Protection Against Late-Onset Doxorubicin Myotoxicity Using Creatine and Resistance Exercise
Main Article Content
Abstract
This study examined the effects of creatine supplementation (Cr) and resistance training (RT) on the myotoxicity that accompanies treatment with the chemotherapy drug doxorubicin (DOX). Male rats were randomly assigned to control (CON), DOX, RT+DOX, Cr+DOX, and Cr+RT+DOX groups. DOX groups received 1 mg/kg daily DOX injections for 12 days, Cr groups were fed a diet supplemented with 3% Cr, and RT groups were housed in resistance training model cages. Forelimb grip strength was assessed at baseline and at day 40 at which time the soleus and extensor digitorum longus were excised and analyzed for positive and negative myogenic regulator factor expression. Grip strength increased from baseline to day 40 only in CON and Cr+RT+DOX groups but not in DOX, Cr+DOX or RT+DOX suggesting that combined Cr and RT helps maintain grip strength with DOX treatment. Myostatin expression was lower in solei from RT+DOX, Cr+DOX, and Cr+RT+DOX when compared to CON but not in DOX, and a trend toward higher muscle ring finger (MuRF) expression in the DOX only group was observed. These data suggest that Cr supplementation with RT may be an effective non-pharmacological therapeutic strategy to battle DOX myotoxicity through modulation of negative myogenic regulatory factors.
Keywords:
Anthracycline, Grip Strength, Glycolytic Muscle, Myogenic Regulatory Factors, Oxidative Muscle
Article Details
How to Cite
KUGLER, Benjamin A; CAPPS, Michael J; HYDOCK, David Scott.
Protection Against Late-Onset Doxorubicin Myotoxicity Using Creatine and Resistance Exercise.
Medical Research Archives, [S.l.], v. 10, n. 6, july 2022.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/2852>. Date accessed: 23 apr. 2024.
doi: https://doi.org/10.18103/mra.v10i6.2852.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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44. van Norren K, van Helvoort A, Argiles JM, et al. Direct effects of doxorubicin on skeletal muscle contribute to fatigue. Br J Cancer. 2009;100(2):311-314.
45. Smuder AJ, Kavazis AN, Min K, Powers SK. Exercise protects against doxorubicin-induced markers of autophagy signaling in skeletal muscle. J Appl Physiol (1985). 2011;111(4):1190-1198.
46. 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. 2012.
47. Kurabayashi M, Jeyaseelan R, Kedes L. Antineoplastic agent doxorubicin inhibits myogenic differentiation of C2 myoblasts. J Biol Chem. 1993;268(8):5524-5529.
48. Quinn CJ, Hydock DS. Effects of endurance exercise and doxorubicin on skeletal muscle myogenic regulatory factor expression. Muscles Ligaments Tendons J. 2017;7(3):418-425.
49. Hydock DS, Lien CY, Jensen BT, Schneider CM, Hayward R. Exercise Preconditioning Provides Long-Term Protection Against Early Chronic Doxorubicin Cardiotoxicity. Integr Cancer Ther.
50. Hydock DS, Lien CY, Schneider CM, Hayward R. Exercise preconditioning protects against doxorubicin-induced cardiac dysfunction. Med Sci Sports Exerc. 2008;40(5):808-817.
51. Wonders KY, Hydock DS, Schneider CM, Hayward R. Acute exercise protects against doxorubicin cardiotoxicity. Integr Cancer Ther. 2008;7(3):147-154.
52. Chicco AJ, Hydock DS, Schneider CM, Hayward R. Low-intensity exercise training during doxorubicin treatment protects against cardiotoxicity. J Appl Physiol (1985). 2006;100(2):519-527.
53. Hydock DS, Wonders KY, Schneider CM, Hayward R. Voluntary wheel running in rats receiving doxorubicin: effects on running activity and cardiac myosin heavy chain. Anticancer Res. 2009;29(11):4401-4407.
54. Pfannenstiel K, Hayward R. Effects of Resistance Exercise Training on Doxorubicin-Induced Cardiotoxicity. J Cardiovasc Pharmacol. 2018;71(6):332-339.
55. Smuder AJ, Kavazis AN, Min K, Powers SK. Exercise protects against doxorubicin-induced oxidative stress and proteolysis in skeletal muscle. J Appl Physiol (1985). 2011;110(4):935-942.
56. Hochberg L, Busekrus R, Hydock D. The effects of wheel running on skeletal muscle function during and following doxorubicin treatment. Rehabilitation Oncology. 2019;37(3):8.
