Biology Bulletin

, Volume 46, Issue 6, pp 615–625 | Cite as

Increased Oxidative Damage Contributes to Mitochondrial Dysfunction in Muscle of Depressed Rats Induced by Chronic Mild Stress Probably Mediated by SIRT3 Pathway

  • Qingfeng Xiao
  • Ze Xiong
  • Xiaoxian Xie
  • Chunan Yu
  • Qichen Shen
  • Jiafeng Zhou
  • Zhengwei FuEmail author


Depressed individuals are at an increased risk of developing age-related physiological diseases. Moreover, although it has been shown to be closely linked to skeletal muscle disease, the underlying mechanism is not well understood. In this study, we further investigated the pathophysiology and possible mechanism in the muscle tissue of depressed rats. The model of depression was developed by chronic mild stress (CMS) for seven weeks as indicated by reduced sucrose preference and a shorter total travelled distance, fewer grid line crossings, less time in the center zone in the open field test than that of controls. In addition, depressed rats exhibited declined physiological activity characterized by reduced locomotor activity and thermogenesis. Moreover, CMS altered the levels of 5-hydroxytryptophan (5-HT), Neuropeptide Y (NPY), and corticosterone (CORT) in serum and hippocampus. What’s more, impaired mitochondrial ultrastructure and function as shown by transmission electron microscope and reduced mitochrondrial DNA (mtDNA) integrity, ATP production, which was associated with increased cellular ROS and decreased superoxide dismutase activity in muscle tissue of CMS-induced depressed rats. Overall, our present study provides a new perspective for depressed individuals accompanied by fatigue and new ideas for future treatment of depression complications.


depression oxidative damage SIRT3 signaling pathway mitochondrial dysfunction skeletal muscle 



The authors express their gratitude to Prof. Qishan Wang (School of Agriculture and Biology, Department of Animal Sciences, Shanghai Jiao Tong University) for his/her help in revising our article for data analysis.


This work was supported by a grant from the National Natural Science Foundation of China (no. 31701028).


Conflict of interests. All authors agree with the presented findings, have contributed to the work and declare no conflict of interest.

Statement on the welfare of animals. Animals were treated in accordance with Guide for the Care and Use of Laboratory Animals (8th edition, National Academies Press), and all the experiments were carried out in accordance with the Guiding Principles for the Use of Animals in Zhejiang University of Technology, Hangzhou, China.

