiol.2004.081083
  10. Mahady GB, Gyllenhall C, Fong HH, Farnsworth NR. Ginsengs: a review of safety and efficacy. Nutr Clin Care 2000;3:90-101.  https://doi.org/10.1046/j.1523-5408.2000.00020.x
  11. Kim JH. Pharmacological and medical applications of Panax ginseng and ginsenosides: a review for use in cardiovascular diseases. J Ginseng Res 2018;42(3):264-9.  https://doi.org/10.1016/j.jgr.2017.10.004
  12. Kim JH, Yi YS, Kim MY, Cho JY. Role of ginsenosides, the main active components of Panax ginseng, in inflammatory responses and diseases. J Ginseng Res 2017;41(4):435-43.  https://doi.org/10.1016/j.jgr.2016.08.004
  13. Ye R, Zhang X, Kong X, Han J, Yang Q, Zhang Y, Chen Y, Li P, Liu J, Shi M, et al. Ginsenoside Rd attenuates mitochondrial dysfunction and sequential apoptosis after transient focal ischemia. Neuroscience 2011;178:169-80.  https://doi.org/10.1016/j.neuroscience.2011.01.007
  14. Jiang GZ, Li JC. Protective effects of ginsenoside Rg1 against colistin sulfate-induced neurotoxicity in PC12 cells. Cell Mol Neurobiol 2014;34(2):167-72.  https://doi.org/10.1007/s10571-013-9998-4
  15. Liu M, Bai X, Yu S, Zhao W, Qiao J, Liu Y, Zhao D, Wang J, Wang S. Ginsenoside Re inhibits ROS/ASK-1 dependent mitochondrial apoptosis pathway and activation of Nrf2-antioxidant response in beta-amyloid-challenged SH-SY5Y cells. Molecules 2019;24(15):2687. 
  16. Huang Q, Gao S, Zhao D, Li X. Review of ginsenosides targeting mitochondrial function to treat multiple disorders: current status and perspectives. J Ginseng Res 2021;45(3):371-9.  https://doi.org/10.1016/j.jgr.2020.12.004
  17. Ma YL, Sun YZ, Yang HH. [Protective effect of RenShen compound and Dan-Huang compound on muscle atrophy in suspended rats]. Space Med Med Eng (Beijing) 1999;12(4):281-3. 
  18. Jiang R, Wang M, Shi L, Zhou J, Ma R, Feng K, Chen X, Xu X, Li X, Li T, et al. Panax ginseng total protein facilitates recovery from dexamethasone-induced muscle atrophy through the activation of glucose consumption in C2C12 myotubes. Biomed Res Int 2019;2019:3719643. 
  19. Li F, Li X, Peng X, Sun L, Jia S, Wang P, Ma S, Zhao H, Yu Q, Huo H. Ginsenoside Rg1 prevents starvation-induced muscle protein degradation via regulation of AKT/mTOR/FoxO signaling in C2C12 myotubes. Exp Ther Med 2017;14(2):1241-7.  https://doi.org/10.3892/etm.2017.4615
  20. Kim JH, Kim JW, Kim CY, Jeong JS, Lim JO, Ko JW, Kim TW. Korean red ginseng ameliorates allergic asthma through reduction of lung inflammation and oxidation. Antioxidants (Basel) 2022;11(8):1422. 
  21. Kim JW, Kim CY, Kim JH, Jeong JS, Lim JO, Ko JW, Kim TW. Prophylactic catechin-rich green tea extract treatment ameliorates pathogenic enterotoxic Escherichia coli-induced colitis. Pathogens 2021;10(12):1573. 
  22. Fortes MA, Marzuca-Nassr GN, Vitzel KF, da Justa Pinheiro CH, Newsholme P, Curi R. Housekeeping proteins: how useful are they in skeletal muscle diabetes studies and muscle hypertrophy models? Anal Biochem 2016;504:38-40.  https://doi.org/10.1016/j.ab.2016.03.023
  23. Nie X, Li C, Hu S, Xue F, Kang YJ, Zhang W. An appropriate loading control for western blot analysis in animal models of myocardial ischemic infarction. Biochem Biophys Rep 2017;12:108-13.  https://doi.org/10.1016/j.bbrep.2017.09.001
  24. Castets P, Rion N, Theodore M, Falcetta D, Lin S, Reischl M, Wild F, Guerard L, Eickhorst C, Brockhoff M, et al. mTORC1 and PKB/Akt control the muscle response to denervation by regulating autophagy and HDAC4. Nat Commun 2019;10(1):3187. 
