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Molecular Medicine

, Volume 13, Issue 9–10, pp 461–470 | Cite as

Transcription Factors in Muscle Atrophy Caused by Blocked Neuromuscular Transmission and Muscle Unloading In Rats

  • Jenny Nordquist
  • Anna-Stina Höglund
  • Holly Norman
  • Xiaorui Tang
  • Barry Dworkin
  • Lars Larsson
Research Article

Abstract

The muscle wasting associated with long-term intensive care unit (ICU) treatment has a negative effect on muscle function resulting in prolonged periods of rehabilitation and a decreased quality of life. To identify mechanisms behind this form of muscle wasting, we have used a rat model designed to mimic the conditions in an ICU. Rats were pharmacologically paralyzed with a postsynaptic blocker of neuromuscular transmission, and mechanically ventilated for one to two weeks, thereby unloading the limb muscles. Transcription factors were analyzed for cellular localization and nuclear concentration in the fast-twitch muscle extensor digitorum longus (EDL) and in the slow-twitch soleus. Significant muscle wasting and upregulation of mRNA for the ubiquitin ligases MAFbx and MuRF1 followed the treatment. The IκB family-member Bcl-3 displayed a concomitant decrease in concentration, suggesting altered κB controlled gene expression, although NFκB p65 was not significantly affected. The nuclear levels of the glucocorticoid receptor (GR) and the thyroid receptor α1 (TRα1) were altered and also suggested as potential mediators of the MAFbx- and MuRF1-induction in the absence of induced Foxo1. We believe that this model, and the strategy of quantifying nuclear proteins, will provide a valuable tool for further, more detailed, analyses of the muscle wasting occurring in patients kept on a mechanical ventilator.

Notes

Acknowledgments

We wish to thank Yvette Hedström, Helena Svahn, and Ann-Marie Gustafson for excellent technical assistance. The study was supported by grants from the Medical Faculty’s Foundation for Psychiatric and Neurological Research at Uppsala University to J.N., and the Swedish Research Council (08651), NIH (AR045627, AR047318, AG014731), Association Française contre les Myopathies (AFM), and the Swedish Cancer Society, to L.L.

