The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
권호 표지
DOI QR코드

DOI QR Code

Effects of exercise on AKT/PGC1-α/FOXO3a pathway and muscle atrophy in cisplatin-administered rat skeletal muscle

  • Bae, Jun Hyun (Health and Exercise Science Laboratory, Institute of Sports Science, Seoul National University) ;
  • Seo, Dae Yun (National Research Laboratory for Mitochondrial Signaling, Department of Physiology, College of Medicine, Smart Marine Therapeutics Center, Cardiovascular and Metabolic Disease Center, Inje University) ;
  • Lee, Sang Ho (Department of Taekwondo, Dong-A University) ;
  • Shin, Chaeyoung (Health and Exercise Science Laboratory, Institute of Sports Science, Seoul National University) ;
  • Jamrasi, Parivash (Health and Exercise Science Laboratory, Institute of Sports Science, Seoul National University) ;
  • Han, Jin (National Research Laboratory for Mitochondrial Signaling, Department of Physiology, College of Medicine, Smart Marine Therapeutics Center, Cardiovascular and Metabolic Disease Center, Inje University) ;
  • Song, Wook (Health and Exercise Science Laboratory, Institute of Sports Science, Seoul National University)
  • Received : 2021.07.09
  • Accepted : 2021.08.26
  • Published : 2021.11.01
Download PDF
⟨ Previous Next ⟩

Abstract

Cisplatin has been reported to cause side effects such as muscle wasting in humans and rodents. The physiological mechanisms involved in preventing muscle wasting, such as the regulation of AKT, PGC1-α, and autophagy-related factor FOXO3a by MuRF 1 and Atrogin-1, remain unclear following different types of exercise and in various skeletal muscle types. Eight-week-old male Wistar rats (n = 34) were assigned to one of four groups: control (CON, n = 6), cisplatin injection (1 mg/kg) without exercise (CC, n = 8), cisplatin (1 mg/kg) + resistance exercise (CRE, n = 9) group, and cisplatin (1 mg/kg) + aerobic exercise (CAE, n = 11). The CRE group performed progressive ladder exercise (starting with 10% of body weight on a 1-m ladder with 2-cm-interval grids, at 85°) for 8 weeks. The CAE group exercised by treadmill running (20 m/min for 60 min daily, 4 times/week) for 8 weeks. Compared with the CC group, the levels of the autophagy-related factors BNIP3, Beclin 1, LC3-II/I ratio, p62, and FOXO3a in the gastrocnemius and soleus muscles were significantly decreased in the CRE and CAE groups. The CRE and CAE groups further showed significantly decreased MuRF 1 and Atrogin-1 levels and increased phosphorylation of AKT, FOXO3a, and PGC1-α. These results suggest that both ladder and aerobic exercise directly affected muscle wasting by modulating the AKT/PGC1-α/FOXO3a signaling pathways regardless of the skeletal muscle type.

Keywords

Acknowledgement

We thank Dr. Jeong Rim Ko for establishing the cisplatin-administered animal models. This work was supported by the Ministry of Education of the Republic of Korea and the National Research Foundation (NRF) of Korea (grant number NRF-2018S1A5A8027802); Ministry of Science and ICT (grant number 2018R1A2A3074998); Basic Research Lab Program (grant number 2020R1A4A1018943); Ministry of Science, ICT, and Future Planning (grant number 2020M3A9D803866011); and Korea Mouse Phenotyping Project (grant number 2013M3A9D5072560). The funding sources had no involvement in the study design, management of study data, writing of the report, or the decision to submit the manuscript for publication.

