Advertisement

Creatine supplementation in Walker-256 tumor-bearing rats prevents skeletal muscle atrophy by attenuating systemic inflammation and protein degradation signaling

  • Paola S. Cella
  • Poliana C. Marinello
  • Fernando H. Borges
  • Diogo F. Ribeiro
  • Patrícia Chimin
  • Mayra T. J. Testa
  • Philippe B. Guirro
  • José A. Duarte
  • Rubens Cecchini
  • Flávia A. Guarnier
  • Rafael DeminiceEmail author
Original Contribution

Abstract

Purpose

The aim of this study was to investigate the effects of creatine supplementation on muscle wasting in Walker-256 tumor-bearing rats.

Methods

Wistar rats were randomly assigned into three groups (n = 10/group): control (C), tumor bearing (T), and tumor bearing supplemented with creatine (TCr). Creatine was provided in drinking water for a total of 21 days. After 11 days of supplementation, tumor cells were implanted subcutaneously into T and TCr groups. The animals’ weight, food and water intake were evaluated along the experimental protocol. After 10 days of tumor implantation (21 total), animals were euthanized for inflammatory state and skeletal muscle cross-sectional area measurements. Skeletal muscle components of ubiquitin–proteasome pathways were also evaluated using real-time PCR and immunoblotting.

Results

The results showed that creatine supplementation protected tumor-bearing rats against body weight loss and skeletal muscle atrophy. Creatine intake promoted lower levels of plasma TNF-α and IL-6 and smaller spleen morphology changes such as reduced size of white pulp and lymphoid follicle compared to tumor-bearing rats. In addition, creatine prevented increased levels of skeletal muscle Atrogin-1 and MuRF-1, key regulators of muscle atrophy.

Conclusion

Creatine supplementation prevents skeletal muscle atrophy by attenuating tumor-induced pro-inflammatory environment, a condition that minimizes Atrogin-1 and MuRF-1-dependent proteolysis.

Keywords

Muscle loss Proteolysis Oxidative stress Cachexia Cancer 

Notes

Acknowledgements

Supported by CAPES-Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Brazil #88881.068035/2014-01.

Compliance with ethical standards

Conflict of interest

All authors declared that there is no potential conflict of interests regarding this article.

