THE MOLECULAR MECHANISMS INVOLVED IN DOXORUBICIN-INDUCED SKELETAL MUSCLE WASTING
DOI:
https://doi.org/10.34635/rpc.930Keywords:
Adriamycin, cachexia, oxidative stress, muscular toxicity, proteolytic pathwaysAbstract
Chemotherapeutic agents like doxorubicin (DOX) are the foundation for the treatment of a variety of malignancies; however, these therapies have several side-effects. DOX may trigger or potentiate the muscle wasting observed in cancer patients, which is particularly worrying in frail old patients. Therefore, it is important to comprehend the mechanisms responsible for DOX-induced toxicity in skeletal muscle, to identify therapeutic targets envisioning the improvement of survival rates and quality of life of these patients. Hence, this review discusses the molecular players that may be involved in DOX-induced muscle wasting. From the analysis performed herein, DOX seems to induce the activation of the proteolytic ubiquitin proteasome pathway (UPP), which in turn can also be enhanced by DOX-induced increase in myostatin and tumor necrosis factor (TNF)-α signaling pathways, as well as insulin resistance. Furthermore, DOX-induced oxidative stress and mitochondrial dysfunction may also be critical contributors for muscle wasting. All these mechanisms may contribute to the loss of skeletal muscle mass and function observed after DOX exposure, which may lead to or aggravate cachexia, responsible for more than 20% of all cancer-related deaths.
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References
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21. Doroshow JH, Tallent C, Schechter JE. Ultrastructural features of adriamycin-induced skeletal and cardiac muscle toxicity. Am J Pathol. 1985;118:288–97.
22. Hayward R, Hydock D, Gibson N, Greufe S, Bredahl E, Parry T. Tissue retention of doxorubicin and its effects on cardiac, smooth, and skeletal muscle function. J Physiol Biochem. 2013;69:177–87.
23. Gibson NM, Quinn CJ, Pfannenstiel KB, Hydock DS, Hayward R. Effects of age on multidrug resistance protein expression and doxorubicin accumulation in cardiac and skeletal muscle. Xenobiotica. 2014;44:472–9.
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27. Gilliam LAA, Moylan JS, Callahan LA, Sumandea MP, Reid MB. Doxorubicin causes diaphragm weakness in murine models of cancer chemotherapy. Muscle and Nerve. 2011;43:94–102.
28. Gilliam LAA, Fisher-Wellman KH, Lin C-T, Maples JM, Cathey BL, Neufer PD. The anticancer agent doxorubicin disrupts mitochondrial energy metabolism and redox balance in skeletal muscle. Free Radic Biol Med. 2013;65:988–96.
29. Bredahl EC, Pfannenstiel KB, Quinn CJ, Hayward R, Hydock DS. Effects of exercise on doxorubicin-induced skeletal muscle dysfunction. Med Sci Sports Exerc. 2016;48:1468–73.
30. Nissinen TA, Degerman J, Räsänen M, Poikonen AR, Koskinen S, Mervaala E, et al. Systemic blockade of ACVR2B ligands prevents chemotherapy-induced muscle wasting by restoring muscle protein synthesis without affecting oxidative capacity or atrogenes. Sci Rep. 2016;6:32695.
31. Huang SC, Wu JF, Saovieng S, Chien WH, Hsu MF, Li XF, et al. Doxorubicin inhibits muscle inflammation after eccentric exercise. J Cachexia Sarcopenia Muscle. 2017;8:277–84.
32. Min K, Kwon O-S, Smuder AJ, Wiggs MP, Sollanek KJ, Christou DD, et al. Increased mitochondrial emission of reactive oxygen species and calpain activation are required for doxorubicin-induced cardiac and skeletal muscle myopathy. J Physiol. 2015;593: 2017–36.
33. Doerr V, Montalvo RN, Kwon OS, Talbert EE, Hain BA, Houston FE, et al. Prevention of doxorubicin-induced autophagy attenuates oxidative stress and skeletal muscle dysfunction. Antioxidants. 2020;9:263.
34. Rudolf R, Khan MM, Labeit S, Deschenes MR. Degeneration of neuromuscular junction in age and dystrophy. Front Aging Neurosci. 2014;6.
35. Ahn B, Ranjit R, Premkumar P, Pharaoh G, Piekarz KM, Matsuzaki S, et al. Mitochondrial oxidative stress impairs contractile function but paradoxically increases muscle mass via fibre branching. J Cachexia Sarcopenia Muscle. 2019;10:411–28.
