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01-10-2016 | Review Article

Mitochondria: Inadvertent targets in chemotherapy-induced skeletal muscle toxicity and wasting?

Authors: James C. Sorensen, Beatrice D. Cheregi, Cara A. Timpani, Kulmira Nurgali, Alan Hayes, Emma Rybalka

Published in: Cancer Chemotherapy and Pharmacology | Issue 4/2016

Abstract

Chemotherapy has been associated with increased mitochondrial reactive oxygen species production, mitochondrial dysfunction and skeletal muscle atrophy leading to severe patient clinical complications including skeletal muscle fatigue, insulin resistance and wasting. The exact mechanisms behind this skeletal muscle toxicity are largely unknown, and as such co-therapies to attenuate chemotherapy-induced side effects are lacking. Here, we review the current literature describing the clinical manifestations and molecular origins of chemotherapy-induced myopathy with a focus on the mitochondria as the target organelle via which chemotherapeutic agents establish toxicity. We explore the likely mechanisms through which myopathy is induced, using the anthracycline doxorubicin, and the platinum-based alkylating agent oxaliplatin, as examples. Finally, we recommend directions for future research and outline the potential significance of these proposed directions.

Steward B, Wild C (2014) World Cancer Report 2014. International Agency for Research on Cancer, Lyon

de Gramont AD et al (2000) Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18(16):2938–2947PubMed

Ogston KN et al (2003) A new histological grading system to assess response of breast cancers to primary chemotherapy: prognostic significance and survival. The Breast 12(5):320–327PubMedCrossRef

Zitvogel L et al (2008) Immunological aspects of cancer chemotherapy. Nat Rev Immunol 8(1):59–73PubMedCrossRef

Gilliam LAA, St. Clair DK (2011) Chemotherapy-induced weakness and fatigue in skeletal muscle: the role of oxidative stress. Antioxid Redox Signal 15(9):2543–2563PubMedPubMedCentralCrossRef

Greene D et al (1993) A comparison of patient-reported side effects among three chemotherapy regimens for breast cancer. Cancer Pract 2(1):57–62

Yin H, Price F, Rudnicki MA (2013) Satellite cells and the muscle stem cell niche. Physiol Rev 93(1):23–67PubMedPubMedCentralCrossRef

Järvelä LS et al (2012) Effects of a home-based exercise program on metabolic risk factors and fitness in long-term survivors of childhood acute lymphoblastic leukemia. Pediatr Blood Cancer 59(1):155–160PubMedCrossRef

van Brussel M et al (2006) Physical function and fitness in long-term survivors of childhood leukaemia. Pediatr Rehabil 9(3):267–274PubMedCrossRef

10.

Scheede-Bergdahl C, Jagoe RT (2013) After the chemotherapy: potential mechanisms for chemotherapy-induced delayed skeletal muscle dysfunction in survivors of acute lymphoblastic leukaemia in childhood. Front Pharmacol 4:49. doi:10.3389/fphar.2013.00049 PubMedPubMedCentralCrossRef

11.

Miyamoto Y et al (2015) Negative impact of skeletal muscle loss after systemic chemotherapy in patients with unresectable colorectal cancer. PLoS ONE 10(6):e0129742PubMedPubMedCentralCrossRef

12.

Larsen S et al (2012) Biomarkers of mitochondrial content in skeletal muscle of healthy young human subjects. J Physiol 590(14):3349–3360PubMedPubMedCentralCrossRef

13.

Argilés JM, López-Soriano FJ, Busquets S (2015) Muscle wasting in cancer: the role of mitochondria. Curr Opin Clin Nutr Metab Care 18(3):221–225PubMedCrossRef

14.

Dobs AS et al (2013) Effects of enobosarm on muscle wasting and physical function in patients with cancer: a double-blind, randomised controlled phase 2 trial. Lancet Oncol 14(4):335–345PubMedPubMedCentralCrossRef

15.

Ness KK et al (2007) Body composition, muscle strength deficits and mobility limitations in adult survivors of childhood acute lymphoblastic leukemia. Pediatr Blood Cancer 49(7):975–981PubMedCrossRef

16.

Gewirtz D (1999) A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin. Biochem Pharmacol 57(7):727–741PubMedCrossRef

17.

Gilliam LA et al (2011) Doxorubicin causes diaphragm weakness in murine models of cancer chemotherapy. Muscle Nerve 43(1):94–102PubMedPubMedCentralCrossRef

18.

Schelman WR et al (2009) A phase I study of Triapine^® in combination with doxorubicin in patients with advanced solid tumors. Cancer Chemother Pharmacol 63(6):1147–1156PubMedCrossRef

19.

