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Muscle wasting and interleukin-6-induced atrogin-I expression in the cachectic Apc Min/+ mouse

  • Integrative Physiology
  • Published:
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Abstract

Interleukin-6 (IL-6) is necessary for cachexia in Apc Min/+ mice, but the mechanisms inducing this myofiber wasting have not been established. The purpose of this study was to examine gastrocnemius muscle wasting in the Apc Min/+ mouse and to determine IL-6 regulated mechanisms contributing to muscle loss. Gastrocnemius type IIB mean fiber cross-sectional area (CSA) from Apc Min/+ mice decreased 32% between 13 and 22 weeks of age. Apc Min/+ mice lacking IL-6 did not have type IIB fiber atrophy, while overexpression of circulating IL-6 exacerbated the loss of type IIB fiber CSA in Apc Min/+ mice. Muscle Atrogin-I mRNA expression was induced at least ninefold at 18 and 22 weeks of age compared to 13-week-old mice. Atrogin-I gene expression was also induced by overexpression of circulating IL-6. These data suggest that high circulating IL-6 levels induce type IIB fiber CSA loss in Apc Min/+ mice, and circulating IL-6 is sufficient to regulate Atrogin-I gene expression in cachectic mice.

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References

  1. Price SA, Tisdale MJ (1998) Mechanism of inhibition of a tumor lipid-mobilizing factor by eicosapentaenoic acid. Cancer Res 58:4827–4831

    PubMed  CAS  Google Scholar 

  2. Giordano A, Calvani M, Petillo O, Carteni M, Melone MR, Peluso G (2003) Skeletal muscle metabolism in physiology and in cancer disease. J Cell Biochem 90:170–186

    Article  PubMed  CAS  Google Scholar 

  3. al-Majid S, McCarthy DO (2001) Resistance exercise training attenuates wasting of the extensor digitorum longus muscle in mice bearing the colon-26 adenocarcinoma. Biol Res Nurs 2:155–166

    Article  PubMed  CAS  Google Scholar 

  4. Ardies CM (2002) Exercise, cachexia, and cancer therapy: a molecular rationale. Nutr Cancer 42:143–157

    Article  PubMed  Google Scholar 

  5. Khalfoun B, Thibault F, Watier H, Bardos P, Lebranchu Y (1997) Docosahexaenoic and eicosapentaenoic acids inhibit in vitro human endothelial cell production of interleukin-6. Adv Exp Med Biol 400B:589–597

    PubMed  CAS  Google Scholar 

  6. Argiles JM, Busquets S, Lopez-Soriano FJ (2003) Cytokines in the pathogenesis of cancer cachexia. Curr Opin Clin Nutr Metab Care 6:401–406

    Article  PubMed  CAS  Google Scholar 

  7. Espat NJ, Auffenberg T, Rosenberg JJ, Rogy M, Martin D, Fang CH, Hasselgren PO, Copeland EM, Moldawer LL (1996) Ciliary neurotrophic factor is catabolic and shares with IL-6 the capacity to induce an acute phase response. Am J Physiol 271:R185–R190

    PubMed  CAS  Google Scholar 

  8. Wallenius V, Wallenius K, Ahren B, Rudling M, Carlsten H, Dickson SL, Ohlsson C, Jansson JO (2002) Interleukin-6-deficient mice develop mature-onset obesity. Nat Med 8:75–79

    Article  PubMed  CAS  Google Scholar 

  9. Tsujinaka T, Ebisui C, Fujita J, Kishibuchi M, Morimoto T, Ogawa A, Katsume A, Ohsugi Y, Kominami E, Monden M (1995) Muscle undergoes atrophy in association with increase of lysosomal cathepsin activity in interleukin-6 transgenic mouse. Biochem Biophys Res Commun 207:168–174

    Article  PubMed  CAS  Google Scholar 

  10. Zhou W, Jiang ZW, Tian J, Jiang J, Li N, Li JS (2003) Role of NF-kappaB and cytokine in experimental cancer cachexia. World J Gastroenterol 9:1567–1570

    PubMed  CAS  Google Scholar 

  11. Goodman MN (1994) Interleukin-6 induces skeletal muscle protein breakdown in rats. Proc Soc Exp Biol Med 205:182–185

    PubMed  CAS  Google Scholar 

  12. Fujita J, Tsujinaka T, Yano M, Ebisui C, Saito H, Katsume A, Akamatsu K, Ohsugi Y, Shiozaki H, Monden M (1996) Anti-interleukin-6 receptor antibody prevents muscle atrophy in colon-26 adenocarcinoma-bearing mice with modulation of lysosomal and ATP-ubiquitin-dependent proteolytic pathways. Int J Cancer 68:637–643