36. Rodríguez Cruz PM, Cossins J, Beeson D, Vincent A. The neuromuscular junction in health and disease: molecular mechanisms governing synaptic formation and homeostasis. Front Mol Neurosci. 2020;13:610964.
37. Huertas AM, Morton AB, Hinkey JM, Ichinoseki-Sekine N, Smuder AJ. Modification of neuromuscular junction protein expression by exercise and doxorubicin. Med Sci Sports Exerc. 2020;52:1477–84.
38. D’Lugos AC, Fry CS, Ormsby JC, Sweeney KR, Brightwell CR, Hale TM, et al. Chronic doxorubicin administration impacts satellite cell and capillary abundance in a muscle-specific manner. Physiol Rep. 2019;7:e14052.
39. de Lima EA, de Sousa LGO, de S. Teixeira AA, Marshall AG, Zanchi NE, Neto JCR. Aerobic exercise, but not metformin, prevents reduction of muscular performance by AMPk activation in mice on doxorubicin chemotherapy. J Cell Physiol. 2018;233: 9652–62.
40. Gilliam LAA, Moylan JS, Ferreira LF, Reid MB. TNF/TNFR1 signaling mediates doxorubicin-induced diaphragm weakness. Am J Physiol – Lung Cell Mol Physiol. 2011;300:L225–31.
41. Sin TK, Tam BT, Yu AP, Yip SP, Yung BY, Chan LW, et al. Acute treatment of resveratrol alleviates doxorubicin-induced myotoxicity in aged skeletal muscle through SIRT1-dependent mechanisms. Journals Gerontol – Ser A Biol Sci Med Sci. 2016;71: 730–9.
42. Hulmi JJ, Nissinen TA, Räsänen M, Degerman J, Lautaoja JH, Hemanthakumar KA, et al. Prevention of chemotherapy-induced cachexia by ACVR2B ligand blocking has different effects on heart and skeletal muscle. J Cachexia Sarcopenia Muscle. 2018;9: 417–32.
43. Gilliam LAA, Moylan JS, Patterson EW, Smith JD, Wilson AS, Rabbani Z, et al. Doxorubicin acts via mitochondrial ROS to stimulate catabolism in C2C12 myotubes. Am J Physiol – Cell Physiol. 2012;302:C195–202.
44. Carnac G, Vernus B, Bonnieu A. Myostatin in the pathophysiology of skeletal muscle. Curr Genomics. 2007;8:415–22.
45. Moreira-Pais A, Ferreira R, Gil da Costa R. Platinum-induced muscle wasting in cancer chemotherapy: mechanisms and potential targets for therapeutic intervention. Life Sci. 2018;208:1–9.
46. Wang L, Chen Q, Qi H, Wang C, Wang C, Zhang J, et al. Doxorubicin-induced systemic inflammation is driven by upregulation of toll-like receptor TLR4 and endotoxin leakage. Cancer Res. 2016;76:6631–42.
47. Karin M, Ben-Neriah Y. Phosphorylation meets ubiquitination: the control of NF-κB activity. Annu Rev Immunol. 2000;18: 621–63.
48. Hardin BJ, Campbell KS, Smith JD, Arbogast S, Smith J, Moylan JS, et al. TNF-α acts via TNFR1 and muscle-derived oxidants to depress myofibrillar force in murine skeletal muscle. J Appl Physiol. 2008;104:694–9.
49. Wang X, Hu Z, Hu J, Du J, Mitch WE. Insulin resistance accelerates muscle protein degradation: activation of the ubiquitin-proteasome pathway by defects in muscle cell signaling. Endocrinology. 2006;147:4160–8.
50. Smuder AJ, Kavazis AN, Min K, Powers SK. Exercise protects against doxorubicin-induced oxidative stress and proteolysis in skeletal muscle. J Appl Physiol. 2011;110:935–42.
51. Harr MW, Distelhorst CW. Apoptosis and autophagy: decoding calcium signals that mediate life or death. Cold Spring Harb Perspect Biol. 2010;2:a005579.
52. Bloemberg D, Quadrilatero J. Autophagy, apoptosis, and mitochondria: molecular integration and physiological relevance in skeletal muscle. Am J Physiol – Cell Physiol. 2019;317:C111–30.