Lu P (2005) Monitoring cardiac function in patients receiving doxorubicin. Semin Nucl Med 35(3):197–201PubMedCrossRef

20.

Agudelo D et al (2014) Intercalation of antitumor drug doxorubicin and its analogue by DNA duplex: structural features and biological implications. Int J Biol Macromol 66:144–150PubMedCrossRef

21.

Quach B, Birk A, Szeto H (2014) Mechanism of preventing doxorubicin-induced mitochondrial toxicity with cardiolipin-targeted peptide, SS-31 (966.1). FASEB J 28(1 Supplement):966.1

22.

Cheregi B et al (2015) Chemotherapy-induced mitochondrial respiratory dysfunction, oxidant production and death in healthy skeletal muscle C2C12 myoblast and myotube models. Neuromuscul Disord 25(Supplement 2):S202CrossRef

23.

Deavall DG et al (2012) Drug-induced oxidative stress and toxicity. J Toxicol 2012:645460PubMedPubMedCentralCrossRef

24.

Sawyer DB et al (2010) Mechanisms of anthracycline cardiac injury: Can we identify strategies for cardioprotection? Prog Cardiovasc Dis 53(2):105–113PubMedPubMedCentralCrossRef

25.

Sarosiek KA, Chonghaile TN, Letai A (2013) Mitochondria: gatekeepers of response to chemotherapy. Trends Cell Biol 23(12):612–619PubMedCrossRef

26.

Wallace DC (2012) Mitochondria and cancer. Nat Rev Cancer 12(10):685–698PubMedPubMedCentralCrossRef

27.

Zorov DB, Juhaszova M, Sollott SJ (2014) Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release. Physiol Rev 94(3):909–950PubMedPubMedCentralCrossRef

28.

Davies K, Doroshow J (1986) Redox cycling of anthracyclines by cardiac mitochondria. I. Anthracycline radical formation by NADH dehydrogenase. J Biol Chem 261(7):3060–3067PubMed

29.

Doroshow J, Davies K (1986) Redox cycling of anthracyclines by cardiac mitochondria. II. Formation of superoxide anion, hydrogen peroxide, and hydroxyl radical. J Biol Chem 261(7):3068–3074PubMed

30.

Chen Q et al (2003) Production of reactive oxygen species by mitochondria central role of complex III. J Biol Chem 278(38):36027–36031PubMedCrossRef

31.

Chen Y et al (2007) Collateral damage in cancer chemotherapy: oxidative stress in nontargeted tissues. Mol Interv 7(3):147PubMedCrossRef

32.

Dirks-Naylor AJ et al (2013) The effects of acute doxorubicin treatment on proteome lysine acetylation status and apical caspases in skeletal muscle of fasted animals. J Cachexia Sarcopenia Muscle 4(3):239–243PubMedPubMedCentralCrossRef

33.

Gilliam LAA et al (2012) Doxorubicin acts via mitochondrial ROS to stimulate catabolism in C2C12 myotubes. Am J Physiol Cell Physiol 302:C195–C202PubMedCrossRef

34.

Xu X, Persson HL, Richardson DR (2005) Molecular pharmacology of the interaction of anthracyclines with iron. Mol Pharmacol 68(2):261–271PubMed

35.

Finn NA, Findley HW, Kemp ML (2011) A switching mechanism in doxorubicin bioactivation can be exploited to control doxorubicin toxicity. PLoS Comput Biol 7(9):e1002151PubMedPubMedCentralCrossRef

36.

Ismail HM et al (2013) Inhibition of iPLA2β and of stretch-activated channels by doxorubicin alters dystrophic muscle function. Br J Pharmacol 169(7):1537–1550PubMedPubMedCentralCrossRef

37.

Conklin KA (2004) Chemotherapy-associated oxidative stress: impact on chemotherapeutic effectiveness. Integr Cancer Ther 3(4):294–300PubMedCrossRef

38.

Bai P et al (2011) PARP-1 inhibition increases mitochondrial metabolism through SIRT1 activation. Cell Metab 13(4):461–468PubMedPubMedCentralCrossRef

39.

Goodwin P et al (1978) The effect of gamma radiation and neocarzinostatin of NAD and ATP levels in mouse leukaemia cells. Biochimica et Biophysica Acta (BBA) Gen Subj 543(4):576–582CrossRef

40.

Skidmore CJ et al (1979) The Involvement of poly (ADP-ribose) polymerase in the degradation of NAD caused by γ-radiation and N-methyl-N-nitrosourea. Eur J Biochem 101(1):135–142PubMedCrossRef

41.