References

  1. Conte E, Bresciani E, Rizzi L, Cappellari O, De Luca A, Torsello A, Liantonio A. Cisplatin-induced skeletal muscle dysfunction: mechanisms and counteracting therapeutic strategies. Int J Mol Sci. 2020;21:1242. https://doi.org/10.3390/ijms21041242
  2. Fearon K, Strasser F, Anker SD, Bosaeus I, Bruera E, Fainsinger RL, Jatoi A, Loprinzi C, MacDonald N, Mantovani G, Davis M, Muscaritoli M, Ottery F, Radbruch L, Ravasco P, Walsh D, Wilcock A, Kaasa S, Baracos VE. Definition and classification of cancer cachexia: an international consensus. Lancet Oncol. 2011;12:489-495. https://doi.org/10.1016/S1470-2045(10)70218-7
  3. Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J, Greenberg ME. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell. 1999;96:857-868. https://doi.org/10.1016/S0092-8674(00)80595-4
  4. Mammucari C, Milan G, Romanello V, Masiero E, Rudolf R, Del Piccolo P, Burden SJ, Di Lisi R, Sandri C, Zhao J, Goldberg AL, Schiaffino S, Sandri M. FoxO3 controls autophagy in skeletal muscle in vivo. Cell Metab. 2007;6:458-471. https://doi.org/10.1016/j.cmet.2007.11.001
  5. Galluzzi L, Baehrecke EH, Ballabio A, Boya P, Bravo-San Pedro JM, Cecconi F, Choi AM, Chu CT, Codogno P, Colombo MI, Cuervo AM, Debnath J, Deretic V, Dikic I, Eskelinen EL, Fimia GM, Fulda S, Gewirtz DA, Green DR, Hansen M, et al. Molecular definitions of autophagy and related processes. EMBO J. 2017;36:1811-1836. https://doi.org/10.15252/embj.201796697
  6. Dehoux M, Van Beneden R, Pasko N, Lause P, Verniers J, Underwood L, Ketelslegers JM, Thissen JP. Role of the insulin-like growth factor I decline in the induction of atrogin-1/MAFbx during fasting and diabetes. Endocrinology. 2004;145:4806-4812. https://doi.org/10.1210/en.2004-0406
  7. Clavel S, Coldefy AS, Kurkdjian E, Salles J, Margaritis I, Derijard B. Atrophy-related ubiquitin ligases, atrogin-1 and MuRF1 are upregulated in aged rat Tibialis Anterior muscle. Mech Ageing Dev. 2006;127:794-801. https://doi.org/10.1016/j.mad.2006.07.005
  8. Bresciani E, Rizzi L, Molteni L, Ravelli M, Liantonio A, Ben Haj Salah K, Fehrentz JA, Martinez J, Omeljaniuk RJ, Biagini G, Locatelli V, Torsello A. JMV2894, a novel growth hormone secretagogue, accelerates body mass recovery in an experimental model of cachexia. Endocrine. 2017;58:106-114. https://doi.org/10.1007/s12020-016-1184-2
  9. Conte E, Camerino GM, Mele A, De Bellis M, Pierno S, Rana F, Fonzino A, Caloiero R, Rizzi L, Bresciani E, Ben Haj Salah K, Fehrentz JA, Martinez J, Giustino A, Mariggio MA, Coluccia M, Tricarico D, Lograno MD, De Luca A, Torsello A, et al. Growth hormone secretagogues prevent dysregulation of skeletal muscle calcium homeostasis in a rat model of cisplatin-induced cachexia. J Cachexia Sarcopenia Muscle. 2017;8:386-404. https://doi.org/10.1002/jcsm.12185
  10. Fanzani A, Zanola A, Rovetta F, Rossi S, Aleo MF. Cisplatin triggers atrophy of skeletal C2C12 myotubes via impairment of Akt signalling pathway and subsequent increment activity of proteasome and autophagy systems. Toxicol Appl Pharmacol. 2011;250:312-321. https://doi.org/10.1016/j.taap.2010.11.003
  11. Lee K, Ochi E, Song H, Nakazato K. Activation of AMP-activated protein kinase induce expression of FoxO1, FoxO3a, and myostatin after exercise-induced muscle damage. Biochem Biophys Res Commun. 2015;466:289-294. https://doi.org/10.1016/j.bbrc.2015.08.126
  12. Luo L, Lu AM, Wang Y, Hong A, Chen Y, Hu J, Li X, Qin ZH. Chronic resistance training activates autophagy and reduces apoptosis of muscle cells by modulating IGF-1 and its receptors, Akt/mTOR and Akt/FOXO3a signaling in aged rats. Exp Gerontol. 2013;48:427-436. https://doi.org/10.1016/j.exger.2013.02.009
  13. Hojman P, Fjelbye J, Zerahn B, Christensen JF, Dethlefsen C, Lonkvist CK, Brandt C, Gissel H, Pedersen BK, Gehl J. Voluntary exercise prevents cisplatin-induced muscle wasting during chemotherapy in mice. PLoS One. 2014;9:e109030. https://doi.org/10.1371/journal.pone.0109030