53. U.S. Department of Health and Human Services. Guidance for industry: estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers. Food and Drug Administration, Center for Drug Evaluation and Research. Rockville, MD; 2005.
54. Aluise CD, Miriyala S, Noel T, Sultana R, Jungsuwadee P, Taylor TJ, et al. 2-mercaptoethane sulfonate prevents doxorubicin-induced plasma protein oxidation and TNF-α release: implications for the reactive oxygen species-mediated mechanisms of chemobrain. Free Radic Biol Med. 2011;50:1630–8.
2. Geneva: World Health Organization. Decade of healthy ageing: baseline report. 2020.
3. van der Zanden SY, Qiao X, Neefjes J. New insights into the activities and toxicities of the old anticancer drug doxorubicin. FEBS J. 2020;
4. Thorn CF, Oshiro C, Marsh S, Hernandez-Boussard T, McLeod H, Klein TE, et al. Doxorubicin pathways: pharmacodynamics and adverse effects. Pharmacogenet Genomics. 2011;21:440–6.
5. Gorini S, De Angelis A, Berrino L, Malara N, Rosano G, Ferraro E. Chemotherapeutic drugs and mitochondrial dysfunction: focus on doxorubicin, trastuzumab, and sunitinib. Oxid Med Cell Longev. 2018;2018:7582730.
6. Prasanna PL, Renu K, Gopalakrishnan AV. New molecular and biochemical insights of doxorubicin-induced hepatotoxicity. Life Sci. 2020;250:117599.
7. Kalyanaraman B. Teaching the basics of the mechanism of doxorubicin-induced cardiotoxicity: have we been barking up the wrong tree? Redox Biol. 2020;29:101394.
8. Ongnok B, Chattipakorn N, Chattipakorn SC. Doxorubicin and cisplatin induced cognitive impairment: the possible mechanisms and interventions. Exp Neurol. 2020;324:113118.
9. Afsar T, Razak S, Almajwal A, Al-Disi D. Doxorubicin-induced alterations in kidney functioning, oxidative stress, DNA damage, and renal tissue morphology; Improvement by Acacia hydaspica tannin-rich ethyl acetate fraction. Saudi J Biol Sci. 2020;27: 2251–60.
10. Hiensch AE, Bolam KA, Mijwel S, Jeneson JAL, Huitema ADR, Kranenburg O, et al. Doxorubicin-induced skeletal muscle atrophy: elucidating the underlying molecular pathways. Acta Physiol. 2020;229:e13400.
11. Neidhart JA, Gochnour D, Roach R, Hoth D, Young D. A comparison of mitoxantrone and doxorubicin in breast cancer. J Clin Oncol. 1986;4:672–7.
12. Gilliam LAA, St. Clair DK. Chemotherapy-induced weakness and fatigue in skeletal muscle: the role of oxidative stress. Antioxidants Redox Signal. 2011;15:2543–63.
13. Aoyagi T, Terracina KP, Raza A, Matsubara H, Takabe K. Cancer cachexia, mechanism and treatment. World J Gastrointest Oncol. 2015;7:17–29.
14. Peterson SJ, Mozer M. Differentiating sarcopenia and cachexia among patients with cancer. Nutr Clin Pract. 2017;32:30–9.
15. Porporato PE. Understanding cachexia as a cancer metabolism syndrome. Oncogenesis. 2016;5:e200.
16. Yazar T, Olgun Yazar H. Prevalance of sarcopenia according to decade. Clin Nutr ESPEN. 2019;29:137–41.
17. Rao A, Cohen HJ. Symptom management in the elderly cancer patient: fatigue, pain, and depression. J Natl Cancer Inst Monogr. 2004;27710:150–7.
18. Pilleron S, Sarfati D, Janssen-Heijnen M, Vignat J, Ferlay J, Bray F, et al. Global cancer incidence in older adults, 2012 and 2035: a population-based study. Int J Cancer. 2019;144:49–58.
19. Freireich EJ, Gehan EA, Rall DP, Schmidt LH, Skipper HE. Quantitative comparison of toxicity of anticancer agents in mouse, rat, hamster, dog, monkey, and man. Cancer Chemother Reports. 1966;50:219–44.
20. Fabris S, MacLean DA. Skeletal muscle an active compartment in the sequestering and metabolism of doxorubicin chemotherapy. PLoS One. 2015;10:e0139070.
