DOI QR코드

DOI QR Code

Effects of cisplatin on mitochondrial function and autophagy-related proteins in skeletal muscle of rats

  • 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) ;
  • Bae, Jun Hyun (Health & Exercise Science Laboratory, Institute of Sports Science, Seoul National University) ;
  • Zhang, Didi (School of Physical Education, Xiang Minzu University) ;
  • Song, Wook (Health & Exercise Science Laboratory, Institute of Sports Science, Seoul National University) ;
  • Kwak, Hyo-Bum (Department of Biomedical Science and Engineering, Inha University) ;
  • Heo, Jun-Won (Department of Biomedical Science and Engineering, Inha University) ;
  • Jung, Su-Jeen (Department of Leisure Sports, Seoil University) ;
  • Yun, Hyeong Rok (National Research Laboratory for Mitochondrial Signaling, Department of Physiology, College of Medicine, Smart Marine Therapeutics Center, Cardiovascular and Metabolic Disease Center, Inje University) ;
  • Kim, Tae Nyun (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) ;
  • Kim, Amy Hyein (National Research Laboratory for Mitochondrial Signaling, Department of Physiology, College of Medicine, Smart Marine Therapeutics Center, Cardiovascular and Metabolic Disease Center, Inje University) ;
  • Jeong, Dae Hoon (Department of Obstetrics and Gynecology, Busan Paik Hospital, College of Medicine, Inje University) ;
  • Kim, Hyoung Kyu (National Research Laboratory for Mitochondrial Signaling, Department of Physiology, College of Medicine, Smart Marine Therapeutics Center, Cardiovascular and Metabolic Disease Center, Inje 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)
  • Received : 2021.07.05
  • Accepted : 2021.10.06
  • Published : 2021.11.30

Abstract

Cisplatin is widely known as an anti-cancer drug. However, the effects of cisplatin on mitochondrial function and autophagy-related proteins levels in the skeletal muscle are unclear. The purpose of this study was to investigate the effect of different doses of cisplatin on mitochondrial function and autophagy-related protein levels in the skeletal muscle of rats. Eight-week-old male Wistar rats (n = 24) were assigned to one of three groups; the first group was administered a saline placebo (CON, n = 10), and the second and third groups were given 0.1 mg/kg body weight (BW) (n = 6), and 0.5 mg/kg BW (n = 8) of cisplatin, respectively. The group that had been administered 0.5 mg cisplatin exhibited a reduced BW, skeletal muscle tissue weight, and mitochondrial function and upregulated levels of autophagy-related proteins, including LC3II, Beclin 1, and BNIP3. Moreover, this group had a high LC3 II/I ratio in the skeletal muscle; i.e., the administration of a high dose of cisplatin decreased the muscle mass and mitochondrial function and increased the levels of autophagy-related proteins. These results, thus, suggest that reducing mitochondrial dysfunction and autophagy pathways may be important for preventing skeletal muscle atrophy following cisplatin administration.

Keywords

Acknowledgement

This work was supported by the Ministry of Education of the Republic of Korea and the National Research Foundation of Korea (NRF-2018S1A5A8027802). We thank Dr. Jeong Rim Ko for performing cisplatin-administered animal models.