  25. Siu PM, Pistilli EE, Alway SE. Apoptotic responses to hindlimb suspension in gastrocnemius muscles from young adult and aged rats. Am J Physiol Regul Integr Comp Physiol 2005;289(4):R1015-26.  https://doi.org/10.1152/ajpregu.00198.2005
  26. Babiker LB, Gadkariem EA, Alashban RM, Aljohar HI. Investigation of stability of Korean ginseng in herbal drug product. Am. J. Appl 2014;11:160-70.  https://doi.org/10.3844/ajassp.2014.160.170
  27. Shin EJ, Jo S, Choi S, Cho CW, Lim WC, Hong HD, Lim TG, Jang YJ, Jang M, Byun S, et al. Red ginseng improves exercise endurance by promoting mitochondrial biogenesis and myoblast differentiation. Molecules 2020;25(4):865. 
  28. Wang Y, Pessin JE. Mechanisms for fiber-type specificity of skeletal muscle atrophy. Curr Opin Clin Nutr Metab Care 2013;16(3):243-50.  https://doi.org/10.1097/MCO.0b013e328360272d
  29. Ika PY, Triadi DA, Herawati L. Non-invasive method on slow-twitch quadriceps muscle fibers dominate a high level of fitness. In: Proceedings of Surabaya International Physiology Seminar; 2017. p. 182-5. 
  30. Giacomello E, Crea E, Torelli L, Bergamo A, Reggiani C, Sava G, Toniolo L. Age dependent modification of the metabolic profile of the tibialis anterior muscle fibers in C57BL/6J mice. Int J Mol Sci 2020;21(11):3923. 
  31. Siu PM, Alway SE. Id2 and p53 participate in apoptosis during unloading-induced muscle atrophy. Am J Physiol Cell Physiol 2005;288(5):C1058-73.  https://doi.org/10.1152/ajpcell.00495.2004
  32. Salmon AB, Richardson A, Perez VI. Update on the oxidative stress theory of aging: does oxidative stress play a role in aging or healthy aging? Free Radic Biol Med 2010;48(5):642-55.  https://doi.org/10.1016/j.freeradbiomed.2009.12.015
  33. Xiang Y, You Z, Huang X, Dai J, Zhang J, Nie S, Xu L, Jiang J, Xu J. Oxidative stress-induced premature senescence and aggravated denervated skeletal muscular atrophy by regulating progerin-p53 interaction. Skelet Muscle 2022;12(1):19. 
  34. Ban JY, Kang SW, Lee JS, Chung JH, Ko YG, Choi HS. Korean red ginseng protects against neuronal damage induced by transient focal ischemia in rats. Exp Ther Med 2012;3(4):693-8.  https://doi.org/10.3892/etm.2012.449
  35. Lee YM, Yoon H, Park HM, Song BC, Yeum KJ. Implications of red Panax ginseng in oxidative stress associated chronic diseases. J Ginseng Res 2017;41(2):113-9.  https://doi.org/10.1016/j.jgr.2016.03.003
  36. Horsley V, Pavlath GK. Forming a multinucleated cell: molecules that regulate myoblast fusion. Cells Tissues Organs 2004;176(1-3):67-78.  https://doi.org/10.1159/000075028
  37. Krauss RS. Regulation of promyogenic signal transduction by cell-cell contact and adhesion. Exp Cell Res 2010;316(18):3042-9.  https://doi.org/10.1016/j.yexcr.2010.05.008
  38. Schmidt M, Schuler SC, Huttner SS, von Eyss B, von Maltzahn J. Adult stem cells at work: regenerating skeletal muscle. Cell Mol Life Sci 2019;76(13):2559-70.  https://doi.org/10.1007/s00018-019-03093-6
  39. Moresi V, Williams AH, Meadows E, Flynn JM, Potthoff MJ, McAnally J, Shelton JM, Backs J, Klein WH, Richardson JA, et al. Myogenin and class II HDACs control neurogenic muscle atrophy by inducing E3 ubiquitin ligases. Cell 2010;143(1):35-45.  https://doi.org/10.1016/j.cell.2010.09.004
  40. 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(11):1014-9.  https://doi.org/10.1038/ncb1101-1014
  41. Yoon MS. mTOR as a key regulator in maintaining skeletal muscle mass. Front Physiol 2017;8:788. 
  42. Tang D, Okada H, Ruland J, Liu L, Stambolic V, Mak TW, Ingram AJ. Akt is activated in response to an apoptotic signal. J Biol Chem 2001;276(32):30461-6. https://doi.org/10.1074/jbc.M102045200