21. Doroshow JH, Tallent C, Schechter JE. Ultrastructural features of adriamycin-induced skeletal and cardiac muscle toxicity. Am J Pathol. 1985;118:288–97.
22. Hayward R, Hydock D, Gibson N, Greufe S, Bredahl E, Parry T. Tissue retention of doxorubicin and its effects on cardiac, smooth, and skeletal muscle function. J Physiol Biochem. 2013;69:177–87.
23. Gibson NM, Quinn CJ, Pfannenstiel KB, Hydock DS, Hayward R. Effects of age on multidrug resistance protein expression and doxorubicin accumulation in cardiac and skeletal muscle. Xenobiotica. 2014;44:472–9.
24. Sodani K, Patel A, Kathawala RJ, Chen Z-S. Multidrug resistance associated proteins in multidrug resistance. Chin J Cancer. 2012;31:58–72.
25. de Lima Junior EA, Yamashita AS, Pimentel GD, De Sousa LGO, Santos RVT, Gonçalves CL, et al. Doxorubicin caused severe hyperglycaemia and insulin resistance, mediated by inhibition in AMPk signalling in skeletal muscle. J Cachexia Sarcopenia Muscle. 2016;7:615–25.
26. Gilliam LAA, Ferreira LF, Bruton JD, Moylan JS, Westerblad H, St. Clair DK, et al. Doxorubicin acts through tumor necrosis factor receptor subtype 1 to cause dysfunction of murine skeletal muscle. J Appl Physiol. 2009;107:1935–42.
27. Gilliam LAA, Moylan JS, Callahan LA, Sumandea MP, Reid MB. Doxorubicin causes diaphragm weakness in murine models of cancer chemotherapy. Muscle and Nerve. 2011;43:94–102.
28. Gilliam LAA, Fisher-Wellman KH, Lin C-T, Maples JM, Cathey BL, Neufer PD. The anticancer agent doxorubicin disrupts mitochondrial energy metabolism and redox balance in skeletal muscle. Free Radic Biol Med. 2013;65:988–96.
29. Bredahl EC, Pfannenstiel KB, Quinn CJ, Hayward R, Hydock DS. Effects of exercise on doxorubicin-induced skeletal muscle dysfunction. Med Sci Sports Exerc. 2016;48:1468–73.
30. Nissinen TA, Degerman J, Räsänen M, Poikonen AR, Koskinen S, Mervaala E, et al. Systemic blockade of ACVR2B ligands prevents chemotherapy-induced muscle wasting by restoring muscle protein synthesis without affecting oxidative capacity or atrogenes. Sci Rep. 2016;6:32695.
31. Huang SC, Wu JF, Saovieng S, Chien WH, Hsu MF, Li XF, et al. Doxorubicin inhibits muscle inflammation after eccentric exercise. J Cachexia Sarcopenia Muscle. 2017;8:277–84.
32. Min K, Kwon O-S, Smuder AJ, Wiggs MP, Sollanek KJ, Christou DD, et al. Increased mitochondrial emission of reactive oxygen species and calpain activation are required for doxorubicin-induced cardiac and skeletal muscle myopathy. J Physiol. 2015;593: 2017–36.
33. Doerr V, Montalvo RN, Kwon OS, Talbert EE, Hain BA, Houston FE, et al. Prevention of doxorubicin-induced autophagy attenuates oxidative stress and skeletal muscle dysfunction. Antioxidants. 2020;9:263.
34. Rudolf R, Khan MM, Labeit S, Deschenes MR. Degeneration of neuromuscular junction in age and dystrophy. Front Aging Neurosci. 2014;6.
35. Ahn B, Ranjit R, Premkumar P, Pharaoh G, Piekarz KM, Matsuzaki S, et al. Mitochondrial oxidative stress impairs contractile function but paradoxically increases muscle mass via fibre branching. J Cachexia Sarcopenia Muscle. 2019;10:411–28.
36. Rodríguez Cruz PM, Cossins J, Beeson D, Vincent A. The neuromuscular junction in health and disease: molecular mechanisms governing synaptic formation and homeostasis. Front Mol Neurosci. 2020;13:610964.
37. Huertas AM, Morton AB, Hinkey JM, Ichinoseki-Sekine N, Smuder AJ. Modification of neuromuscular junction protein expression by exercise and doxorubicin. Med Sci Sports Exerc. 2020;52:1477–84.