57. Bredahl EC, Pfannenstiel KB, Quinn CJ, Hayward R, Hydock DS. Effects of Exercise on Doxorubicin-Induced Skeletal Muscle Dysfunction. Med Sci Sports Exerc. 2016.
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2. Takemura G, Fujiwara H. Doxorubicin-induced cardiomyopathy from the cardiotoxic mechanisms to management. Prog Cardiovasc Dis. 2007;49(5):330-352.
3. Chatterjee K, Zhang J, Honbo N, Karliner JS. Doxorubicin cardiomyopathy. Cardiology. 2010;115(2):155-162.
4. Jacobsen PB, Hann DM, Azzarello LM, Horton J, Balducci L, Lyman GH. Fatigue in women receiving adjuvant chemotherapy for breast cancer: characteristics, course, and correlates. J Pain Symptom Manage. 1999;18(4):233-242.
5. Ertunc M, Sara Y, Korkusuz P, Onur R. Differential contractile impairment of fast- and slow-twitch skeletal muscles in a rat model of doxorubicin-induced congestive heart failure. Pharmacology. 2009;84(4):240-248.
6. Gilliam LA, St Clair DK. Chemotherapy-induced weakness and fatigue in skeletal muscle: the role of oxidative stress. Antioxid Redox Signal. 2011;15(9):2543-2563.
7. Min K, Kwon OS, Smuder AJ, 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(8):2017-2036.
8. Montazeri A. Quality of life data as prognostic indicators of survival in cancer patients: an overview of the literature from 1982 to 2008. Health Qual Life Outcomes. 2009;7:102.
9. Richard C, Ghibu S, Delemasure-Chalumeau S, et al. Oxidative stress and myocardial gene alterations associated with Doxorubicin-induced cardiotoxicity in rats persist for 2 months after treatment cessation. J Pharmacol Exp Ther. 2011;339(3):807-814.
10. Velez JM, Miriyala S, Nithipongvanitch R, et al. p53 Regulates oxidative stress-mediated retrograde signaling: a novel mechanism for chemotherapy-induced cardiac injury. PLoS One. 2011;6(3):e18005.
11. Sayed-Ahmed MM, Al-Shabanah OA, Hafez MM, Aleisa AM, Al-Rejaie SS. Inhibition of gene expression of heart fatty acid binding protein and organic cation/carnitine transporter in doxorubicin cardiomyopathic rat model. Eur J Pharmacol. 2010;640(1-3):143-149.
12. Sestili P, Martinelli C, Bravi G, et al. Creatine supplementation affords cytoprotection in oxidatively injured cultured mammalian cells via direct antioxidant activity. Free Radic Biol Med. 2006;40(5):837-849.
13. Gotshalk LA, Kraemer WJ, Mendonca MA, et al. Creatine supplementation improves muscular performance in older women. Eur J Appl Physiol. 2008;102(2):223-231.
14. Moura IM, Santos FF, Moura JA, Curi R, Fernandes LC. Creatine supplementation induces alteration in cross-sectional area in skeletal muscle fibers of wistar rats under swimming training. Journal of sports science & medicine. 2002;1(3):87-95.
15. Gualano B, Artioli GG, Poortmans JR, Lancha Junior AH. Exploring the therapeutic role of creatine supplementation. Amino Acids. 2010;38(1):31-44.
16. Bredahl EC, Hydock DS. Creatine Supplementation and Doxorubicin-Induced Skeletal Muscle Dysfunction: An Ex Vivo Investigation. Nutr Cancer. 2017:1-9.
17. Schneider CM, Hsieh CC, Sprod LK, Carter SD, Hayward R. Cancer treatment-induced alterations in muscular fitness and quality of life: the role of exercise training. Ann Oncol. 2007;18(12):1957-1962.
18. Cakir-Atabek H, Demir S, PinarbaŞili RD, Gündüz N. Effects of different resistance training intensity on indices of oxidative stress. J Strength Cond Res. 2010;24(9):2491-2497.
19. Mascher H, Tannerstedt J, Brink-Elfegoun T, Ekblom B, Gustafsson T, Blomstrand E. Repeated resistance exercise training induces different changes in mRNA expression of MAFbx and MuRF-1 in human skeletal muscle. Am J Physiol Endocrinol Metab. 2008;294(1):E43-51.
20. Stefani GP, Nunes RB, Dornelles AZ, et al. Effects of creatine supplementation associated with resistance training on oxidative stress in different tissues of rats. J Int Soc Sports Nutr. 2014;11(1):11.