    Article  PubMed  CAS  Google Scholar 

  13. Tsujinaka T, Fujita J, Ebisui C, Yano M, Kominami E, Suzuki K, Tanaka K, Katsume A, Ohsugi Y, Shiozaki H, Monden M (1996) Interleukin 6 receptor antibody inhibits muscle atrophy and modulates proteolytic systems in interleukin 6 transgenic mice. J Clin Invest 97:244–249

    Article  PubMed  CAS  Google Scholar 

  14. Zaki MH, Nemeth JA, Trikha M (2004) CNTO 328, a monoclonal antibody to IL-6, inhibits human tumor-induced cachexia in nude mice. Int J Cancer 111:592–595

    Article  PubMed  CAS  Google Scholar 

  15. Moser AR, Pitot HC, Dove WF (1990) A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse. Science 247:322–324

    Article  PubMed  CAS  Google Scholar 

  16. Mehl KA, Davis JM, Berger FG, Carson JA (2005) Myofiber degeneration/regeneration is induced in the cachectic ApcMin/+ mouse. J Appl Physiol 99:2379–2387

    Article  PubMed  CAS  Google Scholar 

  17. Baltgalvis KA, Berger FG, Pena MM, Davis JM, Muga SJ, Carson JA (2008) Interleukin-6 and cachexia in ApcMin/+ mice. Am J Physiol Regul Integr Comp Physiol 294:R393–R401

    PubMed  CAS  Google Scholar 

  18. Sandri M, Lin J, Handschin C, Yang W, Arany ZP, Lecker SH, Goldberg AL, Spiegelman BM (2006) PGC-1alpha protects skeletal muscle from atrophy by suppressing FoxO3 action and atrophy-specific gene transcription. Proc Natl Acad Sci U S A 103:16260–16265

    Article  PubMed  CAS  Google Scholar 

  19. Li P, Waters RE, Redfern SI, Zhang M, Mao L, Annex BH, Yan Z (2007) Oxidative phenotype protects myofibers from pathological insults induced by chronic heart failure in mice. Am J Pathol 170:599–608

    Article  PubMed  CAS  Google Scholar 

  20. Hulland TJ (1981) Histochemical and morphometric evaluation of skeletal muscle of cachectic sheep. Vet Pathol 18:279–298

    PubMed  CAS  Google Scholar 

  21. Allen DL, Harrison BC, Sartorius C, Byrnes WC, Leinwand LA (2001) Mutation of the IIB myosin heavy chain gene results in muscle fiber loss and compensatory hypertrophy. Am J Physiol Cell Physiol 280:C637–645

    PubMed  CAS  Google Scholar 

  22. Liang H, Ward WF (2006) PGC-1alpha: a key regulator of energy metabolism. Adv Physiol Educ 30:145–151

    Article  PubMed  Google Scholar 

  23. Lin J, Wu H, Tarr PT, Zhang CY, Wu Z, Boss O, Michael LF, Puigserver P, Isotani E, Olson EN, Lowell BB, Bassel-Duby R, Spiegelman BM (2002) Transcriptional co-activator PGC-1 alpha drives the formation of slow-twitch muscle fibres. Nature 418:797–801

    Article  PubMed  CAS  Google Scholar 

  24. Kwak KS, Zhou X, Solomon V, Baracos VE, Davis J, Bannon AW, Boyle WJ, Lacey DL, Han HQ (2004) Regulation of protein catabolism by muscle-specific and cytokine-inducible ubiquitin ligase E3alpha-II during cancer cachexia. Cancer Res 64:8193–8198

    Article  PubMed  CAS  Google Scholar 

  25. Tisdale MJ (2003) The ‘cancer cachectic factor’. Support Care Cancer 11:73–78

    PubMed  Google Scholar 

  26. Lecker SH, Jagoe RT, Gilbert A, Gomes M, Baracos V, Bailey J, Price SR, Mitch WE, Goldberg AL (2004) Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression. Faseb J 18:39–51

    Article  PubMed  CAS  Google Scholar 

  27. Khal J, Wyke SM, Russell ST, Hine AV, Tisdale MJ (2005) Expression of the ubiquitin–proteasome pathway and muscle loss in experimental cancer cachexia. Br J Cancer 93:774–780

    Article  PubMed  CAS  Google Scholar 

  28. Sacheck JM, Hyatt JP, Raffaello A, Jagoe RT, Roy RR, Edgerton VR, Lecker SH, Goldberg AL (2007) Rapid disuse and denervation atrophy involve transcriptional changes similar to those of muscle wasting during systemic diseases. Faseb J 21:140–155

