The Growth Factor Myostatin, a Key Regulator in Skeletal Muscle Growth and Homeostasis

Abstract

Skeletal muscle possesses the ability to both respond and adapt to changing environmental stimuli, leading to a set of metabolic and morphological adaptations, which allow it to better meet the energy demands of sustained physical activity. Great progress has been achieved over the past years by means of innovative molecular techniques, which has led to the discovery of new growth factors and the identification of molecular mechanisms involved in the regulation of muscle development. These findings provide new starting points to understand the molecular mechanisms involved in the adaptation of skeletal muscle to exercise training. One of these new identified growth factors is myostatin, a member of the transforming growth factor-β family of proteins that has been demonstrated to play a fundamental role in the regulation of skeletal muscle growth during embryogenesis. Blocking of the myostatin signalling transduction pathway by specific inhibitors and genetic manipulations has been shown to result in a dramatic increase of skeletal muscle mass. This review focuses on the importance of myostatin in mediating skeletal muscle homeostasis in response to training as well as during the progress of myogenic disease, like atrophy or dystrophy. Manipulations of myostatin signalling may be useful for agriculture applications, treatment of muscle diseases, inhibition of muscle atrophy and last but not least as life style drugs in antiaging therapies or manipulations of the muscle to fat ratio. Drugs with the ability to modulate myostatin signalling may have the potential to enhance physical performance in athletes and therefore they probably represent a new class of doping substances.