References

  1. 1.
    Tan BHL, Fearon KCH (2008) Cachexia: prevalence and impact in medicine. Curr Opin Clin Nutr Metab Care 11:400–407CrossRefGoogle Scholar
  2. 2.
    Galvão DA, Spry NA, Taaffe DR et al (2008) Changes in muscle, fat and bone mass after 36 weeks of maximal androgen blockade for prostate cancer. BJU Int 102:44–47.  https://doi.org/10.1111/j.1464-410X.2008.07539.x CrossRefGoogle Scholar
  3. 3.
    Argilés JM, Busquets S, Stemmler B, López-Soriano FJ (2014) Cancer cachexia: understanding the molecular basis. Nat Rev Cancer 14:754–762CrossRefGoogle Scholar
  4. 4.
    Lenk K, Schuler G, Adams V (2010) Skeletal muscle wasting in cachexia and sarcopenia: molecular pathophysiology and impact of exercise training. J Cachexia Sarcopenia Muscle 1:9–21CrossRefGoogle Scholar
  5. 5.
    Penna F, Bonetto A, Muscaritoli M et al (2010) Muscle atrophy in experimental cancer cachexia: is the IGF-1 signaling pathway involved? Int J Cancer 127:1706–1717.  https://doi.org/10.1002/ijc.25146 CrossRefGoogle Scholar
  6. 6.
    Balkwill FR, Mantovani A (2012) Cancer-related inflammation: common themes and therapeutic opportunities. Semin Cancer Biol 22:33–40CrossRefGoogle Scholar
  7. 7.
    Powers SK, Morton AB, Ahn B, Smuder AJ (2016) Redox control of skeletal muscle atrophy. Free Radic Biol Med 98:208–217.  https://doi.org/10.1016/j.freeradbiomed.2016.02.021 CrossRefGoogle Scholar
  8. 8.
    Yuan L, Han J, Meng Q et al (2015) Muscle-specific E3 ubiquitin ligases are involved in muscle atrophy of cancer cachexia: an in vitro and in vivo study. Oncol Rep 33:2261–2268.  https://doi.org/10.3892/or.2015.3845 CrossRefGoogle Scholar
  9. 9.
    Gomes-Marcondes MCC, Tisdale MJ (2002) Induction of protein catabolism and the ubiquitin-proteasome pathway by mild oxidative stress. Cancer Lett 180:69–74.  https://doi.org/10.1016/S0304-3835(02)00006-X CrossRefGoogle Scholar
  10. 10.
    Johnston APW, Burke DG, MacNeil LG, Candow DG (2009) Effect of creatine supplementation during cast-induced immobilization on the preservation of muscle mass, strength, and endurance. J Strength Cond Res 23:116–120.  https://doi.org/10.1519/JSC.0b013e31818efbcc CrossRefGoogle Scholar
  11. 11.
    Gualano B, Artioli GG, Poortmans JR, Lancha Junior AH (2010) Exploring the therapeutic role of creatine supplementation. Amino Acids 38:31–44.  https://doi.org/10.1007/s00726-009-0263-6 CrossRefGoogle Scholar
  12. 12.
    Gualano B, Roschel H, Lancha AH et al (2012) In sickness and in health: the widespread application of creatine supplementation. Amino Acids 43:519–529.  https://doi.org/10.1007/s00726-011-1132-7 CrossRefGoogle Scholar
  13. 13.
    Mazzini L, Balzarini C, Colombo R et al (2001) Effects of creatine supplementation on exercise performance and muscular strength in amyotrophic lateral sclerosis: preliminary results. J Neurol Sci 191:139–144.  https://doi.org/10.1016/S0022-510X(01)00611-6 CrossRefGoogle Scholar
  14. 14.
    Menezes LG, Sobreira C, Neder L et al (2007) Creatine supplementation attenuates corticosteroid-induced muscle wasting and impairment of exercise performance in rats. J Appl Physiol 102:698–703.  https://doi.org/10.1152/japplphysiol.01188.2005 CrossRefGoogle Scholar
  15. 15.
    Sakkas GK, Schambelan M, Mulligan K (2009) Can the use of creatine supplementation attenuate muscle loss in cachexia and wasting? Curr Opin Clin Nutr Metab Care 12:623–627CrossRefGoogle Scholar
  16. 16.
    Smith RN, Agharkar AS, Gonzales EB (2014) A review of creatine supplementation in age-related diseases: more than a supplement for athletes. F1000 Res 3:222–233.  https://doi.org/10.12688/f1000research.5218.1 CrossRefGoogle Scholar
  17. 17.
    Tarnopolsky MA, Mahoney DJ, Vajsar J et al (2004) Creatine monohydrate enhances strength and body composition in Duchenne muscular dystrophy. Neurology 62:1771–1777.  https://doi.org/10.1212/01.WNL.0000125178.18862.9D CrossRefGoogle Scholar
  18. 18.
    Wallimann T, Tokarska-Schlattner M, Schlattner U (2011) The creatine kinase system and pleiotropic effects of creatine. Amino Acids 40:1271–1296.  https://doi.org/10.1007/s00726-011-0877-3 CrossRefGoogle Scholar
  19. 19.
