Skip to main content

Advertisement

Log in

The expression of neuregulin and erbB receptors in human skeletal muscle: effects of progressive resistance training

  • Original Article
  • Published:
European Journal of Applied Physiology Aims and scope Submit manuscript

Abstract

The neuregulin/erbB-signaling axis contributes to the development and growth of multiple mammalian tissues including skeletal muscle. In this study, we sought to characterize the native expression of this system in human skeletal muscle and test the hypothesis that a program of progressive resistance training (PRT) would regulate the expression of neuregulin (NRG) and its cognate receptors. Twelve healthy-male subjects underwent 8-weeks of lower-extremity PRT and muscle biopsies were performed at baseline and following 1- and 8-weeks of the intervention. PRT resulted in significant gains in skeletal muscle strength without appreciable changes in fiber size or myosin heavy chain (MHC) composition. At baseline, Western Blot analysis demonstrated expression of erbB2, erbB3 and erbB4 receptors and multiple NRG isoforms. Following 1- and 8-weeks of PRT, no changes erbB2, erbB4 or NRG expression were observed. ErbB3 expression, however, was significantly increased at both time points compared to baseline. Double labeling of muscle cross-sections revealed increased expression of erbB3 following PRT was not exclusive to fibers staining positive for MHC IIa. Thus, erbB2, erbB3, erbB4 and multiple NRG isoforms are natively expressed in human skeletal muscle. Following PRT, a significant increase in erbB3 was observed. The ability to detect basal expression and alterations in response to physiologic stimuli merit further studies examining the role of this system in skeletal muscle.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Aguilar Z, Slamon DJ (2001) The transmembrane heregulin precursor is functionally active. J Biol Chem 276:44099–44107

    CAS  PubMed  Google Scholar 

  • Carraway KL, III, Sliwkowski MX, Akita R, Platko JV, Guy PM, Nuijens A, Diamonti AJ, Vandlen RL, Cantley LC, Cerione RA (1994) The erbB3 gene product is a receptor for heregulin. J Biol Chem 269:14303–14306

    CAS  PubMed  Google Scholar 

  • Fielding RA, LeBrasseur NK, Cuoco A, Bean J, Mizer K, Fiatarone Singh MA (2002) High-velocity resistance training increases skeletal muscle peak power in older women. J Am Geriatr Soc 50:655–662

    PubMed  Google Scholar 

  • 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 271:12699–12702

    CAS  PubMed  Google Scholar 

  • Gassmann M, Casagranda F, Orioli D, Simon H, Lai C, Klein R, Lemke G (1995) Aberrant neural and cardiac development in mice lacking the ErbB4 neuregulin receptor. Nature 378: 390–394

    CAS  PubMed  Google Scholar 

  • Hellyer NJ, Cheng K, Koland JG (1998) ErbB3 (HER3) interaction with the p85 regulatory subunit of phosphoinositide 3-kinase. Biochem J 333(Pt 3):757–763

    CAS  PubMed  Google Scholar 

  • Holmes WE, Sliwkowski MX, Akita RW, Henzel WJ, Lee J, Park JW, Yansura D, Abadi N, Raab H, Lewis GD (1992) Identification of heregulin, a specific activator of p185erbB2. Science 256:1205–1210

    CAS  PubMed  Google Scholar 

  • 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 274:15395–15400

    CAS  PubMed  Google Scholar 

  • 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–C1155

    CAS  PubMed  Google Scholar 

  • Lee KF, Simon H, Chen H, Bates B, Hung MC, Hauser C (1995) Requirement for neuregulin receptor erbB2 in neural and cardiac development [see comments]. Nature 378:394–398

    CAS  PubMed  Google Scholar 

  • Leu M, Bellmunt E, Schwander M, Farinas I, Brenner HR, Muller U (2003) Erbb2 regulates neuromuscular synapse formation and is essential for muscle spindle development. Development 130:2291–2301

    CAS  PubMed  Google Scholar 

  • Li L, Cleary S, Mandarano MA, Long W, Birchmeier C, Jones FE (2002) The breast proto-oncogene, HRGalpha regulates epithelial proliferation and lobuloalveolar development in the mouse mammary gland. Oncogene 21:4900–4907

