본문 바로가기
KERD
논문KCI 등재

Treadmill Exercise Ameliorates Chemotherapy-Induced Muscle Weakness and Central Fatigue by Enhancing Mitochondrial Function and Inhibiting Apoptosis

허준원|곽효범|유수지|김태운|박혜상|정형모|박상서|노미현
대한배뇨장애요실금학회 (Korean Continence Society)|2019.11|International Neurourology Journal|제23권 제1호|pp. 32-39|DOI 10.5213/inj.1938046.023

1

조회

0

다운로드

8

인용

0

참고문헌

키워드

FatigueApoptosisChemotherapyMuscle strengthDoxorubicinMitochondrial function

초록

Purpose: Chemotherapy is associated with the side effects including damage to the mitochondrial DNA. Doxorubicin (DOX) serves as a chemotherapeutic agent for the patients with breast cancer or prostate cancer. DOX causes muscle weakness and fatigue. We investigated the effects of treadmill exercise on DOX-induced apoptosis and mitochondrial dysfunction in relation to central fatigue. For this study, we used the rat model of DOX-induced muscle damage. Methods: DOX (2 mg/kg) was intraperitoneally injected 1 time per week for 4 weeks. Treadmill running continued 5 days per week for 4 weeks. Muscle strength and fatigue index in the gastrocnemius were measured. Immunohistochemistry for the expressions of tryptophan hydroxylase (TPH) and 5-hydroxytryptamine (5-HT) in the dorsal raphe was conducted. We used western blot analysis for the expressions of Bax, Bcl-2, and caspases-3 in the gastrocnemius. Mitochondrial function in the gastrocnemius was also evaluated. Results: DOX treatment decreased muscle strength with increase of fatigue index in the gastrocnemius. Mitochondria function was deteriorated and apoptosis in the gastrocnemius was enhanced by DOX treatment. Expressions of TPH and 5-HT in the dorsal raphe were increased by DOX treatment. Treadmill exercise attenuated DOX-induced muscle fatigue and impairment of mitochondria function. Apoptosis in the gastrocnemius was inhibited and over-expression of TPH and 5-HT was suppressed by treadmill exercise. Conclusions: Apoptosis was enhanced and mitochondria function was deteriorated by DOX treatment, resulting in muscle weakness and central fatigue. Treadmill exercise suppressed apoptosis and prevented deterioration of mitochondria function in muscle, resulting in alleviation of muscle weakness and central fatigue during DOX therapy.

Abstract

Purpose: Chemotherapy is associated with the side effects including damage to the mitochondrial DNA. Doxorubicin (DOX) serves as a chemotherapeutic agent for the patients with breast cancer or prostate cancer. DOX causes muscle weakness and fatigue. We investigated the effects of treadmill exercise on DOX-induced apoptosis and mitochondrial dysfunction in relation to central fatigue. For this study, we used the rat model of DOX-induced muscle damage. Methods: DOX (2 mg/kg) was intraperitoneally injected 1 time per week for 4 weeks. Treadmill running continued 5 days per week for 4 weeks. Muscle strength and fatigue index in the gastrocnemius were measured. Immunohistochemistry for the expressions of tryptophan hydroxylase (TPH) and 5-hydroxytryptamine (5-HT) in the dorsal raphe was conducted. We used western blot analysis for the expressions of Bax, Bcl-2, and caspases-3 in the gastrocnemius. Mitochondrial function in the gastrocnemius was also evaluated. Results: DOX treatment decreased muscle strength with increase of fatigue index in the gastrocnemius. Mitochondria function was deteriorated and apoptosis in the gastrocnemius was enhanced by DOX treatment. Expressions of TPH and 5-HT in the dorsal raphe were increased by DOX treatment. Treadmill exercise attenuated DOX-induced muscle fatigue and impairment of mitochondria function. Apoptosis in the gastrocnemius was inhibited and over-expression of TPH and 5-HT was suppressed by treadmill exercise. Conclusions: Apoptosis was enhanced and mitochondria function was deteriorated by DOX treatment, resulting in muscle weakness and central fatigue. Treadmill exercise suppressed apoptosis and prevented deterioration of mitochondria function in muscle, resulting in alleviation of muscle weakness and central fatigue during DOX therapy.

참고문헌 (33)