Supplementary material


  1. 1.
    Antoniuk, S., Bijata, M., Ponimaskin, E., and Wlodarczyk, J., Chronic unpredictable mild stress for modeling depression in rodents: meta-analysis of model reliability, Neurosci. Biobehav. Rev., 2019, vol. 99, pp. 101–116.PubMedCrossRefGoogle Scholar
  2. 2.
    Balaban, R.S., Nemoto, S., and Finkel, T., Mitochondria, oxidants, and aging, Cell, 2005, vol. 120, no. 4, pp. 483–495.PubMedCrossRefGoogle Scholar
  3. 3.
    Barja, G., Aging in vertebrates, and the effect of caloric restriction: a mitochondrial free radical production—DNA damage mechanism?, Biol. Rev., 2004, vol. 79, no. 2, pp. 235–251.PubMedCrossRefGoogle Scholar
  4. 4.
    Belmaker, R.H. and Agam, G., Major depressive disorder, N. Engl. J. Med., 2008, vol. 358, pp. 55–68.PubMedCrossRefGoogle Scholar
  5. 5.
    Brothers, S.P. and Wahlestedt, C., Therapeutic potential of neuropeptide Y (NPY) receptor ligands, EMBO Mol. Med., 2010, vol. 2, no. 11, pp. 429–439.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Camargo, A., Dalmagro, A.P., Rikel, L., Silva, E.B., Simao da Silva, K.A.B., and Zeni, A.L.B., Cholecalciferol counteracts depressive-like behavior and oxidative stress induced by repeated corticosterone treatment in mice, Eur. J. Pharmacol., 2018, vol. 833, pp. 451–461.PubMedCrossRefGoogle Scholar
  7. 7.
    Caro, P., Gomez, J., Sanz, A., Portero-Otin, M., Pamplona, R., and Barja, G., Effect of graded corticosterone treatment on aging-related markers of oxidative stress in rat liver mitochondria, Biogerontology, 2018, vol. 8, no. 1, pp. 1–11.CrossRefGoogle Scholar
  8. 8.
    Chang, K.V., Hsu, T.H., Wu, W.T., Huang, K.C., and Han, D.S., Is sarcopenia associated with depression? A systematic review and meta-analysis observational studies, Age Ageing, 2017, vol. 46, no. 12, pp. 738–746.PubMedCrossRefGoogle Scholar
  9. 9.
    Christiansen, S.L., Hojgaard, K., Wiborg, O., and Bouzinova, E.V., Disturbed diurnal rhythm of three classical phase markers in the chronic mild stress rat model of depression, Neurosci. Res., 2016, vol. 110, pp. 43–48.PubMedCrossRefGoogle Scholar
  10. 10.
    Czermak, C., Hauger, R., Drevets, W.C., Luckenbaugh, D.A., Geraci, M., Charney, D.S., and Neumeister, A., Plasma, NPY: concentrations during tryptophan and sham depletion in medication-free patients with remitted depression, J. Afferct. Disord., 2008, vol. 110, no. 3, pp. 277–281.CrossRefGoogle Scholar
  11. 11.
    Fang, E.F., Scheibye-Knudsen, M., Chua, K.F., Mattson, M.P., Croteau, D.L., and Bohr, V.A., Nuclear DNA damage signalling to mitochondria in ageing, Nat. Rev. Mol. Cell Biol., 2016, vol. 17, no. 5, pp. 308–321.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Fernandez-Rojas, B., Rodriguez-Rangel, D.S., Granados-Castro, L.F., Negrette-Guzman, M., Leon-Contreras, J.C., Hernandez-Pando, R., Molina-Jijon, E., Reyes, J.L., Zazueta, C., and Pedraza-Chaverri, J., C-phycocyanin prevents cisplatin-induced mitochondrial dysfunction and oxidative stress, Mol. Cell. Biochem., 2015, vol. 406, nos. 1–2, pp. 183–197.PubMedCrossRefGoogle Scholar
  13. 13.
    Fiorucci, S. and Baldelli, F., Farnesoid X receptor agonists in biliary tract disease, Curr. Opin. Gastroenterol., 2009, vol. 25, no. 3, pp. 252–259.PubMedCrossRefGoogle Scholar
  14. 14.
    Gold, P.W., The organization of the stress system and its dysregulation in depressive illness, Mol. Psychiatry, 2015, vol. 20, no. 1, pp. 32–47.PubMedCrossRefGoogle Scholar
  15. 15.
    Gomes, A.P., Price, N.L., Ling, A.J., Moslehi, J.J., Montgomery, M.K., Rajman, L., White, J.P., Teodoro, J.S., Wrann, C.D., Hubbard, B.P., et al., Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging, Cell, 2015, vol. 155, no. 7, pp. 1624–1638.CrossRefGoogle Scholar
  16. 16.
    Gong, Y., Chai, Y., Ding, J.H., Sun, X.L., and Hu, G., Chronic mild stress damages mitochondrial ultrastructure and function in mouse brain, Neurosci. Lett., 2011, vol. 488, no. 1, pp. 76–80.PubMedCrossRefGoogle Scholar
  17. 17.
    Gullo, H.L., Fleming, J., Bennett, S., and Shum, D.H.K., Cognitive and physical fatigue are associated with distinct problems in daily functioning, role fulfillment, and quality of life in multiple sclerosis, Mult. Scler. Relat. Disord., 2019, vol. 31, pp. 118–123.PubMedCrossRefGoogle Scholar
  18. 18.
    Hei, M., Chen, P., Wang, S., Li, X., Xu, M., Zhu, X., Wang, Y., Duan, J., Huang, Y., and Zhao, S., Effects of chronic mild stress induced depression on synaptic plasticity in mouse hippocampus, Behav. Brain Res., 2019, vol. 365, pp. 26–35.PubMedCrossRefGoogle Scholar