Ying W, Garnier P, Swanson RA (2003) NAD⁺ repletion prevents PARP-1-induced glycolytic blockade and cell death in cultured mouse astrocytes. Biochem Biophys Res Commun 308(4):809–813PubMedCrossRef

42.

Zong WX et al (2004) Alkylating DNA damage stimulates a regulated form of necrotic cell death. Genes Dev 18(11):1272–1282PubMedPubMedCentralCrossRef

43.

Niere M et al (2008) Functional localization of two poly (ADP-ribose)-degrading enzymes to the mitochondrial matrix. Mol Cell Biol 28(2):814–824PubMedCrossRef

44.

Lai Y et al (2008) Identification of poly-ADP-ribosylated mitochondrial proteins after traumatic brain injury. J Neurochem 104(6):1700–1711PubMedCrossRef

45.

Bai P et al (2011) PARP-2 regulates SIRT1 expression and whole-body energy expenditure. Cell Metab 13(4):450–460PubMedPubMedCentralCrossRef

46.

Devalaraja-Narashimha K, Padanilam BJ (2010) PARP1 deficiency exacerbates diet-induced obesity in mice. J Endocrinol 205(3):243–252PubMedCrossRef

47.

Kourie JI (1998) Interaction of reactive oxygen species with ion transport mechanisms. Am J Physiol Cell Physiol 275:C1–C24

48.

Leeuwenburgh C (2003) Role of apoptosis in sarcopenia. J Gerontol Ser A Biol Sci Med Sci 58(11):999–1001CrossRef

49.

Powers SK, Kavazis AN, DeRuisseau KC (2005) Mechanisms of disuse muscle atrophy: role of oxidative stress. Am J Physiol Regul Integr Comp Physiol 288:R337–R344PubMedCrossRef

50.

Du J et al (2004) Activation of caspase-3 is an initial step triggering accelerated muscle proteolysis in catabolic conditions. J Clin Investig 113(1):115–123PubMedPubMedCentralCrossRef

51.

Smuder AJ et al (2011) Exercise protects against doxorubicin-induced oxidative stress and proteolysis in skeletal muscle. J Appl Physiol 110:935–942PubMedPubMedCentralCrossRef

52.

Lecker SH et al (1999) Muscle protein breakdown and the critical role of the ubiquitin–proteasome pathway in normal and disease states. J Nutr 129(1):227S–237SPubMed

53.

Lecker SH, Goldberg AL, Mitch WE (2006) Protein degradation by the ubiquitin–proteasome pathway in normal and disease states. J Am Soc Nephrol 17(7):1807–1819PubMedCrossRef

54.

Bonnard C et al (2008) Mitochondrial dysfunction results from oxidative stress in the skeletal muscle of diet-induced insulin-resistant mice. J Clin Investig 118(2):789–800PubMedPubMedCentral

55.

Adachi K et al (1993) A deletion of mitochondrial DNA in murine doxorubicin-induced cardiotoxicity. Biochem Biophys Res Commun 195(2):945–951PubMedCrossRef

56.

Gouspillou G et al (2015) Anthracycline-containing chemotherapy causes long-term impairment of mitochondrial respiration and increased reactive oxygen species release in skeletal muscle. Sci Rep 5:8717. doi:10.1038/srep08717 PubMedPubMedCentralCrossRef

57.

Raymond E et al (1998) Oxaliplatin: mechanism of action and antineoplastic activity. Semin Oncol 25(2 Suppl 5):4–12PubMed

58.

André T et al (2004) Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 350(23):2343–2351PubMedCrossRef

59.

Raymond E et al (1998) Oxaliplatin: a review of preclinical and clinical studies. Ann Oncol 9(10):1053–1071PubMedCrossRef

60.

Talvensaari KK et al (1995) Decreased isokinetic trunk muscle strength and performance in long-term survivors of childhood malignancies: correlation with hormonal defects. Arch Phys Med Rehabil 76(11):983–988PubMedCrossRef

61.

Gourdier I et al (2004) Oxaliplatin-induced mitochondrial apoptotic response of colon carcinoma cells does not require nuclear DNA. Oncogene 23(45):7449–7457PubMedCrossRef

62.

Lutsenko S et al (2007) Function and regulation of human copper-transporting ATPases. Physiol RevVol. 87:1011–1046CrossRef

63.

Wisnovsky SP et al (2013) Targeting mitochondrial DNA with a platinum-based anticancer agent. Chem Biol 20(11):1323–1328PubMedPubMedCentralCrossRef

64.

