Abstract
As a member of the TGF-β superfamily, myostatin is a specific negative regulator of skeletal muscle development. Loss of myostatin function in knock-out mice results in “double-muscle” phenotype observed in cattle breeds such as the Belgian Blue and the Piedmontese. In this chapter, we have included most recent observations on myostatin research, including the proteolytic processing of myostatin, its receptors, and the components in myostatin signaling pathway. In addition, we also discuss the role of myostatin in adipose tissue and glucose metabolism, and its relationship with rhabdomyosarcoma tumors.
Key Words
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsPreview
Unable to display preview. Download preview PDF.
References
McPherron AC, Lawler AM, Lee SJ. Regulation of skeletal muscle mass in mice by a new TGF-β superfamily member. Nature 1997;387:83–90.
Arnold H, Della-Fera MA, Baile CA. Review of myostatin history, physiology and applications. LifeXY 2001;1:1001–1013.
McPherron AC, Lee SJ. Suppression of body fat accumulation in myostatin-deficient mice. J Clin Invest 2002;109:595–601.
Lin J, Arnold HB, Della-Fera MA, Azain MJ, Hartzell DL, Baile CA. Myostatin knockout in mice increases myogenesis, and decreases adipogenesis. Biochem Biophys Res Commun 2002;291:701–706.
Zimmers TA, Davies MV, Koniaris LG, et al. Induction of cachexia in mice by systemically administered myostatin. Science 2002;296:1486–1488.
McPherron AC, Lee SJ. Double muscling in cattle due to mutations in the myostatin gene. Proc Natl Acad Sci USA 1997;94:12,457–12,461.
Kambadur R, Sharma M, Smith TP, Bass JJ. Mutations in myostatin (GDF8) in double-muscled Belgian Blue and Piedmontese cattle. Genome Res 1997;7:910–916.
Grobet L, Martin LJ, Poncelet D, et al. A deletion in the bovine myostatin gene causes the doublemuscled phenotype in cattle. Nat Genet. 1997;17:71–74.
Schuelke M, Wagner KR, Stolz LE, et al. Myostatin mutation associated with gross muscle hypertrophy in a child. N Engl J Med. 2004;350:2682–2688.
Derynck R, Jarrett JA, Chen EY, et al. Human transforming growth factor-β complementary DNA sequence and expression in normal and transformed cells. Nature 1985;316:701–705.
Wozney JM, Rosen V, Celeste AJ, et al. Novel regulators of bone formation: molecular clones and activities. Science 1988;242:1528–1534.
Thies RS, Chen T, Davies MV, et al. GDF-8 propeptide binds to GDF-8 and antagonizes biological activity by inhibiting GDF-8 receptor binding. Growth Factors 2001;18:251–259.
Lee SJ, McPherron AC. Regulation of myostatin activity and muscle growth. Proc Natl Acad Sci USA 2001;98:9306–9311.
Jiang MS, Liang LF, Wang S, et al. Characterization and identification of the inhibitory domain of GDF-8 propeptide. Biochem Biophys Res Commun 2004;315:525–531.
Thomad G. Furin at the cutting edge: from protein traffic to embryogenesis and disease. Nat Rev Mol Cell Biol. 2002;3:753–766.
McFarlane C, Langley B, Thomas A, et al. Proteolytic processing of myostatin is auto-regulated during myogenesis. Dev Biol 2005;283:58–69.
Hill JJ, Davies MV, Pearson AA, et al. The myostatin propeptide and the follistatin-related gene are inhibitory binding proteins of myostatin in normal serum. J Biol Chem 2002;277:40,735–40,741.
Hill JJ, Qiu Y, Hewick RM, Wolfman NM. Regulation of myostatin in vivo by growth and differentiation factor-associated serum protein-1: A novel protein with protease inhibitor and follistatin domains. Mol Endocrinol 2003;17:1144–1154.
Nicholas G, Thomas M, Lasngley B, et al. Titin-cap associates with, and regulates secretion of, Myostatin. J Cell Physiol 2002;193:120–131.
Wang H, Zhang Q, Zhu D. hSGT interacts with the N-terminal region of myostatin. Biochem Biophys Res Commun 2003;311:877–883.
Wolfman NM, McPherron AC, Pappano WN, et al. Activation of latent myostatin by the BMP-1/tolloid family of metalloproteinases. Proc Natl Acad Sci USA 2003; 100:15,842–15,846.