    Article  PubMed  CAS  Google Scholar 

  29. Gomes MD, Lecker SH, Jagoe RT, Navon A, Goldberg AL (2001) Atrogin-1, a muscle-specific F-box protein highly expressed during muscle atrophy. Proc Natl Acad Sci U S A 98:14440–14445

    Article  PubMed  CAS  Google Scholar 

  30. Bodine SC, Latres E, Baumhueter S, Lai VK, Nunez L, Clarke BA, Poueymirou WT, Panaro FJ, Na E, Dharmarajan K, Pan ZQ, Valenzuela DM, DeChiara TM, Stitt TN, Yancopoulos GD, Glass DJ (2001) Identification of ubiquitin ligases required for skeletal muscle atrophy. Science 294:1704–1708

    Article  PubMed  CAS  Google Scholar 

  31. Costelli P, Muscaritoli M, Bossola M, Penna F, Reffo P, Bonetto A, Busquets S, Bonelli G, Lopez-Soriano FJ, Doglietto GB, Argiles JM, Baccino FM, Rossi Fanelli F (2006) Igf-1 Is Down-Regulated in Experimental Cancer Cachexia. Am J Physiol Regul Integr Comp Physiol 291:R674–683

    PubMed  CAS  Google Scholar 

  32. Fareed MU, Evenson AR, Wei W, Menconi M, Poylin V, Petkova V, Pignol B, Hasselgren PO (2006) Treatment of rats with calpain inhibitors prevents sepsis-induced muscle proteolysis independent of atrogin-1/MAFbx and MuRF1 expression. Am J Physiol Regul Integr Comp Physiol 290:R1589–R1597

    PubMed  CAS  Google Scholar 

  33. Sandri M, Sandri C, Gilbert A, Skurk C, Calabria E, Picard A, Walsh K, Schiaffino S, Lecker SH, Goldberg AL (2004) Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. Cell 117:399–412

    Article  PubMed  CAS  Google Scholar 

  34. Fielitz J, Kim MS, Shelton JM, Latif S, Spencer JA, Glass DJ, Richardson JA, Bassel-Duby R, Olson EN (2007) Myosin accumulation and striated muscle myopathy result from the loss of muscle RING finger 1 and 3. J Clin Invest 117:2486–2495

    Article  PubMed  CAS  Google Scholar 

  35. Hanai JI, Cao P, Tanksale P, Imamura S, Koshimizu E, Zhao J, Kishi S, Yamashita M, Phillips PS, Sukhatme VP, Lecker SH (2007) The muscle-specific ubiquitin ligase atrogin-1/MAFbx mediates statin-induced muscle toxicity. J Clin Invest 117:3940–3951

    PubMed  CAS  Google Scholar 

  36. Ebisui C, Tsujinaka T, Morimoto T, Kan K, Iijima S, Yano M, Kominami E, Tanaka K, Monden M (1995) Interleukin-6 induces proteolysis by activating intracellular proteases (cathepsins B and L, proteasome) in C2C12 myotubes. Clin Sci (Lond) 89:431–439

    CAS  Google Scholar 

  37. Fattori E, Cappelletti M, Zampaglione I, Mennuni C, Calvaruso F, Arcuri M, Rizzuto G, Costa P, Perretta G, Ciliberto G, La Monica N (2005) Gene electro-transfer of an improved erythropoietin plasmid in mice and non-human primates. J Gene Med 7:228–236

    Article  PubMed  CAS  Google Scholar 

  38. Mehl KA, Davis JM, Clements JM, Berger FG, Pena MM, Carson JA (2005) Decreased intestinal polyp multiplicity is related to exercise mode and gender in ApcMin/+ mice. J Appl Physiol 98:2219–2225

    Article  PubMed  Google Scholar 

  39. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods (San Diego, Calif) 25:402–408

    CAS  Google Scholar 

  40. Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254

    Article  PubMed  CAS  Google Scholar 

  41. Tucker JM, Davis C, Kitchens ME, Bunni MA, Priest DG, Spencer HT, Berger FG (2002) Response to 5-fluorouracil chemotherapy is modified by dietary folic acid deficiency in Apc(Min/+) mice. Cancer Lett 187:153–162

    Article  PubMed  CAS  Google Scholar 

  42. Acharyya S, Ladner KJ, Nelsen LL, Damrauer J, Reiser PJ, Swoap S, Guttridge DC (2004) Cancer cachexia is regulated by selective targeting of skeletal muscle gene products. J Clin Invest 114:370–378