  19. 19.
    Hirsch, D., NPY and stress 30 years later: the peripheral view, Cell. Mol. Neurobiol., 2012, vol. 32, no. 5, pp. 645–659.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Hou, C., Jia, F., Liu, Y., and Li, L., CSF serotonin, 5-hydroxyindolacetic acid and neuropeptide Y levels in severe major depressive disorder, Brain Res., 2006, vol. 1095, no. 1, pp. 154–158.PubMedCrossRefGoogle Scholar
  21. 21.
    Jia, N., Sun, Q., Su, Q., Dang, S., and Chen, G., Taurine promotes cognitive function in prenatally stressed juvenile rats via activating the Akt-CREB-PGC1 pathway, Redox Biol., 2016, vol. 10, pp. 179–190.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Jin, D.Q., Lim, C.S., Hwang, J.K., Ha, I., and Han, J.S., Anti-oxidant and anti-inflammatory activities of macelignan in murine hippocampal cell line and primary culture of rat microglial cells, Biochem. Biophys. Res. Commun., 2005, vol. 331, no. 4, pp. 1264–1269.PubMedCrossRefGoogle Scholar
  23. 23.
    Johnson, S.A., Fournier, N.M., Kalynchuk, L.E., Johnson, S.A., Fournier, N.M., and Kalynchuk, L.E., Effect of different doses of corticosterone on depression-like behavior and HPA axis responses to a novel stressor, Behav. Brain Res., 2006, vol. 168, no. 2, pp. 280–288.PubMedCrossRefGoogle Scholar
  24. 24.
    Karl, T., Pabst, R., and von Horsten, S., Behavioral phenotyping of mice in pharmacological and toxicological research, Exp. Toxicol. Pathol., 2003, vol. 55, no. 1, pp. 69–83.PubMedCrossRefGoogle Scholar
  25. 25.
    Lopez-Lopez, A.L. and Jaime, H.B., Escobar Villanueva M.D.C., Padilla M.B., Palacios G.V., and Aguilar F.J.A. Chronic unpredictable mild stress generates oxidative stress and systemic inflammation in rats, Physiol. Behav., 2016, vol. 161, pp. 15–23.PubMedCrossRefGoogle Scholar
  26. 26.
    Lu, Y., Ho, C.S., McIntyre, R.S., Wang, W., and Ho, R.C., Effects of vortioxetine and fluoxetine on the level of brain derived neurotrophic factors (BDNF) in the hippocampus of chronic unpredictable mild stress-induced depressive rats, Brain Res. Bull., 2018, vol. 142, pp. 1–7.PubMedCrossRefGoogle Scholar
  27. 27.
    Lucca, G., Comim, C.M., Valvassori, S.S., Réus, G.Z., Vuolo, F., Petronilho, F., Gavioli, E.C., Dalpizzol, F., and Quevedo, J., Increased oxidative stress in submitochondrial particles into the brain of rats submitted to the chronic mild stress paradigm, J. Psychiatr. Res., 2009, vol. 43, no. 9, pp. 864–869.PubMedCrossRefGoogle Scholar
  28. 28.
    Mathers, The Global Burden of Disease: 2004 Update, World Health Organization, 2008.Google Scholar
  29. 29.
    Mougeot, F., Martinez-Padilla, J., Webster, L.M., Blount, J.D., Perez-Rodriguez, L., and Piertney, S.B., Honest sexual signalling mediated by parasite and testosterone effects on oxidative balance, Proc. Biol. Sci., 2009, vol. 276, no. 1659, pp. 1093–1100.PubMedCrossRefGoogle Scholar
  30. 30.
    Otsuka, T., Kawai, M., Togo, Y., Goda, R., Kawase, T., Matsuo, H., Iwamoto, A., Nagasawa, M., Furuse, M., and Yasuo, S., Photoperiodic responses of depression-like behavior, the brain serotonergic system, and peripheral metabolism in laboratory mice, Psychoneuroendocrinology, 2014, vol. 40, pp. 37–47.PubMedCrossRefGoogle Scholar
  31. 31.
    Pekala, K., Michalak, A., Kruk-Slomka, M., Budzynska, B., and Biala, G., Impacts of cannabinoid receptor ligands on nicotine-and chronic mild stress-induced cognitive and depression-like effects in mice, Behav. Brain Res., 2018, vol. 347, pp. 167–174.PubMedCrossRefGoogle Scholar
  32. 32.
    Qiu, X., Brown, K., Hirschey, M.D., Verdin, E., and Chen, D., Calorie restriction reduces oxidative stress bySIRT3-mediated SOD2 activation, Cell Metab., 2010, vol. 12, no. 6, pp. 662–667.PubMedCrossRefGoogle Scholar
  33. 33.
    Rezin, G., Amboni, G., Zugno, A.I., Quevedo, J., and El, S., Mitochondrial dysfunction and psychiatric disorders, Biomed. J., 2009, vol. 32, no. 4, pp. 370–379.Google Scholar
  34. 34.
    Santos-Alves, E., Marques-Aleixo, I., Rizo-Roca, D., Torrella, J.R., Oliveira, P.J., Magalhaes, J., and Ascensao, A., Exercise modulates liver cellular and mitochondrial proteins related to quality control signaling, Life Sci., 2015, vol. 135, pp. 124–130.PubMedCrossRefGoogle Scholar
  35. 35.