  1. Serrano J, "Cardioselective and cumulative oxidation of mitochondrial DNA following subchronic doxorubicin administration1", Biochim Biophys Acta, 1411, pp.201~205 (1999)
  2. Gilliam LA, "Doxorubicin causes diaphragm weakness in murine models of cancer chemotherapy", Muscle Nerve, 43, pp.94~102 (2011)
  3. Gilliam LA, "TNF", TNFR1 signaling mediates doxorubicin-induced diaphragm weakness, 2011, pp.300, L225~31
  4. Vichaya EG, "Mechanisms of chemotherapy-induced behavioral toxicities", Front Neurosci, 9, pp.131~ (2015)
  5. Zhou S, "Cumulative and irreversible cardiac mitochondrial dysfunction induced by doxorubicin", Cancer Res, 61, pp.771~777 (2001)
  6. Oliveira PJ, "Carvedilol-mediated antioxidant protection against doxorubicin-induced cardiac mitochondrial toxicity", Toxicol Appl Pharmacol, 200, pp.159~168 (2004)
  7. van Norren K, "Direct effects of doxorubicin on skeletal muscle contribute to fatigue", Br J Cancer, 100, pp.311~314 (2009)
  8. Yamamoto Y, "Atrogin-1 ubiquitin ligase is upregulated by doxorubicin via p38-MAP kinase in cardiac myocytes", Cardiovasc Res, 79, pp.89~96 (2008)
  9. Yu AP, "Acylated and unacylated ghrelin inhibit doxorubicin-induced apoptosis in skeletal muscle", Acta Physiol(Oxf), 211, pp.201~213 (2014)
  10. António A, "Endurance exercise training attenuates morphological signs of cardiac muscle damage induced by doxorubicin in male mice", Basic Appl Myol, 16, pp.27~35 (2006)
  11. Green PS, "Mitochondrial dysfunction is an early indicator of doxorubicin-induced apoptosis", Biochim Biophys Acta, 1588, pp.94~101 (2002)
  12. Childs AC, "Doxorubicin treatment in vivo causes cytochrome C release and cardiomyocyte apoptosis, as well as increased mitochondrial efficiency, superoxide dismutase activity, and Bcl-2 : Bax ratio", Cancer Res, 62, pp.4592~4598 (2002)
  13. 김선영, "Doxorubicin-induced reactive oxygen species generation and intracellular Ca2+ increase are reciprocally modulated in rat cardiomyocytes", Experimental and Molecular Medicine, 38(5), pp.535~545 (2006), 생화학분자생물학회
  14. Tangpong J, "Adriamycin-induced, TNF-alpha-mediated central nervous system toxicity", Neurobiol Dis, 23, pp.127~139 (2006)
  15. Tangpong J, "Adriamycin-mediated nitration of manganese superoxide dismutase in the central nervous system : insight into the mechanism of chemobrain", J Neurochem, 100, pp.191~201 (2007)
  16. Smuder AJ, "Exercise protects against doxorubicin-induced oxidative stress and proteolysis in skeletal muscle", J Appl Physiol(1985), 110, pp.935~942 (2011)
  17. Supinski GS, "Free radical-mediated skeletal muscle dysfunction in inflammatory conditions", J Appl Physiol(1985), 102, pp.2056~2063 (2007)
  18. Powers SK, "Exercise-induced oxidative stress : cellular mechanisms and impact on muscle force production", Physiol Rev, 88, pp.1243~1276 (2008)
  19. Kavazis AN, "Effects of short-term endurance exercise training on acute doxorubicin-induced FoxO transcription in cardiac and skeletal muscle", J Appl Physiol(1985), 117, pp.223~230 (2014)
  20. Smuder AJ, "Exercise protects against doxorubicin-induced markers of autophagy signaling in skeletal muscle", J Appl Physiol(1985), 111, pp.1190~1198 (2011)
  21. Ascensão A, "Acute exercise protects against calcium-induced cardiac mitochondrial permeability transition pore opening in doxorubicin-treated rats", Clin Sci(Lond), 120, pp.37~49 (2011)
  22. Davis JM, "Serotonin and central nervous system fatigue : nutritional considerations", Am J Clin Nutr, 72, pp.573S~578S (2000)
  23. Seo JH, "Effects of Phellinus linteus administration on serotonin synthesis in the brain and expression of monocarboxylate transporters in the muscle during exhaustive exercise in rats", J Nutr Sci Vitaminol(Tokyo), 57, pp.95~103 (2011)
  24. Blomstrand E, "Amino acids and central fatigue", Amino Acids, 20, pp.25~34 (2001)
  25. Blomstrand E, "A role for branched-chain amino acids in reducing central fatigue", J Nutr, 136, pp.544S~547S (2006)
  26. Fernstrom JD, "Exercise, serum free tryptophan, and central fatigue", J Nutr, 136, pp.553S~559S (2006)
  27. Foley TE, "Neuroplasticity of dopamine circuits after exercise : implications for central fatigue", Neuromolecular Med, 10, pp.67~80 (2008)
  28. Park HS, "Physical exercise prevents cognitive impairment by enhancing hippocampal neuroplasticity and mitochondrial function in doxorubicin-induced chemobrain", Neuropharmacology, 133, pp.451~461 (2018)
  29. 지은상, "Treadmill exercise ameliorates depressive symptoms through increasing serotonin expression in postpartum depression rats", Journal of exercise rehabilitation, 13(2), pp.130~136 (2017), 한국운동재활학회
  30. 송상혁, "Treadmill exercise and wheel exercise improve motor function by suppressing apoptotic neuronal cell death in brain inflammation rats", Journal of exercise rehabilitation, 14(6), pp.911~919 (2018), 한국운동재활학회
  31. Tsujimoto Y1, "Role of the mitochondrial membrane permeability transition in cell death", Apoptosis, 12, pp.835~840 (2007)
  32. 이재민, "Treadmill exercise improves memory function by inhibiting hippocampal apoptosis in pilocarpine-induced epileptic rats", Journal of exercise rehabilitation, 14(5), pp.713~723 (2018), 한국운동재활학회
  33. 조정완, "Treadmill exercise ameliorates social isolation-induced depression through neuronal generation in rat pups", Journal of exercise rehabilitation, 13(6), pp.627~633 (2017), 한국운동재활학회

이 간행물의 다른 논문 (23건)

Knowledge Knows No Boundaries이택pp. 1-2How to Interpret the Effects Shown in Animal Study김계환pp. 1-2In Search of a New Prostate-Specific Antigen김진욱pp. 3-4Mitochondrial Dysfunction as a Cause of Neurological Diseases김창주pp. 3-4For Physicians Managing Voiding Dysfunction, Improving the Detection Rate of Early Prostate Cancer and Discrimination From Benign Prostatic Hyperplasia, in a Molecular Biomarker Aspects김원태, 윤석중, 김원재pp. 5-12
원문 보기