  14. Miyagi MY, Seelaender M, Castoldi A, de Almeida DC, Bacurau AV, Andrade-Oliveira V, Enjiu LM, Pisciottano M, Hayashida CY, Hiyane MI, Brum PC, Camara NO, Amano MT. Long-term aerobic exercise protects against cisplatin-induced nephrotoxicity by modulating the expression of IL-6 and HO-1. PLoS One. 2014;9:e108543. https://doi.org/10.1371/journal.pone.0108543
  15. Sirago G, Conte E, Fracasso F, Cormio A, Fehrentz JA, Martinez J, Musicco C, Camerino GM, Fonzino A, Rizzi L, Torsello A, Lezza AMS, Liantonio A, Cantatore P, Pesce V. Growth hormone secretagogues hexarelin and JMV2894 protect skeletal muscle from mitochondrial damages in a rat model of cisplatin-induced cachexia. Sci Rep. 2017;7:13017. https://doi.org/10.1038/s41598-017-13504-y
  16. Li T, Wei S, Shi Y, Pang S, Qin Q, Yin J, Deng Y, Chen Q, Wei S, Nie S, Liu L. The dose-response effect of physical activity on cancer mortality: findings from 71 prospective cohort studies. Br J Sports Med. 2016;50:339-345. https://doi.org/10.1136/bjsports-2015-094927
  17. Tong CKW, Lau B, Davis MK. Exercise training for cancer survivors. Curr Treat Options Oncol. 2020;21:53. https://doi.org/10.1007/s11864-020-00752-w
  18. Fernandez de Mattos S, Villalonga P, Clardy J, Lam EW. FOXO3a mediates the cytotoxic effects of cisplatin in colon cancer cells. Mol Cancer Ther. 2008;7:3237-3246. https://doi.org/10.1158/1535-7163.MCT-08-0398
  19. Lu M, Chen X, Xiao J, Xiang J, Yang L, Chen D. FOXO3a reverses the cisplatin resistance in ovarian cancer. Arch Med Res. 2018;49:84-88. https://doi.org/10.1016/j.arcmed.2018.04.014
  20. Rashtchizadeh N, Argani H, Ghorbanihaghjo A, Sanajou D, Hosseini V, Dastmalchi S, Nazari Soltan Ahmad S. AMPK: a promising molecular target for combating cisplatin toxicities. Biochem Pharmacol. 2019;163:94-100. https://doi.org/10.1016/j.bcp.2019.02.006
  21. Zeng Z, Liang J, Wu L, Zhang H, Lv J, Chen N. Exercise-induced autophagy suppresses sarcopenia through Akt/mTOR and Akt/FoxO3a signal pathways and AMPK-mediated mitochondrial quality control. Front Physiol. 2020;11:583478. https://doi.org/10.3389/fphys.2020.583478
  22. Sun M, Huang C, Wang C, Zheng J, Zhang P, Xu Y, Chen H, Shen W. Ginsenoside Rg3 improves cardiac mitochondrial population quality: mimetic exercise training. Biochem Biophys Res Commun. 2013;441:169-174. https://doi.org/10.1016/j.bbrc.2013.10.039
  23. Kim HJ, So B, Choi M, Kang D, Song W. Resistance exercise training increases the expression of irisin concomitant with improvement of muscle function in aging mice and humans. Exp Gerontol. 2015;70:11-17. https://doi.org/10.1016/j.exger.2015.07.006
  24. 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
  25. Sandri M. Autophagy in skeletal muscle. FEBS Lett. 2010;584:1411-1416. https://doi.org/10.1016/j.febslet.2010.01.056
  26. Brandt N, Gunnarsson TP, Bangsbo J, Pilegaard H. Exercise and exercise training-induced increase in autophagy markers in human skeletal muscle. Physiol Rep. 2018;6:e13651. https://doi.org/10.14814/phy2.13651
  27. Sakai H, Kimura M, Isa Y, Yabe S, Maruyama A, Tsuruno Y, Kai Y, Sato F, Yumoto T, Chiba Y, Narita M. Effect of acute treadmill exercise on cisplatin-induced muscle atrophy in the mouse. Pflugers Arch. 2017;469:1495-1505. https://doi.org/10.1007/s00424-017-2045-4
  28. Stefanetti RJ, Lamon S, Wallace M, Vendelbo MH, Russell AP, Vissing K. Regulation of ubiquitin proteasome pathway molecular markers in response to endurance and resistance exercise and training. Pflugers Arch. 2015;467:1523-1537. https://doi.org/10.1007/s00424-014-1587-y
  29. Vainshtein A, Hood DA. The regulation of autophagy during exercise in skeletal muscle. J Appl Physiol (1985). 2016;120:664-673. https://doi.org/10.1152/japplphysiol.00550.2015
  30. Zhao J, Brault JJ, Schild A, Goldberg AL. Coordinate activation of autophagy and the proteasome pathway by FoxO transcription factor. Autophagy. 2008;4:378-380. https://doi.org/10.4161/auto.5633