21. Langley B, Thomas M, Bishop A, Sharma M, Gilmour S, Kambadur R. Myostatin inhibits myoblast differentiation by down-regulating MyoD expression. J Biol Chem. 2002;277(51):49831-49840.
22. Kurabayashi M, Jeyaseelan R, Kedes L. Doxorubicin represses the function of the myogenic helix-loop-helix transcription factor MyoD. Involvement of Id gene induction. J Biol Chem. 1994;269(8):6031-6039.
23. Puri PL, Bhakta K, Wood LD, Costanzo A, Zhu J, Wang JY. A myogenic differentiation checkpoint activated by genotoxic stress. Nat Genet. 2002;32(4):585-593.
24. Trendelenburg AU, Meyer A, Rohner D, Boyle J, Hatakeyama S, Glass DJ. Myostatin reduces Akt/TORC1/p70S6K signaling, inhibiting myoblast differentiation and myotube size. Am J Physiol Cell Physiol. 2009;296(6):C1258-1270.
25. Yamamoto Y, Hoshino Y, Ito T, et al. Atrogin-1 ubiquitin ligase is upregulated by doxorubicin via p38-MAP kinase in cardiac myocytes. Cardiovasc Res. 2008;79(1):89-96.
26. Saremi A, Gharakhanloo R, Sharghi S, Gharaati MR, Larijani B, Omidfar K. Effects of oral creatine and resistance training on serum myostatin and GASP-1. Mol Cell Endocrinol. 2010;317(1-2):25-30.
27. Willoughby DS, Rosene JM. Effects of oral creatine and resistance training on myogenic regulatory factor expression. Med Sci Sports Exerc. 2003;35(6):923-929.
28. Yao W, Jee WS, Chen J, et al. Making rats rise to erect bipedal stance for feeding partially prevented orchidectomy-induced bone loss and added bone to intact rats. J Bone Miner Res. 2000;15(6):1158-1168.
29. Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976;72:248-254.
30. Miller KD, Siegel RL, Lin CC, et al. Cancer treatment and survivorship statistics, 2016. CA Cancer J Clin. 2016;66(4):271-289.
31. Hydock DS, Lien CY, Jensen BT, Schneider CM, Hayward R. Characterization of the effect of in vivo doxorubicin treatment on skeletal muscle function in the rat. Anticancer Res. 2011;31(6):2023-2028.
32. Hydock D, Omar A, Bredahl E, Quinn C. In vivo Skeletal Muscle Function and Doxorubicin Treatment in the Rat. The FASEB Journal. 2015;29(1_supplement):1055.1021.
33. Bonifati DM, Ori C, Rossi CR, Caira S, Fanin M, Angelini C. Neuromuscular damage after hyperthermic isolated limb perfusion in patients with melanoma or sarcoma treated with chemotherapeutic agents. Cancer Chemother Pharmacol. 2000;46(6):517-522.
34. Hayward R, Hydock DS. Doxorubicin cardiotoxicity in the rat: an in vivo characterization. J Am Assoc Lab Anim Sci. 2007;46(4):20-32.
35. Lipshultz SE, Lipsitz SR, Sallan SE, et al. Chronic progressive cardiac dysfunction years after doxorubicin therapy for childhood acute lymphoblastic leukemia. J Clin Oncol. 2005;23(12):2629-2636.
36. Belham M, Kruger A, Mepham S, Faganello G, Pritchard C. Monitoring left ventricular function in adults receiving anthracycline-containing chemotherapy. Eur J Heart Fail. 2007;9(4):409-414.
37. Celik T, Iyisoy A, Celik M, Yuksel UC, Isik E. Muscle wastage in heart failure: orphan of the heart failure. Int J Cardiol. 2009;135(2):233-236.
38. van Hees HW, van der Heijden HF, Ottenheijm CA, et al. Diaphragm single-fiber weakness and loss of myosin in congestive heart failure rats. Am J Physiol Heart Circ Physiol. 2007;293(1):H819-828.
39. Harrington D, Anker SD, Chua TP, et al. Skeletal muscle function and its relation to exercise tolerance in chronic heart failure. J Am Coll Cardiol. 1997;30(7):1758-1764.
40. De Beer EL, Finkle H, Voest EE, Van Heijst BG, Schiereck P. Doxorubicin interacts directly with skinned single skeletal muscle fibres. Eur J Pharmacol. 1992;214(1):97-100.