38. D’Lugos AC, Fry CS, Ormsby JC, Sweeney KR, Brightwell CR, Hale TM, et al. Chronic doxorubicin administration impacts satellite cell and capillary abundance in a muscle-specific manner. Physiol Rep. 2019;7:e14052.
39. de Lima EA, de Sousa LGO, de S. Teixeira AA, Marshall AG, Zanchi NE, Neto JCR. Aerobic exercise, but not metformin, prevents reduction of muscular performance by AMPk activation in mice on doxorubicin chemotherapy. J Cell Physiol. 2018;233: 9652–62.
40. Gilliam LAA, Moylan JS, Ferreira LF, Reid MB. TNF/TNFR1 signaling mediates doxorubicin-induced diaphragm weakness. Am J Physiol – Lung Cell Mol Physiol. 2011;300:L225–31.
41. Sin TK, Tam BT, Yu AP, Yip SP, Yung BY, Chan LW, et al. Acute treatment of resveratrol alleviates doxorubicin-induced myotoxicity in aged skeletal muscle through SIRT1-dependent mechanisms. Journals Gerontol – Ser A Biol Sci Med Sci. 2016;71: 730–9.
42. Hulmi JJ, Nissinen TA, Räsänen M, Degerman J, Lautaoja JH, Hemanthakumar KA, et al. Prevention of chemotherapy-induced cachexia by ACVR2B ligand blocking has different effects on heart and skeletal muscle. J Cachexia Sarcopenia Muscle. 2018;9: 417–32.
43. Gilliam LAA, Moylan JS, Patterson EW, Smith JD, Wilson AS, Rabbani Z, et al. Doxorubicin acts via mitochondrial ROS to stimulate catabolism in C2C12 myotubes. Am J Physiol – Cell Physiol. 2012;302:C195–202.
44. Carnac G, Vernus B, Bonnieu A. Myostatin in the pathophysiology of skeletal muscle. Curr Genomics. 2007;8:415–22.
45. Moreira-Pais A, Ferreira R, Gil da Costa R. Platinum-induced muscle wasting in cancer chemotherapy: mechanisms and potential targets for therapeutic intervention. Life Sci. 2018;208:1–9.
46. Wang L, Chen Q, Qi H, Wang C, Wang C, Zhang J, et al. Doxorubicin-induced systemic inflammation is driven by upregulation of toll-like receptor TLR4 and endotoxin leakage. Cancer Res. 2016;76:6631–42.
47. Karin M, Ben-Neriah Y. Phosphorylation meets ubiquitination: the control of NF-κB activity. Annu Rev Immunol. 2000;18: 621–63.
48. Hardin BJ, Campbell KS, Smith JD, Arbogast S, Smith J, Moylan JS, et al. TNF-α acts via TNFR1 and muscle-derived oxidants to depress myofibrillar force in murine skeletal muscle. J Appl Physiol. 2008;104:694–9.
49. Wang X, Hu Z, Hu J, Du J, Mitch WE. Insulin resistance accelerates muscle protein degradation: activation of the ubiquitin-proteasome pathway by defects in muscle cell signaling. Endocrinology. 2006;147:4160–8.
50. Smuder AJ, Kavazis AN, Min K, Powers SK. Exercise protects against doxorubicin-induced oxidative stress and proteolysis in skeletal muscle. J Appl Physiol. 2011;110:935–42.
51. Harr MW, Distelhorst CW. Apoptosis and autophagy: decoding calcium signals that mediate life or death. Cold Spring Harb Perspect Biol. 2010;2:a005579.
52. Bloemberg D, Quadrilatero J. Autophagy, apoptosis, and mitochondria: molecular integration and physiological relevance in skeletal muscle. Am J Physiol – Cell Physiol. 2019;317:C111–30.
53. U.S. Department of Health and Human Services. Guidance for industry: estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers. Food and Drug Administration, Center for Drug Evaluation and Research. Rockville, MD; 2005.
54. Aluise CD, Miriyala S, Noel T, Sultana R, Jungsuwadee P, Taylor TJ, et al. 2-mercaptoethane sulfonate prevents doxorubicin-induced plasma protein oxidation and TNF-α release: implications for the reactive oxygen species-mediated mechanisms of chemobrain. Free Radic Biol Med. 2011;50:1630–8.
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2022-02-02
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