Zhang Y, Derynck R. Regulation of Smad signalling by protein associations and signalling crosstalk. Trends Cell Biol 1999;9:274–279.
Massagué J, Wotton D. Transcriptional control by the TGF-beta/Smad signaling system. EMBO J 2000;19:1745–1754.
Roberts AB. The ever-increasing complexity of TGF-beta signaling. Cytokine Growth Factor Rev 2002;13:3–5.
Mehra A, Wrana JL. TGF-beta and the Smad signal transduction pathway. Biochem Cell Bio 2002; 180:605–622.
Franzen P, ten Dijke P, Ichijo H, et al. Cloning of a TGF beta type I receptor that forms a heteromeric complex with the TGF beta type II receptor. Cell 1993;75:681–692.
Nakao A, Imamura T, Souchelnytskyi S, et al. TGF-beta receptor-mediated signalling through Smad2, Smad3 and Smad4. EMBO J 1997;16:5353–5362.
Roberts AB. TGF-beta signaling from receptors to the nucleus. Microbes Infect 1999;1:1265–1273.
Dennler S, Itoh S, Vivien D, ten Dijke P, Huet S, Gauthier JM. Direct binding of Smad3 and Smad4 to critical TGF beta-inducible elements in the promoter of human plasminogen activator inhibitor-type 1 gene. EMBO J 1998;17:3091–3100.
Feng XH, Lin X, Derymck R. Smad2, Smad3 and Smad4 cooperate with Sp1 to induce p15(Ink4B) transcription in response to TGF-beta. EMBO J 2000;19:5178–5193.
Attisano L, Wrana JL. Smads as transcriptional co-modulators. Curr Opin Cell Biol 2000;12:235–243.
Hoodless PA, Haerry T, Abdollah S, et al. MADR1, a MAD-related protein that functions in BMP2 signaling pathways. Cell 1996;85:489–500.
Liu F, Hata A, Baker JC, et al. A human Mad protein acting as a BMP-regulated transcriptional activator. Nature 1996;381:620–623.
Imamura T, Takase M, Nishihara A, et al. Smad6 inhibits signalling by the TGF-beta superfamily. Nature 1997;389:622–626.
Zhao H, Shi W, Chen H, Warburton D. Smad7 and Smad6 differentially modulate transforming growth factor beta-induced inhibition of embryonic lung morphogenesis. J Biol Chem. 2000;275: 23,992–23,997.
Chen Y, Lebrun JJ, Vale W. Regulation of transforming growth factor beta-and activin-induced transcription by mammalian Mad proteins. Proc Natl Acad Sci USA 1996;93:12,992–12,997.
Hata A, Lagna G, Massagué J, Hemmati P, Hemmati-Brivanlou A. Smad6 inhibits BMP/Smad1 signaling by specifically competing with the Smad4 tumor suppressor. Genes Dev 1998;12:186–197.
Ishisaki A, Yamato K, Hashimoto S, et al. Differential inhibition of Smad6 and Smad7 on bone morphogenetic protein-and activin-mediated growth arrest and apoptosis in B cells. J Biol Chem 1999;274:13637–13642.
Nakao A, Afrakhte M, Moren A, et al. Identification of Smad7, a TGFbeta-inducible antagonist of TGF-beta signalling. Nature 1997;389:631–635.
Hayashi H, Abdollah S, Qiu Y, et al. The MAD-related protein Smad7 associates with the TGFbeta receptor and functions as an antagonist of TGFbeta signaling. Cell 1997;89:1165–1173.
Ishisaki A, Yamato K, Nakao A, et al. Smad7 is an activin-inducible inhibitor of activin-induced growth arrest and apoptosis in mouse B cells. J Biol Chem 1998;273:24,293–24,296.
Rebbapragada A, Benchabane H, Wrana JL, Celeste AJ, Attisano L. Myostatin signals through a transforming growth factor beta-like signaling pathway to block adipogenesis. Mol Cell Biol 2003; 20:7230–7242.
Muenster U, Harrison CA, Donaldson C, Vale W, Fisher WH. An activin-A/C chimera exhibits activin and myostatin antagonistic properties. J Biol Chem 2005;280:36,623–36,632.
Philip B, Lu Z, Gao Y. Regulation of GDF-8 signaling by the p38 MAPK. Cell Signal 2005;17:365–375.