Stojanovska V, McQuade RM, Stewart M, Timpani CA, Sorensen J, Orbell J, Rybalka E, Nurgali K (2015) Platinum accumulation and changes in mitochondrial function of the longitudinal muscle & myenteric plexus following oxaliplatin administration. In: Proceedings of the Australian Physiology Society

65.

Gilliam LAA et al (2013) The anticancer agent doxorubicin disrupts mitochondrial energy metabolism and redox balance in skeletal muscle. Free Radic Biol Med 65:988–996PubMedCrossRef

66.

Powers SK et al (2012) Mitochondrial signaling contributes to disuse muscle atrophy. Am J Physiol Endocrinol Metab 303:E31–E39PubMedPubMedCentralCrossRef

67.

Min K et al (2011) Mitochondrial-targeted antioxidants protect skeletal muscle against immobilization-induced muscle atrophy. J Appl Physiol 111:1459–1466PubMedPubMedCentralCrossRef

68.

Singh K, Hood DA (2011) Effect of denervation-induced muscle disuse on mitochondrial protein import. American Physiol Cell Physiol 300:C138–C145CrossRef

69.

Min K et al (2015) Increased mitochondrial emission of reactive oxygen species and calpain activation are required for doxorubicin-induced cardiac and skeletal muscle myopathy. J Physiol 593(8):2017–2036PubMedPubMedCentralCrossRef

70.

Powers SK, Talbert EE, Adhihetty PJ (2011) Reactive oxygen and nitrogen species as intracellular signals in skeletal muscle. J Physiol 589(9):2129–2138PubMedPubMedCentralCrossRef

71.

Sena LA, Chandel NS (2012) Physiological roles of mitochondrial reactive oxygen species. Mol Cell 48(2):158–167PubMedPubMedCentralCrossRef

72.

Lokireddy S et al (2012) The ubiquitin ligase Mul1 induces mitophagy in skeletal muscle in response to muscle-wasting stimuli. Cell Metab 16(5):613–624PubMedCrossRef

73.

Sorensen J, Timpani CA, Campelj D, Petersen AC, Hayes A, Rybalka E (2015) Idebenone protects against chemotherapy-induced skeletal muscle wasting and mitochondrial dysfunction in mice. Proc Aust Physiol Soc 46:142

74.

Jackman RW, Kandarian SC (2004) The molecular basis of skeletal muscle atrophy. Am J Physiol Cell Physiol 287:C834–C843PubMedCrossRef

75.

Jang YC et al (2010) Increased superoxide in vivo accelerates age-associated muscle atrophy through mitochondrial dysfunction and neuromuscular junction degeneration. FASEB J 24(5):1376–1390PubMedPubMedCentralCrossRef

76.

Bonaldo P, Sandri M (2013) Cellular and molecular mechanisms of muscle atrophy. Dis Models Mech 6(1):25–39CrossRef

77.

Lenaz G (2012) Mitochondria and reactive oxygen species. Which role in physiology and pathology? In: Scatena R, Bottoni P, Giardina B (eds) Advances in mitochondrial medicine. Springer, Dordrecht, pp 93–136CrossRef

78.

Kurihara Y et al (2012) Mitophagy plays an essential role in reducing mitochondrial production of reactive oxygen species and mutation of mitochondrial DNA by maintaining mitochondrial quantity and quality in yeast. J Biol Chem 287(5):3265–3272PubMedCrossRef

79.

Neel BA, Lin Y, Pessin JE (2013) Skeletal muscle autophagy: a new metabolic regulator. Trends Endocrinol Metab TEM. doi:10.1016/j.tem.2013.09.004 PubMed

80.

Maccarrone M, Melino G, Finazzi-Agro A (2001) Lipoxygenases and their involvement in programmed cell death. Cell Death Differ 8(8):776–784PubMedCrossRef

81.

England K, Cotter T (2005) Direct oxidative modifications of signalling proteins in mammalian cells and their effects on apoptosis. Redox Rep 10(5):237–245PubMedCrossRef

82.

Moylan JS, Reid MB (2007) Oxidative stress, chronic disease, and muscle wasting. Muscle Nerve 35(4):411–429PubMedCrossRef

83.

Ranek M, Wang X (2009) Activation of the ubiquitin–proteasome system in doxorubicin cardiomyopathy. Curr Hypertens Rep 11(6):389–395PubMedPubMedCentralCrossRef

84.

Corradetti RM (2014) Chemotherapy-induced peripheral neuropathy. Chemotherapy 249:279

85.

Lind MJ (2008) Principles of cytotoxic chemotherapy. Medicine 36(1):19–23CrossRef

86.