References

  1. Frezza M, Hindo S, Chen D et al (2010) Novel metals and metal complexes as platforms for cancer therapy. Curr Pharm Des 16, 1813-1825 https://doi.org/10.2174/138161210791209009
  2. Kelland L (2007) The resurgence of platinum-based cancer chemotherapy. Nat Rev Cancer 7, 573-584 https://doi.org/10.1038/nrc2167
  3. Jung ET, Koh DS, Lim YH, Shin SY and Lee YH (2020) Overcoming multidrug resistance by activating unfolded protein response of the endoplasmic reticulum in cisplatin-resistant A2780/CisR ovarian cancer cells. BMB Rep 53, 88-93 https://doi.org/10.5483/bmbrep.2020.53.2.108
  4. Sakai H, Sagara A, Arakawa K et al (2014) Mechanisms of cisplatin-induced muscle atrophy. Toxicol Appl Pharmacol 278, 190-199 https://doi.org/10.1016/j.taap.2014.05.001
  5. Jin YJ, Huynh DTN, Kang KW, Myung CS and Heo KS (2019) Inhibition of p90RSK activation sensitizes triple-negative breast cancer cells to cisplatin by inhibiting proliferation, migration and EMT. BMB Rep 52, 706-711 https://doi.org/10.5483/BMBRep.2019.52.12.234
  6. Conte E, Bresciani E, Rizzi L et al (2020) Cisplatin-induced skeletal muscle dysfunction: mechanisms and counteracting therapeutic strategies. Int J Mol Sci 21, 1242 https://doi.org/10.3390/ijms21041242
  7. Fearon K, Strasser F, Anker SD et al (2011) Definition and classification of cancer cachexia: an international consensus. Lancet Oncol 12, 489-495 https://doi.org/10.1016/S1470-2045(10)70218-7
  8. Conte E, Camerino GM, Mele A et al (2017) Growth hormone secretagogues prevent dysregulation of skeletal muscle calcium homeostasis in a rat model of cisplatin-induced cachexia. J Cachexia Sarcopenia Muscle 8, 386-404 https://doi.org/10.1002/jcsm.12185
  9. Bresciani E, Rizzi L, Molteni L et al (2017) JMV2894, a novel growth hormone secretagogue, accelerates body mass recovery in an experimental model of cachexia. Endocrine 58, 106-114 https://doi.org/10.1007/s12020-016-1184-2
  10. Sakai H, Sagara A, Arakawa K et al (2014) Mechanisms of cisplatin-induced muscle atrophy. Toxicol Appl Pharmacol 278, 190-199 https://doi.org/10.1016/j.taap.2014.05.001
  11. Dickey DT, Muldoon LL, Doolittle ND, Peterson DR, Kraemer DF and Neuwelt EA (2008) Effect of N-acetylcysteine route of administration on chemoprotection against cisplatin-induced toxicity in rat models. Cancer Chemother Pharmacol 62, 235-241 https://doi.org/10.1007/s00280-007-0597-2
  12. Garcia JM, Cata JP, Dougherty PM and Smith RG (2008) Ghrelin prevents cisplatin-induced mechanical hyperalgesia and cachexia. Endocrinology 149, 455-460 https://doi.org/10.1210/en.2007-0828
  13. Park SE, Choi JH, Park JY et al (2020) Loss of skeletal muscle mass during palliative chemotherapy is a poor prognostic factor in patients with advanced gastric cancer. Sci Rep 10, 17683 https://doi.org/10.1038/s41598-020-74765-8
  14. Lin JF, Lin YC, Tsai TF, Chen HE, Chou KY and Hwang TIS (2017) Cisplatin induces protective autophagy through activation of BECN1 in human bladder cancer cells. Drug Des Devel Ther 11, 1517-1533 https://doi.org/10.2147/DDDT.S126464
  15. Cocetta V, Ragazzi E and Montopoli M (2019) Mitochondrial involvement in cisplatin resistance. Int J Mol Sci 20, 3384 https://doi.org/10.3390/ijms20143384
  16. Lomeli N, Di K, Czerniawski J, Guzowski JF and Bota DA (2017) Cisplatin-induced mitochondrial dysfunction is associated with impaired cognitive function in rats. Free Radic Biol Med 102, 274-286 https://doi.org/10.1016/j.freeradbiomed.2016.11.046
  17. Inapurapu SP, Kudle KR, Bodiga S and Bodiga VL (2017) Cisplatin cytotoxicity is dependent on mitochondrial respiration in Saccharomyces cerevisiae. Iran J Basic Med Sci 20, 83-89
  18. Sartori R, Romanello V, Sandri M (2021) Mechanisms of muscle atrophy and hypertrophy: implications in health and disease. Nat Commun 12, 330 https://doi.org/10.1038/s41467-020-20123-1
  19. Romanello V and Sandri M (2015) Mitochondrial quality control and muscle mass maintenance. Front Physiol 6, 422 https://doi.org/10.3389/fphys.2015.00422
