Acta Neuropathologica

, Volume 113, Issue 4, pp 451–459 | Cite as

Increased expression of neuregulin-1 in differentiating muscle satellite cells and in motoneurons during muscle regeneration

  • Miyuki Hirata
  • Kunihiro Sakuma
  • Seiichiro Okajima
  • Hiroyoshi Fujiwara
  • Shuichiro Inashima
  • Masahiro Yasuhara
  • Toshikazu Kubo
Original Paper


Neuregulins belong to a family of multipotent growth-promoting proteins, and have been shown to have a crucial role in accumulating acetylcholine receptor at neuromuscular junctions. A functional role of neuregulins in muscle regeneration has not yet been identified. Using reverse transcription (RT)-PCR, Western blot and immunofluorescence analysis following bupivacaine injection into rat muscle, we investigated the expression pattern of neuregulin-1 (NRG-1) in normal and regenerating tibialis anterior (TA) muscle. In addition, we examined changes in NRG-1 expression in the spinal cord following muscle damage. Western blotting showed that muscle NRG-1 protein decreased soon after the damage, and increased gradually after the 4th day following the damage. The amount of NRG-1 mRNA in the muscle increased from the 2nd to 6th post-surgical day. The amount of NRG-1 protein, but not mRNA, increased gradually in the spinal cord after muscle damage. Immunofluorescence revealed NRG-1 protein in some quiescent satellite cells identified by c-Met. After 6 and 10 days, clear co-localization between NRG-1 and myogenin was noted in differentiating satellite cells. Thus, NRG-1 may play an important role in the differentiation of satellite cells in muscle regeneration, while increased NRG-1 expression in motoneurons may enhance the remodeling of partially damaged axons.


Neuregulin-1 Muscle regeneration Differentiation Spinal cord Satellite cell 



This work was supported by a research Grant-in-Aid for Young Scientists B (No. 17700500) and Scientific Research C (No. 16591505) from the Ministry of Education, Science, Sports and Culture of Japan, and by the grant for young researcher’s project of Research Center for Future Technology, Toyohashi University of Technology.