    Bassit RA, Curi R, Costa Rosa LFBP (2008) Creatine supplementation reduces plasma levels of pro-inflammatory cytokines and PGE2 after a half-ironman competition. Amino Acids 35:425–431.  https://doi.org/10.1007/s00726-007-0582-4 CrossRefGoogle Scholar
  20. 20.
    Campos-Ferraz PL, Gualano B, das Neves W et al (2016) Exploratory studies of the potential anti-cancer effects of creatine. Amino Acids 48:1993–2001.  https://doi.org/10.1007/s00726-016-2180-9 CrossRefGoogle Scholar
  21. 21.
    Fimognari C, Sestili P, Lenzi M et al (2009) Protective effect of creatine against RNA damage. Mutat Res Fundam Mol Mech Mutagen 670:59–67.  https://doi.org/10.1016/j.mrfmmm.2009.07.005 CrossRefGoogle Scholar
  22. 22.
    Guidi C, Potenza L, Sestili P et al (2008) Differential effect of creatine on oxidatively-injured mitochondrial and nuclear DNA. Biochim Biophys Acta Gen Subj 1780:16–26.  https://doi.org/10.1016/j.bbagen.2007.09.018 CrossRefGoogle Scholar
  23. 23.
    Lawler JM, Barnes WS, Wu G et al (2002) Direct antioxidant properties of creatine. Biochem Biophys Res Commun 290:47–52.  https://doi.org/10.1006/bbrc.2001.6164 CrossRefGoogle Scholar
  24. 24.
    Deminice R, Cella PS, Padilha CS et al (2016) Creatine supplementation prevents hyperhomocysteinemia, oxidative stress and cancer-induced cachexia progression in Walker-256 tumor-bearing rats. Amino Acids 48:2015–2024.  https://doi.org/10.1007/s00726-016-2172-9 CrossRefGoogle Scholar
  25. 25.
    Guarnier FA, Cecchini AL, Suzukawa AA et al (2010) Time course of skeletal muscle loss and oxidative stress in rats with walker 256 solid tumor. Muscle Nerve 42:950–958.  https://doi.org/10.1002/mus.21798 CrossRefGoogle Scholar
  26. 26.
    Padilha CS, Borges FH, Costa Mendes da Silva LE et al (2017) Resistance exercise attenuates skeletal muscle oxidative stress, systemic pro-inflammatory state, and cachexia in Walker-256 tumor-bearing rats. Appl Physiol Nutr Metab 42:916–923.  https://doi.org/10.1139/apnm-2016-0436 CrossRefGoogle Scholar
  27. 27.
    Fonseca H, Powers SK, Gonalves D et al (2012) Physical inactivity is a major contributor to ovariectomy-induced sarcopenia. Int J Sports Med 33:268–278.  https://doi.org/10.1055/s-0031-1297953 CrossRefGoogle Scholar
  28. 28.
    Magdalon J, Chimin P, Belchior T et al (2016) Constitutive adipocyte mTORC1 activation enhances mitochondrial activity and reduces visceral adiposity in mice. Biochim Biophys Acta Mol Cell Biol Lipids 1861:430–438.  https://doi.org/10.1016/j.bbalip.2016.02.023 CrossRefGoogle Scholar
  29. 29.
    Londhe P, Guttridge DC (2015) Inflammation induced loss of skeletal muscle. Bone 80:131–142.  https://doi.org/10.1016/j.bone.2015.03.015 CrossRefGoogle Scholar
  30. 30.
    Carson JA, Baltgalvis KA (2010) Interleukin 6 as a key regulator of muscle mass during cachexia. Exerc Sport Sci Rev 38:168–176.  https://doi.org/10.1097/JES.0b013e3181f44f11 CrossRefGoogle Scholar
  31. 31.
    Narsale AA, Carson JA (2014) Role of interleukin-6 in cachexia: therapeutic implications. Curr Opin Support Palliat Care 8:321–327.  https://doi.org/10.1097/SPC.0000000000000091 CrossRefGoogle Scholar
  32. 32.
    Johns N, Stephens NA, Fearon KCH (2013) Muscle wasting in cancer. Int J Biochem Cell Biol 45:2215–2229.  https://doi.org/10.1016/j.biocel.2013.05.032 CrossRefGoogle Scholar
  33. 33.
    De Larichaudy J, Zufferli A, Serra F et al (2012) TNF- α and tumor-induced skeletal muscle atrophy involves sphingolipid metabolism. Skelet Muscle 2:2–20.  https://doi.org/10.1186/2044-5040-2-2 CrossRefGoogle Scholar
  34. 34.
    Moylan JS, Smith JD, Chambers MA et al (2008) TNF-α induction of atrogin-1/MAFbx mRNA depends on Foxo4 expression but not AKT-Foxo1/3 signaling. AJP Cell Physiol 295:C986–C993.  https://doi.org/10.1152/ajpcell.00041.2008 CrossRefGoogle Scholar
  35. 35.
    Baltgalvis KA, Berger FG, Peña MMO et al (2009) Muscle wasting and interleukin-6-induced atrogin-I expression in the cachectic ApcMin/+mouse. Pflugers Arch Eur J Physiol 457:989–1001.  https://doi.org/10.1007/s00424-008-0574-6 CrossRefGoogle Scholar
  36. 36.
    Glass DJ (2010) Signaling pathways perturbing muscle mass. Curr Opin Clin Nutr Metab Care 13:225–229.  https://doi.org/10.1097/MCO.0b013e32833862df CrossRefGoogle Scholar