Zhu X, Liang LF, Stotish RL. Unpublished data.
Zhu X, Topouzis S, Liang LF, Stotish RL. Myostatin signaling through Smad2, Smad3 and Smad4 is regulated by the inhibitory Smad7 by a negative feedback mechanism. Cytokine 2004;26:262–272.
von Gersdorff G, Susztak K, Rezvani F, Bitzer M, Liang D, Bottinger EP. Smad3 and Smad4 mediate transcriptional activation of the human Smad7 promoter by transforming growth factor beta. J Biol Chem 2000;275:11,320–11,326.
Suzuki C, Murakami G, Fukuchi M, et al. Smurf1 regulates the inhibitory activity of Smad7 by targeting Smad7 to the plasma membrane. J Biol Chem 2002;277:39,919–39,925.
Tajima Y, Goto K, Yoshida M, et al. Chromosomal region maintenance 1 (CRM1)-dependent nuclear export of Smad ubiquitin regulatory factor 1 (Smurf1) is essential for negative regulation of transforming growth factor-beta signaling by Smad7. J Biol Chem 2003;278:10,716–10,721.
Moustakas A, Heldin C-H. Non-Smad TGF-beta signals. J Cell Sci 2005;118:3573–3584.
Edlund S, Landstrom M, Heldin C-H, Aspenstrom P. Transforming growth factor-beta-induced mobilization of actin cytoskeleton requires signaling by small GTPases Cdc42 and RhoA. Mol Biol Cell 2002;13:902–914.
Edlund S, Bu S, Schuster N, et al. Transforming growth factor-beta1 (TGF-beta)-induced apoptosis of prostate cancer cells involves Smad7-dependent activation of p38 by TGF-beta-activated kinase 1 and mitogen-activated protein kinase kinase. Mol Biol Cell 2002;14:529–544.
Engel ME, MaDonnell MA, Law RK, Moses HL. Interdependent SMAD and JNK signaling in transforming growth factor-beta-mediated transcription. J Biol Chem 1999;274:37,413–37,420.
Yue J, Mulder KM. Activation of the mitogen-activated protein kinase pathway by transforming growth factor-beta. Methods Mol Biol. 2000;142:125–131.
Guicheux J, Lemonnier J, Ghayor C, et al. Activation of p38 mitogen-activated protein kinase and c-Jun-NH2-terminal kinase by BMP-2 and their implication in the stimulation of osteoblastic cell differentiation. J Bone Miner Res 2003;11:2060–2068.
Hanafusa H, Ninomiya-Tsuji J, Masuyama N, et al. Involvement of the p38 Mitogen-activated protein kinase pathway in transformation growth factor-β induced gene expression. J Biol Chem 1999;274:27,161–27,167.
Ichikawa K, Nagase T, Ishii S, Asano A, Mimura N. Trans-regulation of myogenin promoter/enhancer activity by c-ski during skeletal-muscle differentiation: the C-terminus of the c-Ski protein is essential for transcriptional regulatory activity in myotubes. Biochem J 1997;328:607–613.
Heyman HC, Stavnezer E. A carboxyl-terminal region of the ski oncoprotein mediates homodimerization as well as heterodimerization with the related protein SnoN. J Biol Chem 1994;269: 26,996–27,003.
Nomura N, Sasamoto S, Ishii S, Date T, Matsui M, Ishizki R. Isolation of human cDNA clones of ski and the ski-related gene, sno. Nucleic Acids Res 1989;17:5489–5500.
Liberati NT, Noniwa M, Borton AJ, Davie JR, Wang XF. An essential role for Mad homology domain 1 in the association of Smad3 with histone deacetylase activity. J Biol Chem 2001;276: 22,595–22,603.
Cohen SB, Nicol R, Stavnezer E. A domain necessary for the transforming activity of SnoN is required for specific DNA binding, transcriptional repression and interaction with TAF(II)110. Oncogene 1998;17:2505–2513.
He J, Tegen SB, Krawitz AR, Matin GS, Luo K. The transforming activity of Ski and SnoN is dependent on their ability to repress the activity of Smad proteins. J Biol Chem 2003;278:30,540–30,547.
Macias-Silva M, Li W, Liu JI, Crissey MA, Tauh R. Up-regulated transcriptional repressors SnoN and Ski bind Smad proteins to antagonize transforming growth factor-beta signals during liver regeneration. J Biol Chem 2002;277:28,483–28,490.