    Santos, J.H., Meyer, J.N., Mandavilli, B.S., and Houten, B.V., Quantitative PCR-based measurement of nuclear and mitochondrial DNA damage and repair in mammalian cells, Methods Mol. Biol., 2014, vol. 1105, pp. 419–437.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Sarandol, A., Sarandol, E., Eker, S.S., Erdinc, S., Vatansever, E., and Kirli, S., Major depressive disorder is accompanied with oxidative stress: short-term antidepressant treatment does not alter oxidative-antioxidative systems, Hum. Psychopharmacol., 2007, vol. 22, no. 2, pp. 67–73.PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Scarpulla, R.C., Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network, Biochim. Biophys. Acta, 2011, vol. 1813, no. 7, pp. 1269–1178.PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Schmittgen, T.D. and Livak, K.J., Analyzing real-time PCR data by the comparative CT method, Nat. Protoc., 2008, vol. 3, no. 6, pp. 1101–1108.PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Sebastian, C. and Mostoslavsky, R., SIRT3 in calorie restriction: can you hear me now?, Cell, 2010, vol. 143, no. 5, pp. 667–668.PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Stordal, E. and Mykletun, A., and Dahl AA. The association between age and depression in the general population: a multivariate examination, Acta Psychiatr. Scand., 2003, vol. 107, pp. 132–141.PubMedCrossRefGoogle Scholar
  41. 41.
    Tao, R., Coleman, M.C., Pennington, J.D., Ozden, O., Park, S.H., Jiang, H., Kim, H.S., Flynn, C.R., Hill, S., and Hayes, M.W., Sirt3-mediated deacetylation of evolutionarily conserved lysine 122 regulates MnSOD activity in response to stress, Mol. Cell, 2010, vol. 40, no. 6, pp. 893–904.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Wang, X., Kong, B., He, B., Wei, L., Zhu, J., Jin, Y., Shan, Y., Wang, W., Pan, C., and Fu, Z., 8:2 Fluorotelomere alcohol causes immunotoxicity and liver injury in adult male C57BL/6 mice, Environ. Toxicol., 2019, vol. 34, no. 2, pp. 141–149.PubMedGoogle Scholar
  43. 43.
    Wu, G., Feder, A., Wegener, G., Bailey, C., Saxena, S., Charney, D., and Mathe, A.A., Central functions of neuropeptide Y in mood and anxiety disorders, Expert Opin. Ther. Targets, 2011, vol. 15, no. 11, pp. 1317–1331.PubMedCrossRefGoogle Scholar
  44. 44.
    Xia, J., Lu, Z., Feng, S., Yang, J., and Ji, M., Different effects of immune stimulation on chronic unpredictable mild stress-induced anxiety-and depression-like behaviors depending on timing of stimulation, Int. Immunopharmacol., 2018, vol. 58, pp. 48–56.PubMedCrossRefGoogle Scholar
  45. 45.
    Xie, X.X., Ma, Y.F., Wang, Q.S., Chen, Z.L., Liao, R.R., and Pan, Y.C., Yeast CUP1 protects HeLa cells against copper-induced stress, Braz. J. Med. Biol. Res., 2015, vol. 48, no. 7, pp. 616–621.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Xie, X., Zhao, B., Huang, L., Shen, Q., Ma, L., Chen, Y., Wu, T., and Fu, Z., Effects of altered photoperiod on circadian clock and lipid metabolism in rats, Chronobiol. Int., 2017a, vol. 34, no. 8, pp. 1094–1104.PubMedCrossRefGoogle Scholar
  47. 47.
    Xie, X., Chen, Y., Ma, L., Shen, Q., Huang, L., Zhao, B., Wu, T., and Fu, Z., Major depressive disorder mediates accelerated aging in rats subjected to chronic mild stress, Behav. Brain Res., 2017b, vol. 329, pp. 96–103.PubMedCrossRefGoogle Scholar
  48. 48.
    Xie, X., Shen, Q., Ma, L., Chen, Y., Zhao, B., and Fu, Z., Chronic corticosterone-induced depression mediates premature aging in rats, J. Affect. Disord., 2018, vol. 229, pp. 254–261.PubMedCrossRefGoogle Scholar
  49. 49.
    Yi, C., Zhu, Z., Shu, Y., Chao, Z., Zhu, Y., Gong, S., Cui, Y., and Wang, J.F., Chronic unpredictable stress impairs endogenous antioxidant defense in rat brain, Neurosci. Lett., 2015, vol. 584, pp. 208–213.CrossRefGoogle Scholar
  50. 50.
    Zhang, L., Hirano, A., Hsu, P.K., Jones, C.R., Sakai, N., Okuro, M., Mcmahon, T., Yamazaki, M., Xu, Y., and Saigoh, N., A PERIOD3 variant causes a circadian phenotype and is associated with a seasonal mood trait, Proc. Natl. Acad. Sci. U. S. A., 2016, vol. 113, no. 11, pp. E1536–E1544.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Pleiades Publishing, Inc. 2019

Authors and Affiliations

  • Qingfeng Xiao
    • 1
  • Ze Xiong
    • 1
  • Xiaoxian Xie
    • 1
  • Chunan Yu
    • 1
  • Qichen Shen
    • 1
  • Jiafeng Zhou
    • 1
  • Zhengwei Fu
    • 1
    Email author
  1. 1.College of Biotechnology and Bioengineering, Zhejiang University of TechnologyHangzhouChina

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