References

  1. 1.
    McKinnell IW, Rudnicki MA. (2004) Molecular mechanisms of muscle atrophy. Cell 119:907–10.CrossRefGoogle Scholar
  2. 2.
    Orzechowski A, Grizard J, Jank M, Gajkowska B, Lokociejewska M, Zaron-Teperek M Godlewski, M. (2002) Dexamethasone-mediated regulation of death and differentiation of muscle cells: Is hydrogen peroxide involved in the process? Reprod. Nutr. Dev. 42:197–216.CrossRefGoogle Scholar
  3. 3.
    Cai D, Frantz JD, Tawa NE, et al. (2004) IKKbeta/NF-kappaB activation causes severe muscle wasting in mice. Cell 119:285–98.CrossRefGoogle Scholar
  4. 4.
    Li YP, Chen Y, John J, Moylan J, Jin B, Mann DL, Reid MB. (2005) TNF-alpha acts via p38 MAPK to stimulate expression of the ubiquitin ligase atrogin1/MAFbx in skeletal muscle. FASEB. J. 19:362–70.CrossRefGoogle Scholar
  5. 5.
    Gomes-Marcondes MC, Tisdale MJ. (2002) Induction of protein catabolism and the ubiquitin-proteasome pathway by mild oxidative stress. Cancer Lett. 180:69–74.CrossRefGoogle Scholar
  6. 6.
    Li YP, Chen Y, Li AS, Reid MB. (2003) Hydrogen peroxide stimulates ubiquitin-conjugating activity and expression of genes for specific E2 and E3 proteins in skeletal muscle myotubes. Am. J. Physiol. Cell Physiol. 285:C806–12.CrossRefGoogle Scholar
  7. 7.
    Michel RN, Dunn SE, Chin ER. (2004) Calcineurin and skeletal muscle growth. Proc. Nutr. Soc. 63:341–9.CrossRefGoogle Scholar
  8. 8.
    Schiaffino S, Serrano A. (2002) Calcineurin signaling and neural control of skeletal muscle fiber type and size. Trends Pharmacol. Sci. 23:569–75.CrossRefGoogle Scholar
  9. 9.
    Sakuma K, Nishikawa J, Nakao R, et al. (2003) Calcineurin is a potent regulator for skeletal muscle regeneration by association with NFATc1 and GATA-2. Acta. Neuropathol. (Berl.) 105:271–80.Google Scholar
  10. 10.
    Chin ER, Olson EN, Richardson JA, et al. (1998) A calcineurin-dependent transcriptional pathway controls skeletal muscle fiber type. Genes Dev. 12:2499–509.CrossRefGoogle Scholar
  11. 11.
    Bodine SC, Latres E, Baumhueter S, et al. (2001) Identification of ubiquitin ligases required for skeletal muscle atrophy. Science 294:1704–8.CrossRefGoogle Scholar
  12. 12.
    Hunter RB, Stevenson E, Koncarevic A, Mitchell-Felton H, Essig DA, Kandarian SC. (2002) Activation of an alternative NF-kappaB pathway in skeletal muscle during disuse atrophy. FASEB J. 16:529–38.CrossRefGoogle Scholar
  13. 13.
    Herridge MS, Cheung AM, Tansey CM, et al. (2003) One-year outcomes in survivors of the acute respiratory distress syndrome. N. Engl. J. Med. 348:683–3.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Cheung AM, Tansey CM, Tomlinson G, et al. (2006) Two-year outcomes, health care use and costs in survivors of ARDS. Am. J. Respir. Crit. Care Med. 174:538–44.CrossRefGoogle Scholar
  15. 15.
    Kubis HP, Hanke N, Scheibe RJ, Meissner JD, Gros G. (2003) Ca2+ transients activate calcineurin/NFATc1 and initiate fast-to-slow transformation in a primary skeletal muscle culture. Am. J. Physiol. Cell Physiol. 285:C56–63.CrossRefGoogle Scholar
  16. 16.
    Molkentin JD, Black BL, Martin JF, Olson EN. (1995) Cooperative activation of muscle gene expression by MEF2 and myogenic bHLH proteins. Cell 83:1125–36.CrossRefGoogle Scholar
  17. 17.
    Lakich MM, Diagana TT, North DL, Whalen RG. (1998) MEF-2 and Oct-1 bind to two homologous promoter sequence elements and participate in the expression of a skeletal muscle-specific gene. J. Biol. Chem. 273:15217–26.CrossRefGoogle Scholar
  18. 18.
    Schmitz ML, Mattioli I, Buss H, Kracht M. (2004) NF-kappaB: a multifaceted transcription factor regulated at several levels. Chembiochem. 5: 1348–58.CrossRefGoogle Scholar
  19. 19.
    Heissmeyer V, Krappmann D, Wulczyn FG, Scheidereit C. (1999) NF-kappaB p105 is a target of IkappaB kinases and controls signal induction of Bcl-3-p50 complexes. Embo. J. 18:4766–78.CrossRefGoogle Scholar
  20. 20.
    Berkes CA, Tapscott SJ. (2005) MyoD and the transcriptional control of myogenesis. Semin. Cell Dev. Biol. 16:585–95.CrossRefGoogle Scholar
  21. 21.
    Tang H, Macpherson P, Argetsinger LS, Cieslak D, Suhr ST, Carter-Su C, Goldman D. (2004) CaM kinase II-dependent phosphorylation of myogenin contributes to activity-dependent suppression of nAChR gene expression in developing rat myotubes. Cell. Signal. 16:551–63.CrossRefGoogle Scholar
  22. 22.
    Tajbakhsh S, Buckingham M. (2000) The birth of muscle progenitor cells in the mouse: spatiotemporal considerations. Curr. Top. Dev. Biol. 48: 225–68.CrossRefGoogle Scholar
  23. 23.
    Thompson AL, Filatov G, Chen C, Porter I, Li Y, Rich MM, Kraner SD. (2005) A selective role for MRF4 in innervated adult skeletal muscle: Na(V) 1.4 Na+ channel expression is reduced in MRF4-null mice. Gene Expr. 12:289–303.CrossRefGoogle Scholar
  24. 24.
    Stitt TN, Drujan D, Clarke BA, et al. (2004) The IGF-1/PI3K/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors. Mol. Cell 14:395–403.CrossRefGoogle Scholar
  25. 25.
    Yu F, Gothe S, Wikstrom L, Forrest D, Vennstrom B, Larsson L. (2000) Effects of thyroid hormone receptor gene disruption on myosin isoform expression in mouse skeletal muscles. Am. J. Physiol. Regul. Integr. Comp. Physiol. 278: R1545–54.CrossRefGoogle Scholar
  26. 26.