  20. Sirago G, Conte E, Fracasso F et al (2017) Growth hormone secretagogues hexarelin and JMV2894 protect skeletal muscle from mitochondrial damages in a rat model of cisplatin-induced cachexia. Sci Rep 7, 1-14 https://doi.org/10.1038/s41598-016-0028-x
  21. Hood DA, Memme JM, Oliveira AN and Triolo M (2019) Maintenance of skeletal muscle mitochondria in health, exercise, and aging. Annu Rev Physiol 81, 19-41 https://doi.org/10.1146/annurev-physiol-020518-114310
  22. Poillet Perez L, Sarry JE and Joffre C (2021) Autophagy is a major metabolic regulator involved in cancer therapy resistance. Cell Rep 36, 109528 https://doi.org/10.1016/j.celrep.2021.109528
  23. Paolini A, Omairi S, Mitchell R et al (2018) Attenuation of autophagy impacts on muscle fibre development, starvation induced stress and fibre regeneration following acute injury. Sci Rep 8, 9062 https://doi.org/10.1038/s41598-018-27429-7
  24. Gasiorkiewicz BM, Koczurkiewicz-Adamczyk P, Piska K and Pekala E (2021) Autophagy modulating agents as chemosensitizers for cisplatin therapy in cancer. Invest New Drugs 39, 538-563 https://doi.org/10.1007/s10637-020-01032-y
  25. Dikic I and Elazar Z (2018) Mechanism and medical implications of mammalian autophagy. Nat Rev Mol Cell Biol 19, 349-364 https://doi.org/10.1038/s41580-018-0003-4
  26. Yu L, Chen Y and Tooze SA (2018) Autophagy pathway: Cellular and molecular mechanisms. Autophagy 14, 207-215 https://doi.org/10.1080/15548627.2017.1378838
  27. Metaxakis A, Ploumi C and Tavernarakis N (2018) Autophagy in age-associated neurodegeneration. Cells 7, 37 https://doi.org/10.3390/cells7050037
  28. Banerjee A and Guttridge DC (2012) Mechanisms for maintaining muscle. Curr Opin Support Palliat Care 6, 451-456 https://doi.org/10.1097/SPC.0b013e328359b681
  29. Youle RJ and Van Der Bliek AM (2012) Mitochondrial fission, fusion, and stress. Science 337, 1062-1065 https://doi.org/10.1126/science.1219855
  30. Kleih M, Bopple K, Dong M et al (2019) Direct impact of cisplatin on mitochondria induces ROS production that dictates cell fate of ovarian cancer cells. Cell Death Dis 10, 851 https://doi.org/10.1038/s41419-019-2081-4
  31. Gordon JA and Gattone N (1986) Mitochondrial alterations in cisplatin-induced acute renal failure. Am J Physiol 250, F991-F998
  32. Choi YM, Kim HK, Shim W et al (2015) Mechanism of cisplatin-induced cytotoxicity is correlated to impaired metabolism due to mitochondrial ROS generation. PLoS One 10, e0135083 https://doi.org/10.1371/journal.pone.0135083
  33. Kruspig B, Valter K, Skender B, Zhivotovsky B and Gogvadze V (2016) Targeting succinate: ubiquinone reductase potentiates the efficacy of anticancer therapy. Biochim Biophys Acta 1863, 2065-2071 https://doi.org/10.1016/j.bbamcr.2016.04.026
  34. Chen J, Zhang L, Zhou H et al (2018) Inhibition of autophagy promotes cisplatin-induced apoptotic cell death through Atg5 and Beclin 1 in A549 human lung cancer cells. Mol Med Rep 17, 6859-6865
  35. Fanzani A, Zanola A, Rovetta F, Rossi S and Aleo MF (2011) Cisplatin triggers atrophy of skeletal C2C12 myotubes via impairment of Akt signalling pathway and sub-sequent increment activity of proteasome and autophagy systems. Toxicol Appl Pharmacol 250, 312-321 https://doi.org/10.1016/j.taap.2010.11.003
  36. Sandri M (2010) Autophagy in skeletal muscle. FEBS Lett 584, 1411-1416 https://doi.org/10.1016/j.febslet.2010.01.056
  37. Sandri M, Sandri C, Gilbert A et al (2004) Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. Cell 117, 399-412 https://doi.org/10.1016/S0092-8674(04)00400-3
  38. Rambold AS and Lippincott-Schwartz J (2011) Mechanisms of mitochondria and autophagy crosstalk. Cell Cycle 10, 4032-4038 https://doi.org/10.4161/cc.10.23.18384
  39. Zhu L, Yuan Y, Yuan L et al (2020) Activation of TFEB-mediated autophagy by trehalose attenuates mitochondrial dysfunction in cisplatin-induced acute kidney injury. Theranostics 10, 5829-5844 https://doi.org/10.7150/thno.44051
  40. Wang J and Wu GS (2014) Role of autophagy in cisplatin resistance in ovarian cancer cells. J Biol Chem 289, 17163-17173 https://doi.org/10.1074/jbc.M114.558288