Key words

GDF-8 - muscle disease - doping abuse - exercise training

References

• 1 Arnold H, della-Ferra M A, Baile C A. Review of myostatin history, physiology and applications.  Int Arch Biosci. 2001;  1014-1022 (online available www.iabs.us)
• 2 Bass J, Oldham J, Sharma M, Kambadur R. Growth factors controlling muscle development.  Domest Anim Endocrinol. 1999;  17 191-197
• 3 Bogdanovich S, Krag T O, Barton E R, Morris L D, Whittemore L A, Ahima R S, Khurana T S. Functional improvement of dystrophic muscle by myostatin blockade.  Nature. 2002;  420 418-421
• 4 Bogdanovich S, Perkins K J, Krag T OB, Khurana T S. Therapeutics for Duchenne muscular dystrophy: current approaches and future directions.  J Mol Med. 2004;  82 102-115
• 5 Carlson C J, Booth F W, Gordon S E. Skeletal muscle myostatin mRNA expression is fiber-type specific and increases during hindlimb unloading.  Am J Physiol. 1999;  277 R601-R606
• 6 Charlier C, Coppieters W, Farnir F, Grobet L, Leroy P L, Michaux C, Mni M, Schwers A, Vanmanshoven P, Hanset R, Georges M. The mh gene causing double-muscling in cattle maps to bovine chromosome 2.  Mamm Genome. 1995;  6 788-792
• 7 Chu E. Bevacizumab targeted therapy: validation of angiogenesis as a key target for advanced colorectal cancer.  Clin Colorectal Cancer. 2004;  4 16-18
• 8 Fiems L O, Cottyn B G, Boucque C V. Effect of yeast supplementation on health, performance and rumen fermentation in beef bulls.  Arch Tierernähr. 1995;  47 295-300
• 9 Flück M, Hoppeler H. Molecular basis of skeletal muscle plasticity-from gene to form and function.  Rev Physiol Biochem Pharmacol. 2003;  146 159-216
• 10 Gonzalez-Cadavid N F, Taylor W E, Yarasheski K, Sinha-Hikim I, Ma K, Ezzat S, Shen R, Lalani R, Asa S, Mamita M, Nair G, Arver S, Bhasin S. Organization of the human myostatin gene and expression in healthy men and HIV-infected men with muscle wasting.  Proc Natl Acad Sci USA. 1998;  95 14938-14943
• 11 Grobet L, Martin L J, Poncelet D, Pirottin D, Brouwers B, Riquet J, Schoeberlein A, Dunner S, Menissier F, Massabanda J, Fries R, Hanset R, Georges M. A deletion in the bovine myostatin gene causes the double-muscled phenotype in cattle.  Nat Genet. 1997;  17 71-74
• 12 Groner B, Hartmann C, Wels W. Therapeutic antibodies.  Curr Mol Med. 2004;  4 539-547
• 13 Huet C, Li Z F, Liu H Z, Black R A, Galliano M F, Engvall E. Skeletal muscle cell hypertrophy induced by inhibitors of metalloproteases; myostatin as a potential mediator.  Am J Physiol. 2001;  281 C1624-C1634
• 14 Huygens W, Thomis M A, Peeters M W, Aerssens J, Janssen R, Vlietinck R F, Beunen G. Linkage of myostatin pathway genes with knee strength in humans.  Physiol Genomics. 2004;  17 264-270
• 15 Ivey F M, Roth S M, Ferrell R E, Tracy B L, Lemmer J T, Hurlbut D E, Martel G F, Siegel E L, Fozard J L, Jeffrey Metter E, Fleg J L, Hurley B F. Effects of age, gender, and myostatin genotype on the hypertrophic response to heavy resistance strength training.  J Gerontol A Biol Sci Med Sci. 2000;  55 M641-M648
• 16 Kawada S, Tachi C, Ishii N. Content and localization of myostatin in mouse skeletal muscles during aging, mechanical unloading and reloading.  J Muscle Res Cell Motil. 2001;  22 627-633
• 17 Khurana T S, Davies K E. Pharmacological strategies for muscular dystrophy.  Nat Rev Drug Discov. 2003;  2 379-390
• 18 Kirk S, Oldham J, Kambadur R, Sharma M, Dobbie P, Bass J. Myostatin regulation during skeletal muscle regeneration.  J Cell Physiol. 2000;  184 356-363
• 19 Kocamis H, Killefer J. Myostatin expression and possible functions in animal muscle growth.  Domest Anim Endocrinol. 2002;  23 447-454
• 20 Lalani R, Bhasin S, Byhower F, Tarnuzzer R, Grant M, Shen R, Asa S, Ezzat S, Gonzalez-Cadavid N F. Myostatin and insulin-like growth factor-I and -II expression in the muscle of rats exposed to the microgravity environment of the NeuroLab space shuttle flight.  J Endocrinol. 2000;  167 417-428
• 21 Langley B, Thomas M, Bishop A, Sharma M, Gilmour S, Kambadur R. Myostatin inhibits myoblast differentiation by down-regulating MyoD expression.  J Biol Chem. 2002;  277 49831-49840
• 22 Lee S J, McPherron A C. Myostatin and the control of skeletal muscle mass.  Curr Opin Genet Dev. 1999;  9 604-607
• 23 Lee S J, McPherron A C. Regulation of myostatin activity and muscle growth.  Proc Natl Acad Sci USA. 2001;  98 9306-9311