Liu X, Sun Y, Weinberg RA, Lodish HF. Ski/Sno and TGF-beta signaling. Cytokine Growth Factor Rev 2001;12:1–8.
Berk M, Desal SY, Heyman HC, Colmanares C. Mice lacking the ski proto-oncogene have defects in neurulation, craniofacial patterning, and skeletal muscle development. Genes Dev 1997;16: 2029–2039.
Sutrave P, Kelly AM, Hughes, SH, Ski can cause selective growth of skeletal muscle in transgenic mice. Genes Dev 1990;4:1462–1472.
Reed JA, Lin Q, Chen D, Main IS, Medrano EE. SKI pathways inducing progression of human melanoma. Cancer Metastasis Rev 2005;242:265–272.
Luo K. Ski and SnoN: negative regulators of TGF-beta signaling. Curr Opin Genet Dev. 2004;14:65–70.
Wagner KR, McPherron AC, Winik N, Lee SJ. Loss of myostatin attenuates severity of muscular dystrophy in mdx mice. Ann Neurol 2002;52:832–836.
Wagner KR, Liu X, Chang X, Aleen RE. Muscle regeneration in the prolonged absence of myostatin. Proc Natl Acad Sci USA 2005;102:2519–2524.
Langley B, Thomas M, Bishop A, Shama M, Gilmour S, Karnbadur R. Myostatin inhibits myoblast differentiation by down-regulating MyoD expression. J Biol Chem 2002;277:49,831–49,840.
Thomas M, Langley B, Berry C, Shama M, Karnbadur R. Myostatin, a negative regulator of muscle growth, functions by inhibiting myoblast proliferation. J Biol Chem 2000;275:40,235–40,243.
Sharma M, Langley B, Bass J, Karnbadur R. Myostatin in muscle growth and repair. Exerc Sport Sci Rev 2001;29:155–158.
Gonzalez-Cadavid NF, Bhasin S. Role of myostatin in metabolism. Curr Opin Clin Nut Metab Care 2004;7:451–457.
Zhao B, Wall RJ, Yang J. Transgenic expression of myostatin propeptide prevents diet-induced obesity and insulin resistance. Biochem Biophys Res Commun 2005;337:248–255.
Yang J, Ratovitski T, Brady JP, Solomon MB, Wells KD, Wall TJ. Expression of myostatin pro domain results in muscular transgenic mice. Mol Reprod Dev 2001;60:351–361.
Hogan BL. Bone morphogenetic proteins in development. Curr Opin Genet Dev 1996;4:432–438.
Hoffman A, Gross G. BMP signaling pathways in cartilage and bone formation. Crit Rev Eukaryot Gene Expr 2001;11:23–45. Review.
Merlino G, Helmon LJ. Rhabdomyosarcoma—working out the pathways. Oncogene 1999;18: 5340–5348.
Dagher R, Helmon LJ. Rhabdomyosarcoma: an overview. Oncologist 1999;4:34–44.
Bouche M, Senni MI, Grossi AM, et al. TPA-induced differentiation of human rhabdomyosarcoma cells: expression of the myogenic regulatory factors. Exp Cell Res. 1993;208(1):209–217.
Langley B, Thomas M, McFarlane C, Gilmour S, Shama M, Karnbadur R. Myostatin inhibits rhabdomyosarcoma cell proliferation through an Rb-independent pathway. Oncogene 2004;23: 524–534.
Ricaud S, Vernus B, Duclos M, et al. Inhibition of autocrine secretion of myostatin enhances terminal differentiation in human rhabdomyosarcoma cells. Oncogene 2003;22:8221–8232.
Author information
Authors and Affiliations
Rights and permissions
Copyright information
© 2008 Humana Press
About this chapter
Cite this chapter
Zhu, X., Liang, Lf., Stotish, R.L. (2008). Myostatin Signaling in Normal and Tumor Cells. In: Transforming Growth Factor-β in Cancer Therapy, Volume I. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1007/978-1-59745-292-2_32
Download citation
DOI: https://doi.org/10.1007/978-1-59745-292-2_32
Publisher Name: Humana Press
Print ISBN: 978-1-58829-714-3
Online ISBN: 978-1-59745-292-2
eBook Packages: MedicineMedicine (R0)