  31. Zhao J, Brault JJ, Schild A, Cao P, Sandri M, Schiaffino S, Lecker SH, Goldberg AL. FoxO3 coordinately activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscle cells. Cell Metab. 2007;6:472-483. https://doi.org/10.1016/j.cmet.2007.11.004
  32. van der Vos KE, Eliasson P, Proikas-Cezanne T, Vervoort SJ, van Boxtel R, Putker M, van Zutphen IJ, Mauthe M, Zellmer S, Pals C, Verhagen LP, Groot Koerkamp MJ, Braat AK, Dansen TB, Holstege FC, Gebhardt R, Burgering BM, Coffer PJ. Modulation of glutamine metabolism by the PI(3)K-PKB-FOXO network regulates autophagy. Nat Cell Biol. 2012;14:829-837. https://doi.org/10.1038/ncb2536
  33. Milan G, Romanello V, Pescatore F, Armani A, Paik JH, Frasson L, Seydel A, Zhao J, Abraham R, Goldberg AL, Blaauw B, DePinho RA, Sandri M. Regulation of autophagy and the ubiquitin-proteasome system by the FoxO transcriptional network during muscle atrophy. Nat Commun. 2015;6:6670. https://doi.org/10.1038/ncomms7670
  34. Christensen JF, Jones LW, Tolver A, Jorgensen LW, Andersen JL, Adamsen L, Hojman P, Nielsen RH, Rorth M, Daugaard G. Safety and efficacy of resistance training in germ cell cancer patients undergoing chemotherapy: a randomized controlled trial. Br J Cancer. 2014;111:8-16. https://doi.org/10.1038/bjc.2014.273
  35. Saran U, Guarino M, Rodriguez S, Simillion C, Montani M, Foti M, Humar B, St-Pierre MV, Dufour JF. Anti-tumoral effects of exercise on hepatocellular carcinoma growth. Hepatol Commun. 2018;2:607-620. https://doi.org/10.1002/hep4.1159
  36. White JP, Puppa MJ, Gao S, Sato S, Welle SL, Carson JA. Muscle mTORC1 suppression by IL-6 during cancer cachexia: a role for AMPK. Am J Physiol Endocrinol Metab. 2013;304:E1042-E1052. https://doi.org/10.1152/ajpendo.00410.2012
  37. Hardee JP, Counts BR, Carson JA. Understanding the role of exercise in cancer cachexia therapy. Am J Lifestyle Med. 2017;13:46-60. https://doi.org/10.1177/1559827617725283
  38. Salomao EM, Toneto AT, Silva GO, Gomes-Marcondes MC. Physical exercise and a leucine-rich diet modulate the muscle protein metabolism in Walker tumor-bearing rats. Nutr Cancer. 2010;62:1095-1104. https://doi.org/10.1080/01635581.2010.492082
  39. Pigna E, Berardi E, Aulino P, Rizzuto E, Zampieri S, Carraro U, Kern H, Merigliano S, Gruppo M, Mericskay M, Li Z, Rocchi M, Barone R, Macaluso F, Di Felice V, Adamo S, Coletti D, Moresi V. Aerobic exercise and pharmacological treatments counteract cachexia by modulating autophagy in colon cancer. Sci Rep. 2016;6:26991. https://doi.org/10.1038/srep26991
  40. Aversa Z, Pin F, Lucia S, Penna F, Verzaro R, Fazi M, Colasante G, Tirone A, Rossi Fanelli F, Ramaccini C, Costelli P, Muscaritoli M. Autophagy is induced in the skeletal muscle of cachectic cancer patients. Sci Rep. 2016;6:30340. https://doi.org/10.1038/srep30340
  41. Moller AB, Lonbro S, Farup J, Voss TS, Rittig N, Wang J, Hojris I, Mikkelsen UR, Jessen N. Molecular and cellular adaptations to exercise training in skeletal muscle from cancer patients treated with chemotherapy. J Cancer Res Clin Oncol. 2019;145:1449-1460. https://doi.org/10.1007/s00432-019-02911-5
  42. Toth MJ, Callahan DM, Miller MS, Tourville TW, Hackett SB, Couch ME, Dittus K. Skeletal muscle fiber size and fiber type distribution in human cancer: effects of weight loss and relationship to physical function. Clin Nutr. 2016;35:1359-1365. https://doi.org/10.1016/j.clnu.2016.02.016
  43. Mijwel S, Cardinale DA, Norrbom J, Chapman M, Ivarsson N, Wengstrom Y, Sundberg CJ, Rundqvist H. Exercise training during chemotherapy preserves skeletal muscle fiber area, capillarization, and mitochondrial content in patients with breast cancer. FASEB J. 2018;32:5495-5505. https://doi.org/10.1096/fj.201700968r
  44. Paolini A, Omairi S, Mitchell R, Vaughan D, Matsakas A, Vaiyapuri S, Ricketts T, Rubinsztein DC, Patel K. Attenuation of autophagy impacts on muscle fibre development, starvation induced stress and fibre regeneration following acute injury. Sci Rep. 2018;8:9062. https://doi.org/10.1038/s41598-018-27429-7