  1. 1.
    Adlkofer K, Lai C (2000) Role of neuregulins in glial cell development. Glia 29:104–111PubMedCrossRefGoogle Scholar
  2. 2.
    Canto C, Suarez E, Lizcano JM, Grino E, Shepherd PR, Fryer LGD, Carling D, Bertran J, Palacin M, Zorzano A, Guma A (2004) Neuregulin signaling on glucose transport in muscle cells. J Biol Chem 279:12260–12268PubMedCrossRefGoogle Scholar
  3. 3.
    DeFazio A, Leary JA, Hedley DW, Tattersal MH (1987) Immunohistochemical detection of proliferating cells in vivo. J Histochem Cytochem 35:571–577PubMedGoogle Scholar
  4. 4.
    Florini JR, Samuel DS, Ewton DZ, Kirk C, Sklar RM (1996) Stimulation of myogenic differentiation by a neuregulin, glial growth factor 2. Are neuregulins the long-sought muscle trophic factors secreted by nerves? J Biol Chem 271:12699–12702PubMedCrossRefGoogle Scholar
  5. 5.
    Ford BD, Han B, Fischbach GD (2003) Differentiation-dependent regulation of skeletal myogenesis by neuregulin-1. Biochem Biophys Res Commun 306:276–281PubMedCrossRefGoogle Scholar
  6. 6.
    Golding M, Ruhrberg C, Sandle J, Gullick WJ (2004) Mapping nucleolar and spliceosome localization sequences of neuregulin1-beta3. Exp Cell Res 299:110–118PubMedCrossRefGoogle Scholar
  7. 7.
    Hawke TJ, Garry DJ (2001) Myogenic satellite cells: physiology to molecular biology. J Appl Physiol 91:534–551PubMedGoogle Scholar
  8. 8.
    Jo SA, Zhu X, Marchionni MA, Burden SJ (1995) Neuregulins are concentrated at nerve-muscle synapses and activate ACh-receptor gene expression. Nature 373:158–161PubMedCrossRefGoogle Scholar
  9. 9.
    Kami K, Morikawa Y, Kawai Y, Senba E (1999) Leukemia inhibitory factor, glial cell line-derived neurotrophic factor, and their receptor expressions following muscle crush injury. Muscle Nerve 22:1576–1586PubMedCrossRefGoogle Scholar
  10. 10.
    Kim D, Chi S, Lee KH, Rhee S, Kwon YK, Chung CH, Kwon H, Kang MS (1999) Neuregulin stimulates myogenic differentiation in an autocrine manner. J Biol Chem 274:15395–15400PubMedCrossRefGoogle Scholar
  11. 11.
    Laemmli UK (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227:680–685PubMedCrossRefGoogle Scholar
  12. 12.
    Lebrasseur NK, Cote GM, Miller TA, Fielding RA, Sawyer DB (2003) Regulation of neuregulin/ErbB signaling by contractile activity in skeletal muscle. Am J Physiol Cell Physiol 284:C1149–C1155PubMedGoogle Scholar
  13. 13.
    Leitner ML, Molliver DC, Osborne PA, Vejsada R, Golden JP, Lampe PA, Kato AC, Milbrandt J, Johnson Jr EM (1999) Analysis of the retrograde transport of glial cell line-derived neurotrophic factor (GDNF), neurturin, and persephin suggests that in vivo signaling for the GDNF family is GFRα coreceptor-specific. J Neurosci 19:9322–9331PubMedGoogle Scholar
  14. 14.
    Lemke G (1996) Neuregulins in development. Mol Cell Neurosci 7:247–262PubMedCrossRefGoogle Scholar
  15. 15.
    Li W, Park JW, Nuijens A, Sliwkowski MX, Keller GA (1996) Heregulin is rapidly translocated to the nucleus and its transport is correlated with c-myc induction in breast cancer cells. Oncogene 12:2473–2477PubMedGoogle Scholar
  16. 16.
    Loeb JA, Fishbach GD (1997) Neurotrophic factors increase neuregulin expression in embryonic ventral spinal cord neurons. J Neurosci 17:1416–1424PubMedGoogle Scholar
  17. 17.
    Marchionni MA, Goodearl ADJ, Chen MS, Bermingham-McDonogh O, Kirk C, Hendricks M, Danehy F, Misumi D, Sudhalter J, Kobayashi K, Wroblewski D, Lynch C, Baldassare M, Hiles I, Davis JB, Hsuan JJ, Totty NF, Otsu M, McBurney RN, Waterfield MD, Stroobant P, Gwynne D (1993) Glial growth factors are alternatively spliced erbB2 ligands expressed in the nervous system. Nature 362:312–318PubMedCrossRefGoogle Scholar
  18. 18.
    Raabe TD, Deadwyler G, Varga JW, Devries GH (2004) Localization of neuregulin isoforms and erbB receptors in myelinating glial cells. Glia 45:197–207PubMedCrossRefGoogle Scholar
  19. 19.
    Rhodes KJ, Trimmer JS (2006) Antibodies as valuable neuroscience research tools versus reagents of mass distraction. J Neurosci 26:8017–8020PubMedCrossRefGoogle Scholar
  20. 20.
    Sakuma K, Nishikawa J, Nakao R, Nakano H, Sano M, Yasuhara M (2003) Serum response factor plays an important role in the mechanically overloaded plantaris muscle of rats. Histochem Cell Biol 119:149–160PubMedGoogle Scholar
  21. 21.
    Sakuma K, Nakao R, Yamasa Y, Yasuhara M (2006) Normal distribution of presenilin-1 and nicastrin in skeletal muscle and the differential responses of these proteins after denervation. Biochim Biophys Acta 1760:980–987PubMedGoogle Scholar
  22. 22.
    Suarez E, Bach D, Cadefau J, Palacin M, Zorzano A, Guma A (2001) A novel role of neuregulin in skeletal muscle. Neuregulin stimulates glucose uptake, glucose transporter translocation, and transporter expression in muscle cells. J Biol Chem 276:18257–18264PubMedCrossRefGoogle Scholar
  23. 23.
    Watson FL, Heerssen HM, Moheban DB, Lin MZ, Sauvageot CM, Bhattacharyya A, Pomeroy SL, Segal RA (1999) Rapid nuclear responses to target-derived neurotrophins require retrograde transport of ligand-receptor complex. J Neurosci 19:7889–7900PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Miyuki Hirata
    • 1
  • Kunihiro Sakuma
    • 3
  • Seiichiro Okajima
    • 1
  • Hiroyoshi Fujiwara
    • 1
  • Shuichiro Inashima
    • 2
  • Masahiro Yasuhara
    • 2
  • Toshikazu Kubo
    • 1
  1. 1.Department of OrthopedicsKyoto Prefectural University of MedicineKyotoJapan
  2. 2.Department of Legal MedicineKyoto Prefectural University of MedicineKyotoJapan
  3. 3.Health Science CenterToyohashi University of TechnologyToyohashiJapan

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