    CAS  PubMed  Google Scholar 

  • Marchionni MA, Goodearl AD, 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 and Gwynne D (1993) Glial growth factors are alternatively spliced erbB2 ligands expressed in the nervous system. Nature 362: 312–318

    CAS  PubMed  Google Scholar 

  • Meyer D, Birchmeier C (1995) Multiple essential functions of neuregulin in development. Nature 378:386–390

    CAS  PubMed  Google Scholar 

  • Mizer K, LeBrasseur NK, Lima R, Forman D, MacLean D, Fielding R (2002) Effects of resistance training on the time course of IGF-1 expression in sedentary males. FASEB J 16:A447

    Google Scholar 

  • Montero JC, Yuste L, Diaz-Rodriguez E, Esparis-Ogando A, Pandiella A (2000) Differential shedding of transmembrane neuregulin isoforms by the tumor necrosis factor-alpha-converting enzyme. Mol Cell Neurosci 16:631–648

    CAS  PubMed  Google Scholar 

  • Parkington JD, Siebert AP, LeBrasseur NK, Fielding RA (2003) Differential activation of mTOR signaling by contractile activity in skeletal muscle. Am J Physiol Regul Integr Comp Physiol 285:R1086–R1090

    CAS  PubMed  Google Scholar 

  • Plowman GD, Culouscou JM, Whitney GS, Green JM, Carlton GW, Foy L, Neubauer MG, Shoyab M (1993) Ligand-specific activation of HER4/p180erbB4, a fourth member of the epidermal growth factor receptor family. Proc Natl Acad Sci U S A 90:1746–50

    CAS  PubMed  Google Scholar 

  • Shirakabe K, Wakatsuki S, Kurisaki T, Fujisawa-Sehara A (2001) Roles of Meltrin beta /ADAM19 in the processing of neuregulin. J Biol Chem 276: 9352–9358

    CAS  PubMed  Google Scholar 

  • Si J, Tanowitz M, Won S, Mei L (1998) Regulation by ARIA/neuregulin of acetylcholine receptor gene transcription at the neuromuscular junction. Life Sci 62:1497–1502

    CAS  PubMed  Google Scholar 

  • 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 276:18257–18264

    CAS  PubMed  Google Scholar 

  • Tansey MG, Chu GC, Merlie JP (1996) ARIA/HRG regulates AChR epsilon subunit gene expression at the neuromuscular synapse via activation of phosphatidylinositol 3-kinase and Ras/MAPK pathway. J Cell Biol 134:465–476

    CAS  PubMed  Google Scholar 

  • Tzahar E, Levkowitz G, Karunagaran D, Yi L, Peles E, Lavi S, Chang D, Liu N, Yayon A, Wen D (1994) ErbB-3 and ErbB-4 function as the respective low and high affinity receptors of all Neu differentiation factor/heregulin isoforms. J Biol Chem 269:25226–25233

    CAS  PubMed  Google Scholar 

  • Wang JY, Miller SJ, Falls DL (2001) The N-terminal region of neuregulin isoforms determines the accumulation of cell surface and released neuregulin ectodomain. J Biol Chem 276: 2841–2851

    CAS  PubMed  Google Scholar 

  • Yarden Y, Sliwkowski MX (2001) Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2:127–137

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by Pfizer Global Research and Development (R.A. Fielding) and by grants to D.B. Sawyer from the National Institutes of Health (HL-68144) and the Juvenile Diabetes Research Foundation. N.K. LeBrasseur was supported by an NIH NRSA Postdoctoral Fellowship (DK-007201). This material is based on work supported by U.S. Department of Agriculture, under agreement No.58-1950-4-401. Any opnions, findings, conclusions, or recommendations expressed in this publication are those of the authors and do not neccessarily reflect the view of the U.S. Dept. of Agriculture.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Nathan K. LeBrasseur.

Rights and permissions

Reprints and permissions

About this article

Cite this article

LeBrasseur, N.K., Mizer, K.C., Parkington, J.D. et al. The expression of neuregulin and erbB receptors in human skeletal muscle: effects of progressive resistance training. Eur J Appl Physiol 94, 371–375 (2005). https://doi.org/10.1007/s00421-005-1333-4

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00421-005-1333-4

Keywords

Navigation