Coates A et al (1983) On the receiving end—patient perception of the side-effects of cancer chemotherapy. Eur J Cancer Clin Oncol 19(2):203–208PubMedCrossRef

87.

Courneya KS et al (2004) Exercise issues in older cancer survivors. CritRev Oncol Hematol 51(3):249–261CrossRef

88.

Willemse P-PM et al (2014) Abdominal visceral and subcutaneous fat increase, insulin resistance and hyperlipidemia in testicular cancer patients treated with cisplatin-based chemotherapy. Acta Oncol 53(3):351–360PubMedCrossRef

89.

Kent-Braun JA, Fitts RH, Christie A (2012) Skeletal muscle fatigue. Compr Physiol 2:997–1044PubMed

90.

MacIntosh BR, Holash RJ, Renaud J-M (2012) Skeletal muscle fatigue–regulation of excitation–contraction coupling to avoid metabolic catastrophe. J Cell Sci 125(9):2105–2114PubMedCrossRef

91.

Jacobs RA et al (2013) Improvements in exercise performance with high-intensity interval training coincide with an increase in skeletal muscle mitochondrial content and function. J Appl Physiol 115(6):785–793PubMedCrossRef

92.

Gejl K et al. (2015) Repeated high-intensity exercise modulates Ca2+ sensitivity of human skeletal muscle fibers. Scand J Med Sci Sports 26(5):488–97PubMedCrossRef

93.

Kano Y et al (2012) Mechanisms of exercise-induced muscle damage and fatigue: intracellular calcium accumulation. J Phys Fit Sports Med 1(3):505–512CrossRef

94.

Hydock D et al (2015) Protective effects of endurance or resistance training exercise on chemotherapy-induced skeletal muscle weakness and fatigue. FASEB J 29(1 Supplement):LB660

95.

Grisold W, Cavaletti G, Windebank AJ (2012) Peripheral neuropathies from chemotherapeutics and targeted agents: diagnosis, treatment, and prevention. Neuro-oncology 14(suppl 4):iv45–iv54PubMedPubMedCentralCrossRef

96.

Wall BT, Dirks ML, van Loon LJC (2013) Skeletal muscle atrophy during short-term disuse: implications for age-related sarcopenia. Ageing Res Rev 12(4):898–906PubMedCrossRef

97.

Franchi M et al (2014) Architectural, functional and molecular responses to concentric and eccentric loading in human skeletal muscle. Acta Physiol 210(3):642–654CrossRef

98.

McQuade RM, Bornstein JC, Nurgali K (2014) Anti-colorectal cancer chemotherapy-induced diarrhoea: current treatments and side-effects. Int J Clin Med 5(7):393CrossRef

99.

Hovi L et al (1993) Impaired muscle strength in female adolescents and young adults surviving leukemia in childhood. Cancer Phila 72:276CrossRef

100.

Malina RM, Bouchard C, Bar-Or O (2004) Growth, maturation, and physical activity. Human Kinetics, Champaign

101.

Mouly V et al (2005) The mitotic clock in skeletal muscle regeneration, disease and cell mediated gene therapy. Acta Physiol Scand 184(1):3–15PubMedCrossRef

102.

Scully RE, Lipshultz SE (2007) Anthracycline cardiotoxicity in long-term survivors of childhood cancer. Cardiovasc Toxicol 7(2):122–128PubMedCrossRef

103.

Syrjala KL et al (2005) Late effects of hematopoietic cell transplantation among 10-year adult survivors compared with case-matched controls. J Clin Oncol 23(27):6596–6606PubMedCrossRef

104.

Lynch DR, Perlman SL, Meier T (2010) A phase 3, double-blind, placebo-controlled trial of idebenone in Friedreich ataxia. Arch Neurol 67(8):941–947PubMedCrossRef

105.

Literati-Nagy B et al (2009) Improvement of insulin sensitivity by a novel drug, BGP-15, in insulin-resistant patients: a proof of concept randomized double-blind clinical trial. Hormone Metab Res Hormon-und Stoffwechselforschung Hormones et metabolisme 41(5):374–380PubMedCrossRef

Title: Mitochondria: Inadvertent targets in chemotherapy-induced skeletal muscle toxicity and wasting?
Authors: James C. Sorensen
Beatrice D. Cheregi
Cara A. Timpani
Kulmira Nurgali
Alan Hayes
Emma Rybalka
Publication date: 01-10-2016
Publisher: Springer Berlin Heidelberg
Published in: Cancer Chemotherapy and Pharmacology / Issue 4/2016
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-016-3045-3

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