    PubMed  CAS  Google Scholar 

  43. Lieskovska J, Guo D, Derman E (2003) Growth impairment in IL-6-overexpressing transgenic mice is associated with induction of SOCS3 mRNA. Growth Horm IGF Res 13:26–35

    Article  PubMed  CAS  Google Scholar 

  44. Strassmann G, Fong M, Kenney JS, Jacob CO (1992) Evidence for the involvement of interleukin 6 in experimental cancer cachexia. J Clin Invest 89:1681–1684

    Article  PubMed  CAS  Google Scholar 

  45. Brozek W, Bises G, Girsch T, Cross HS, Kaiser HE, Peterlik M (2005) Differentiation-dependent expression and mitogenic action of interleukin-6 in human colon carcinoma cells: relevance for tumour progression. Eur J Cancer 41:2347–2354

    Article  PubMed  CAS  Google Scholar 

  46. Fenton JI, Hursting SD, Perkins SN, Hord NG (2006) Interleukin-6 production induced by leptin treatment promotes cell proliferation in an Apc (Min/+) colon epithelial cell line. Carcinogenesis 27:1507–1515

    Article  PubMed  CAS  Google Scholar 

  47. Steiner H, Godoy-Tundidor S, Rogatsch H, Berger AP, Fuchs D, Comuzzi B, Bartsch G, Hobisch A, Culig Z (2003) Accelerated in vivo growth of prostate tumors that up-regulate interleukin-6 is associated with reduced retinoblastoma protein expression and activation of the mitogen-activated protein kinase pathway. Am J Pathol 162:655–663

    PubMed  CAS  Google Scholar 

  48. Herzfeld A, Legg MA, Greengard O (1978) Human colon tumors: enzymic and histological characteristics. Cancer 42:1280–1283

    Article  PubMed  CAS  Google Scholar 

  49. Leclerc D, Deng L, Trasler J, Rozen R (2004) ApcMin/+ mouse model of colon cancer: gene expression profiling in tumors. J Cell Biochem 93:1242–1254

    Article  PubMed  CAS  Google Scholar 

  50. Williams A, Wang JJ, Wang L, Sun X, Fischer JE, Hasselgren PO (1998) Sepsis in mice stimulates muscle proteolysis in the absence of IL-6. Am J Physiol 275:R1983–R1991

    PubMed  CAS  Google Scholar 

  51. Costelli P, Bossola M, Muscaritoli M, Grieco G, Bonelli G, Bellantone R, Doglietto GB, Baccino FM, Rossi Fanelli F (2002) Anticytokine treatment prevents the increase in the activity of ATP-ubiquitin- and Ca(2+)-dependent proteolytic systems in the muscle of tumour-bearing rats. Cytokine 19:1–5

    Article  PubMed  CAS  Google Scholar 

  52. Galban VD, Evangelista EA, Migliorini RH, do Carmo Kettelhut I (2001) Role of ubiquitin–proteasome-dependent proteolytic process in degradation of muscle protein from diabetic rabbits. Mol Cell Biochem 225:35–41

    Article  PubMed  CAS  Google Scholar 

  53. de Boer MD, Selby A, Atherton P, Smith K, Seynnes OR, Maganaris CN, Maffulli N, Movin T, Narici MV, Rennie MJ (2007) The temporal responses of protein synthesis, gene expression and cell signalling in human quadriceps muscle and patellar tendon to disuse. J Physiol 585:241–251

    Article  PubMed  Google Scholar 

  54. Louis E, Raue U, Yang Y, Jemiolo B, Trappe S (2007) Time course of proteolytic, cytokine, and myostatin gene expression after acute exercise in human skeletal muscle. J Appl Physiol 103:1744–1751

    Article  PubMed  CAS  Google Scholar 

  55. Jagoe RT, Lecker SH, Gomes M, Goldberg AL (2002) Patterns of gene expression in atrophying skeletal muscles: response to food deprivation. Faseb J 16:1697–1712

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

The authors would like to thank Tia Davis, Joseph McClung, and April Wilson for technical assistance. The research described in this report was supported by the National Institutes of Health (NIH) Grant P20 RR-017698 from the National Center for Research Resources. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

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Correspondence to James A. Carson.

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Baltgalvis, K.A., Berger, F.G., Peña, M.M.O. et al. Muscle wasting and interleukin-6-induced atrogin-I expression in the cachectic Apc Min/+ mouse. Pflugers Arch - Eur J Physiol 457, 989–1001 (2009). https://doi.org/10.1007/s00424-008-0574-6

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  • DOI: https://doi.org/10.1007/s00424-008-0574-6

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