  37. 37.
    Wilkinson TJ, Lemmey AB, Jones JG et al (2016) Can creatine supplementation improve body composition and objective physical function in rheumatoid arthritis patients? A Randomized Controlled Trial. Arthritis Care Res (Hoboken) 68:729–737.  https://doi.org/10.1002/acr.22747 CrossRefGoogle Scholar
  38. 38.
    Fuld JP, Kilduff LP, Neder JA et al (2005) Creatine supplementation during pulmonary rehabilitation in chronic obstructive pulmonary disease. Thorax 60:531–537.  https://doi.org/10.1136/thx.2004.030452 CrossRefGoogle Scholar
  39. 39.
    Aoki MS, Lima WP, Miyabara EH et al (2004) Deleteriuos effects of immobilization upon rat skeletal muscle: role of creatine supplementation. Clin Nutr 23:1176–1183.  https://doi.org/10.1016/j.clnu.2004.03.004 CrossRefGoogle Scholar
  40. 40.
    Khanna NK, Madan BR (1978) Studies on the anti-inflammatory activity of creatine. Arch Int Pharmacodyn Thérapie 231:340–350Google Scholar
  41. 41.
    Sestili P, Ambrogini P, Barbieri E et al (2016) New insights into the trophic and cytoprotective effects of creatine in in vitro and in vivo models of cell maturation. Amino Acids 48:1897–1911.  https://doi.org/10.1007/s00726-015-2161-4 CrossRefGoogle Scholar
  42. 42.
    Barbieri E, Guescini M, Calcabrini C et al (2016) Creatine prevents the structural and functional damage to mitochondria in myogenic, oxidatively stressed C2C12 cells and restores their differentiation capacity. Oxid Med Cell Longev 5152029:1–12.  https://doi.org/10.1155/2016/5152029 CrossRefGoogle Scholar
  43. 43.
    Rahimi R, Mirzaei B, Rahmani-Nia F, Salehi Z (2015) Effects of creatine monohydrate supplementation on exercise-induced apoptosis in athletes: a randomized, double-blind, and placebo-controlled study. J Res Med Sci 20:733–738.  https://doi.org/10.4103/1735-1995.168320 CrossRefGoogle Scholar
  44. 44.
    Sestili P, Martinelli C, Colombo E et al (2011) Creatine as an antioxidant. Amino Acids 40:1385–1396CrossRefGoogle Scholar
  45. 45.
    Deminice R, Portari GV, Vannucchi H, Jordao AA (2009) Effects of creatine supplementation on homocysteine levels and lipid peroxidation in rats. Br J Nutr 102:110–116.  https://doi.org/10.1017/S0007114508162985 CrossRefGoogle Scholar
  46. 46.
    Deminice R, da Silva RP, Lamarre SG et al (2011) Creatine supplementation prevents the accumulation of fat in the livers of rats fed a high-fat diet. J Nutr 141:1799–1804.  https://doi.org/10.3945/jn.111.144857 CrossRefGoogle Scholar
  47. 47.
    Nomura A, Zhang M, Sakamoto T et al (2003) Anti-inflammatory activity of creatine supplementation in endothelial cells in vitro. Br J Pharmacol 139:715–720.  https://doi.org/10.1038/sj.bjp.0705316 CrossRefGoogle Scholar
  48. 48.
    Santos RVT, Bassit RA, Caperuto EC, Costa Rosa LFBP (2004) The effect of creatine supplementation upon inflammatory and muscle soreness markers after a 30 km race. Life Sci 75:1917–1924.  https://doi.org/10.1016/j.lfs.2003.11.036 CrossRefGoogle Scholar
  49. 49.
    Deminice R, Rosa FT, Franco GS et al (2013) Effects of creatine supplementation on oxidative stress and inflammatory markers after repeated-sprint exercise in humans. Nutrition 29:1127–1132.  https://doi.org/10.1016/j.nut.2013.03.003 CrossRefGoogle Scholar
  50. 50.
    Wang Y, Pessin JE (2013) Mechanisms for fiber-type specificity of skeletal muscle atrophy. Curr Opin Clin Nutr Metab Care 16:243–250.  https://doi.org/10.1097/MCO.0b013e328360272d CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Paola S. Cella
    • 1
  • Poliana C. Marinello
    • 1
    • 2
  • Fernando H. Borges
    • 2
  • Diogo F. Ribeiro
    • 1
  • Patrícia Chimin
    • 1
  • Mayra T. J. Testa
    • 1
  • Philippe B. Guirro
    • 1
  • José A. Duarte
    • 3
  • Rubens Cecchini
    • 2
  • Flávia A. Guarnier
    • 2
  • Rafael Deminice
    • 1
    Email author
  1. 1.Department of Physical Education, Faculty of Physical Education and SportState University of LondrinaLondrinaBrazil
  2. 2.Department of General PathologyState University of LondrinaLondrinaBrazil
  3. 3.University of Porto, CIAFEL, Faculty of SportPortoPortugal

Personalised recommendations