41. Gilliam LA, Moylan JS, Patterson EW, et al. Doxorubicin acts via mitochondrial ROS to stimulate catabolism in C2C12 myotubes. Am J Physiol Cell Physiol. 2012;302(1):C195-202.
42. Bredahl EC, Busekrus RB, Hydock DS. The combined effect of creatine and resistance training on doxorubicin-induced muscle dysfunction. Nutr Cancer. 2020;72(6):939-947.
43. Gouspillou G, Scheede-Bergdahl C, Spendiff S, et al. Anthracycline-containing chemotherapy causes long-term impairment of mitochondrial respiration and increased reactive oxygen species release in skeletal muscle. Sci Rep. 2015;5:8717.
44. van Norren K, van Helvoort A, Argiles JM, et al. Direct effects of doxorubicin on skeletal muscle contribute to fatigue. Br J Cancer. 2009;100(2):311-314.
45. Smuder AJ, Kavazis AN, Min K, Powers SK. Exercise protects against doxorubicin-induced markers of autophagy signaling in skeletal muscle. J Appl Physiol (1985). 2011;111(4):1190-1198.
46. 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. 2012.
47. Kurabayashi M, Jeyaseelan R, Kedes L. Antineoplastic agent doxorubicin inhibits myogenic differentiation of C2 myoblasts. J Biol Chem. 1993;268(8):5524-5529.
48. Quinn CJ, Hydock DS. Effects of endurance exercise and doxorubicin on skeletal muscle myogenic regulatory factor expression. Muscles Ligaments Tendons J. 2017;7(3):418-425.
49. Hydock DS, Lien CY, Jensen BT, Schneider CM, Hayward R. Exercise Preconditioning Provides Long-Term Protection Against Early Chronic Doxorubicin Cardiotoxicity. Integr Cancer Ther.
50. Hydock DS, Lien CY, Schneider CM, Hayward R. Exercise preconditioning protects against doxorubicin-induced cardiac dysfunction. Med Sci Sports Exerc. 2008;40(5):808-817.
51. Wonders KY, Hydock DS, Schneider CM, Hayward R. Acute exercise protects against doxorubicin cardiotoxicity. Integr Cancer Ther. 2008;7(3):147-154.
52. Chicco AJ, Hydock DS, Schneider CM, Hayward R. Low-intensity exercise training during doxorubicin treatment protects against cardiotoxicity. J Appl Physiol (1985). 2006;100(2):519-527.
53. Hydock DS, Wonders KY, Schneider CM, Hayward R. Voluntary wheel running in rats receiving doxorubicin: effects on running activity and cardiac myosin heavy chain. Anticancer Res. 2009;29(11):4401-4407.
54. Pfannenstiel K, Hayward R. Effects of Resistance Exercise Training on Doxorubicin-Induced Cardiotoxicity. J Cardiovasc Pharmacol. 2018;71(6):332-339.
55. Smuder AJ, Kavazis AN, Min K, Powers SK. Exercise protects against doxorubicin-induced oxidative stress and proteolysis in skeletal muscle. J Appl Physiol (1985). 2011;110(4):935-942.
56. Hochberg L, Busekrus R, Hydock D. The effects of wheel running on skeletal muscle function during and following doxorubicin treatment. Rehabilitation Oncology. 2019;37(3):8.
57. Bredahl EC, Pfannenstiel KB, Quinn CJ, Hayward R, Hydock DS. Effects of Exercise on Doxorubicin-Induced Skeletal Muscle Dysfunction. Med Sci Sports Exerc. 2016.
58. Ingwall JS, Weiner CD, Morales MF, Davis E, Stockdale FE. Specificity of creatine in the control of muscle protein synthesis. J Cell Biol. 1974;62(1):145-151.
59. Parise G, Mihic S, MacLennan D, Yarasheski KE, Tarnopolsky MA. Effects of acute creatine monohydrate supplementation on leucine kinetics and mixed-muscle protein synthesis. J Appl Physiol (1985). 2001;91(3):1041-1047.
60. Volek JS, Duncan ND, Mazzetti SA, et al. Performance and muscle fiber adaptations to creatine supplementation and heavy resistance training. Medicine and science in sports and exercise. 1999;31(8):1147-1156.
61. Felber S, Skladal D, Wyss M, Kremser C, Koller A, Sperl W. Oral creatine supplementation in Duchenne muscular dystrophy: a clinical and 31P magnetic resonance spectroscopy study. Neurological research. 2000;22(2):145-150.
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