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growth/differentiation factor-8; myostatin (GDF-8, MSTN)

Function: 1) negative regulator of skeletal muscle growth 2) may increase tendon strength & flexiblity [6] 3) binds to extracellular activin receptor 2B (ACTR2B) to induce intracellular activation of SMAD proteins, SMAD2 & SMAD3 4) propeptide of GDF8 binds to the mature homodimer to form a latent myostatin complex, thus regulates GDF8 activity by preventing the homodimer from binding to its target receptors 5) myostatin inhibits progression of muscle stem cells through the cell cycle [5] a) effect appears to be specific for type 2 muscle fiber stem cells b) upregulates CDKN1A (p21WAF1) c) supresses CDK2 expression d) inhibits phosphorylation of Rb protein e) may directly inhibit myogenic regulatory factor expression Structure: 1) homodimer, disulfide-linked 2) 26-kD mature glycoprotein 3) 89% sequence homology with GDF11 Compartment: secreted Expression: - expressed uniquely in human skeletal muscle - secreted into the plasma - occurs in both type 1 & type 2 muscle fibers - myostatin plasma levels decline with age in mice, rats, horses & sheep [7] Pathology: - myostatin deficiency [3] is associated with a) skeletal muscle hypertrophy b) increased metabolic rate c) enhanced muscle repair, rejuvenation d) diminished body fat e) no effect on cardiac muscle f) no known adverse effects - may cause tendon stiffness & brittleness [6] - age-related increases in serum myostatin inversely correlate with muscle mass, suggesting that myostatin may contribute to sarcopenia [5] - evidence of age-related loss of muscle mass in myostatin- null mutant mice, suggest myostatin is not the only mediator of sarcopenia - myostatin plasma levels decline with age in mice, rats, horses & sheep [7] - in patients with stable ischemic heart disease, higher GDF11/GDF8 (myostatin) levels are associated with lower risk of cardiovascular events & death [8] Comparative biology: - in mice, recombinant myostatin enhances repair & regeneration of both muscle & bone after musculoskeletal injury [9]

General

glycoprotein growth/differentiation factor (GDF) TGF-beta family protein

Properties

SIZE: MW = 43 kD entity length = 375 aa MOTIF: N-glycosylation site {N71} cysteine residue {C281} MODIFICATION: cysteine residue {C340} cysteine residue {C309} MODIFICATION: cysteine residue {C372} cysteine residue {C313} MODIFICATION: cysteine residue {C374} cysteine residue {C339} MODIFICATION: cysteine residue {C339} cysteine residue {C339} MODIFICATION: cysteine residue {C339} cysteine residue {C340} MODIFICATION: cysteine residue {C281} cysteine residue {C372} MODIFICATION: cysteine residue {C309} cysteine residue {C374} MODIFICATION: cysteine residue {C313}

Database Correlations

OMIM 601788 UniProt O14793 PFAM correlations Entrez Gene 2660 Kegg hsa:2660

References

  1. UniProt :accession O14793
  2. GeneReviews https://www.genecards.org/cgi-bin/carddisp.pl?gene=GDF8
  3. Rare condition gives toddler super strength Associated Press, May 30, 2007 http://www.netscape.com/viewstory/2007/06/02/rare-condition-gives-toddler-super-strength/?url=http%3A%2F%2Fwww.ctv.ca%2Fservlet%2FArticleNews%2Fstory%2FCTVNews%2F20070530%2Fstrong_toddler_070530%2F20070530%3Fhub%3DHealth&frame=true
  4. Saunders MA, Good JM, Lawrence EC, Ferrell RE, Li WH, Nachman MW. Human adaptive evolution at Myostatin (GDF8), a regulator of muscle growth. Am J Hum Genet. 2006 Dec;79(6):1089-97. Epub 2006 Oct 10. PMID: 17186467
  5. McKay BR et al Myostatin is associated with age-related human muscle stem cell dysfunction FASEB J March 7, 2012 PMID: 22403007
  6. No Authors Myostatin inhibitors may make injuries more likely Drug Trial News, January 23, 200 http://www.news-medical.net/news/2008/01/23/34633.aspx?page=2
  7. Poggioli T, Vujic A, Yang P et al Circulating Growth Differentiation Factor 11/8 Levels Decline with Age. Circ Res.. Oct 21, 2015 PMID: 26489925 http://circres.ahajournals.org/content/early/2015/10/21/CIRCRESAHA.115.307521.abstract
  8. Olson KA, Beatty AL, Heidecker B et al Association of growth differentiation factor 11/8, putative anti-ageing factor, with cardiovascular outcomes & overall mortality in humans: analysis of the Heart and Soul and HUNT3 cohorts. European Heart Journal. Aug 20, 2015 PMID: 26294790 http://eurheartj.oxfordjournals.org/content/early/2015/08/20/eurheartj.ehv385
  9. Hamrick MW, Arounleut P, Kellum E et al Recombinant myostatin (GDF-8) propeptide enhances the repair and regeneration of both muscle and bone in a model of deep penetrant musculoskeletal injury J Trauma. 2010 Sep;69(3):579-83. doi: 10.1097/TA.0b013e3181c451f4. PMID: 20173658 Free PMC Article