    Schacke H, Docke WD, Asadullah K. (2002) Mechanisms involved in the side effects of glucocorticoids. Pharmacol. Ther. 96:23–43.CrossRefGoogle Scholar
  27. 27.
    Allen DL, Weber JN, Sycuro LK, Leinwand LA. (2005) Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. J. Biol. Chem. 280:17126–34.CrossRefGoogle Scholar
  28. 28.
    Barth JL, Morris J, Ivarie R. (1998) An Oct-like binding factor regulates Myf-5 expression in primary avian cells. Exp. Cell Res. 238:430–8.CrossRefGoogle Scholar
  29. 29.
    Wieland GD, Nehmann N, Muller D, et al. (2005) Early growth response proteins EGR-4 and EGR-3 interact with immune inflammatory mediators NF-kappaB p50 and p65. J. Cell. Sci. 118: 3203–12.CrossRefGoogle Scholar
  30. 30.
    Dworkin BR, Dworkin S, Tang X. (2000) Carotid and aortic baroreflexes of the rat: I. Open-loop steady-state properties and blood pressure variability. Am. J. Physiol. Regul Integr. Comp. Physiol. 279:R1910–21.CrossRefGoogle Scholar
  31. 31.
    Dignam JD, Lebovitz RM, Roeder RG. (1983) Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res. 11:1475–89.CrossRefGoogle Scholar
  32. 32.
    Norman H, Nordquist J, Andersson P, Ansved T, Tang X, Dworkin B, Larsson L. (2006) Impact of post-synaptic block of neuromuscular transmission, muscle unloading and mechanical ventilation on skeletal muscle protein and mRNA expression. Pflugers Arch. 453:53–66.CrossRefGoogle Scholar
  33. 33.
    Hughes SM, Cho M, Karsch-Mizrachi I, Travis M, Silberstein L, Leinwand LA, Blau HM. (1993) Three slow myosin heavy chains sequentially expressed in developing mammalian skeletal muscle. Dev. Biol. 158:183–99.CrossRefGoogle Scholar
  34. 34.
    Bundy DL, McKeithan TW. (1997) Diverse effects of BCL3 phosphorylation on its modulation of NF-kappaB p52 homodimer binding to DNA. J. Biol. Chem. 272:33132–9.CrossRefGoogle Scholar
  35. 35.
    Bates PW, Miyamoto S. (2004) Expanded nuclear roles for IkappaBs. Sci. STKE 2004. pe48Google Scholar
  36. 36.
    Sultan KR, Henkel B, Terlou M, Haagsman HP. (2006) Quantification of hormone-induced atrophy of large myotubes from C2C12 and L6 cells: atrophy-inducible and atrophy-resistant C2C12 myotubes. Am. J. Physiol. Cell. Physiol. 290: C650–9.CrossRefGoogle Scholar
  37. 37.
    Clement K, Viguerie N, Diehn M, et al. (2002) In vivo regulation of human skeletal muscle gene expression by thyroid hormone. Genome Res. 12: 281–91.CrossRefGoogle Scholar
  38. 38.
    Rooyackers OE, Nair KS. (1997) Hormonal regulation of human muscle protein metabolism. Annu. Rev. Nutr. 17:457–85.CrossRefGoogle Scholar
  39. 39.
    Ma K, Mallidis C, Bhasin S, et al. (2003) Glucocorticoid-induced skeletal muscle atrophy is associated with upregulation of myostatin gene expression. Am. J. Physiol. Endocrinol. Metab. 285: E363–71.CrossRefGoogle Scholar
  40. 40.
    Liu Y, Cseresnyes Z, Randall WR, Schneider MF. (2001) Activity-dependent nuclear translocation and intranuclear distribution of NFATc in adult skeletal muscle fibers. J. Cell Biol. 155:27–39.CrossRefGoogle Scholar
  41. 41.
    McCullagh KJ, Calabria E, Pallafacchina G, et al. (2004) NFAT is a nerve activity sensor in skeletal muscle and controls activity-dependent myosin switching. Proc. Natl. Acad. Sci. USA 101: 10590–5.CrossRefGoogle Scholar
  42. 42.
    Tothova J, Blaauw B, Pallafacchina G, Rudolf R, Argentini C, Reggiani C, Schiaffino S. (2006) NFATc1 nucleocytoplasmic shuttling is controlled by nerve activity in skeletal muscle. J. Cell. Sci. 119:1604–11.CrossRefGoogle Scholar
  43. 43.
    Zammit PS, Heslop L, Hudon V, et al. (2002) Kinetics of myoblast proliferation show that resident satellite cells are competent to fully regenerate skeletal muscle fibers. Exp. Cell Res. 281: 39–49.CrossRefGoogle Scholar
  44. 44.
    Beauchamp JR, Heslop L, Yu DS, et al. (2000) Expression of CD34 and Myf5 defines the majority of quiescent adult skeletal muscle satellite cells. J. Cell Biol. 151:1221–34.CrossRefGoogle Scholar
  45. 45.
    Frey N, Richardson JA, Olson EN. (2000) Calsarcins, a novel family of sarcomeric calcineurinbinding proteins. Proc. Natl. Acad. Sci. U.S.A. 97: 14632–7.CrossRefGoogle Scholar
  46. 46.
    Lange S, Xiang F, Yakovenko A, et al. (2005) The kinase domain of titin controls muscle gene expression and protein turnover. Science 308: 1599–1603.CrossRefGoogle Scholar
  47. 47.
    Ansved T. (1995) Effects of immobilization on the rat soleus muscle in relation to age. Acta Physiol. Scand. 154:291–302.CrossRefGoogle Scholar
  48. 48.
    Ansved T, Larsson L. (1990) Effects of denervation on enzyme-histochemical and morphometrical properties of the rat soleus muscle in relation to age. Acta Physiol. Scand. 139:297–304.CrossRefGoogle Scholar

Copyright information

© Feinstein Institute for Medical Research 2007

Authors and Affiliations

  • Jenny Nordquist
    • 1
  • Anna-Stina Höglund
    • 1
  • Holly Norman
    • 1
  • Xiaorui Tang
    • 2
  • Barry Dworkin
    • 2
  • Lars Larsson
    • 1
    • 3
  1. 1.Department of Neuroscience, Clinical NeurophysiologyUppsala UniversityStockholmSweden
  2. 2.Hershey Medical CenterHersheyUSA
  3. 3.Center for development and Health GeneticsThe pennsylvania State UniversityUniversity ParkUSA

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