• 24 Liu W, Thomas S G, Asa S L, Gonzalez-Cadavid N, Bhasin S, Ezzat S. Myostatin is a skeletal muscle target of growth hormone anabolic action.  J Clin Endocrinol Metab. 2003;  88 5490-5496
• 25 Ma K, Mallidis C, Bhasin S, Mahabadi V, Artaza J, Gonzalez-Cadavid N, Arias J, Salehian B. Glucocorticoid-induced skeletal muscle atrophy is associated with upregulation of myostatin gene expression.  Am J Physiol. 2003;  285 E363-E371
• 26 Mallory A C, Vaucheret H. MicroRNAs: something important between the genes.  Curr Opin Plant Biol. 2004;  7 120-125
• 47 Matsakas A, Friedel A, Hertrampf T, Diel P. Short-term endurance training results in a muscle-specific decrease of myostatin mRNA content in the rat.  Acta Physiol Scand. 2005;  (in press)
• 27 McPherron A C, Lawler A M, Lee S J. Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member.  Nature. 1997;  387 83-90
• 28 McPherron A C, Lee S J. Double muscling in cattle due to mutations in the myostatin gene.  Proc Natl Acad Sci USA. 1997;  94 12457-12461
• 29 McPherron A C, Lee S J. Suppression of body fat accumulation in myostatin-deficient mice.  J Clin Invest. 2002;  109 595-601
• 30 Piek E, Heldin C H, Ten Dijke P. Specificity, diversity, and regulation in TGF-beta superfamily signaling.  FASEB J. 1999;  13 2105-2124
• 31 Ramazanov Z, Jimenez del Rio M, Ziegenfuss T. Sulfated polysaccharides of brown seaweed Cystoseira canariensis bind to serum myostatin protein.  Acta Physiol Pharmacol Bulg. 2003;  27 101-106
• 32 Reardon K A, Davis J, Kapsa R M, Choong P, Byrne E. Myostatin, insulin-like growth factor-1, and leukemia inhibitory factor mRNAs are upregulated in chronic human disuse muscle atrophy.  Muscle Nerve. 2001;  24 893-899
• 33 Rios R, Carneiro I, Arce V M, Devesa J. Myostatin is an inhibitor of myogenic differentiation.  Am J Physiol. 2002;  282 C993-C999
• 34 Rios R, Fernandez-Nocelos S, Carneiro I, Arce V M, Devesa J. Differential response to exogenous and endogenous myostatin in myoblasts suggests that myostatin acts as an autocrine factor in vivo.  Endocrinology. 2004;  145 2795-2803 (Epub 2004, Feb 19)
• 35 Roth S M, Martel G F, Ferrell R E, Metter E J, Hurley B F, Rogers M A. Myostatin gene expression is reduced in humans with heavy-resistance strength training: a brief communication.  Exp Biol Med. 2003;  228 706-709
• 36 Sakuma K, Watanabe K, Sano M, Uramoto I, Totsuka T. Differential adaptation of growth and differentiation factor 8/myostatin, fibroblast growth factor 6 and leukemia inhibitory factor in overloaded, regenerating and denervated rat muscles.  Biochim Biophys Acta. 2000;  1497 77-88
• 37 Schutze N. siRNA technology.  Mol Cell Endocrinol. 2004;  213 115-119
• 38 Sharma M, Kambadur R, Matthews K G, Somers W G, Devlin G P, Conaglen J V, Fowke P J, Bass J J. Myostatin, a transforming growth factor-beta superfamily member, is expressed in heart muscle and is upregulated in cardiomyocytes after infarct.  J Cell Physiol. 1999;  180 1-9
• 39 Sharma M, Langley B, Bass J, Kambadur R. Myostatin in muscle growth and repair.  Exerc Sport Sci Rev. 2001;  29 155-158
• 40 Smith T P, Lopez-Corrales N L, Kappes S M, Sonstegard T S. Myostatin maps to the interval containing the bovine mh locus.  Mamm Genome. 1997;  8 742-744
• 41 Thomas M, Langley B, Berry C, Sharma M, Kirk S, Bass J, Kambadur R. Myostatin, a negative regulator of muscle growth, functions by inhibiting myoblast proliferation.  J Biol Chem. 2000;  275 40235-40243
• 42 Walker K S, Kambadur R, Sharma M, Smith H K. Resistance training alters plasma myostatin but not IGF-1 in healthy men.  Med Sci Sports Exerc. 2004;  36 787-793
• 43 Wehling M, Cai B, Tidball J G. Modulation of myostatin expression during modified muscle use.  FASEB J. 2000;  14 103-110
• 44 Whittemore L A, Song K, Li X, Aghajanian J, Davies M, Girgenrath S, Hill J J, Jalenak M, Kelley P, Knight A, Maylor R, O'Hara D, Pearson A, Quazi A, Ryerson S, Tan X Y, Tomkinson K N, Veldman G M, Widom A, Wright J F, Wudyka S, Zhao L, Wolfman N M. Inhibition of myostatin in adult mice increases skeletal muscle mass and strength.  Biochem Biophys Res Commun. 2003;  300 965-971
• 45 Willoughby D S. Effects of heavy resistance training on myostatin mRNA and protein expression.  Med Sci Sports Exerc. 2004;  36 574-582
• 46 Wolfman N M, McPherron A C, Pappano W N, Davies M V, Song K, Tomkinson K N, Wright J F, Zhao L, Sebald S M, Greenspan D S, Lee S J. Activation of latent myostatin by the BMP-1/tolloid family of metalloproteinases.  Proc Natl Acad Sci USA. 2003;  100 15842-15846