Myostatin

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Myostatin
Other names: GDF-8, Myostatin
Genetic data
Locus: Chr. 2 q32.2
Gene code: HUGO: GDF8
Protein Structure/Function
Protein type: TGF beta superfamily
Functions: Negative regulator of skeletal muscle growth
Domains: TGFβ domain
Other
Taxa expressing: Homo sapiens; homologs: many metazoan phyla
Cell types: many, skeletal muscle
Subcellular localization: Extracellular
Medical/Biotechnological data
Diseases: Muscle hypertrophy
Database Links
Entrez: 2660
OMIM: 601788
RefSeq: NM_005259
UniProt: O14793


Myostatin (formerly known as Growth differentiation factor 8) is a growth factor that limits muscle tissue growth, i.e. higher concentrations of myostatin in the body may cause the individual to have less developed muscles. The myostatin protein is produced primarily in skeletal muscle cells, circulates in the blood and lymph and acts on muscle tissue, apparently by slowing down the development of muscle stem cells. The precise mechanism remains unknown. Its functions in non-mammalian vertebrates appear to be somewhat conserved as muscle-specific actions have been demonstrated in birds. However, it is produced in many different fish tissues, suggesting that it may regulate more than just muscle mass in these vertebrates.

Contents

[edit] Discovery and sequencing

Myostatin and the associated gene were discovered in 1997 by geneticists Alexandra McPherron and Se-Jin Lee, who also produced a strain of mutant mice that lack the gene and have about twice as much muscle as normal mice.[1] These mice were subsequently named "mighty mice". The gene has been sequenced in humans, mice, several other mammals and many different fish species, most of which are current or potential cultivars. The primary coding sequence is highly conserved among all vertebrates [2] as is the genomic organization [3]. These and other recent studies also indicate that the myostatin gene in fish has been duplicated as most fish species possess two distinct myostatin genes (MSTN-1 & -2) while salmonids have four (MSTN-1a, -1b, -2a & -2b) [4][5][6] This further suggests that the physiological and developmental aspects of myostatin biology may be quite different from that in mammals.

[edit] Effects of inactivated myostatin

Lee and others found in 1997 that the double muscled cattle breeds Belgian Blue and Piedmontese have defective myostatin genes; these strains have been produced through breeding. [7][8][9]

In 2004, a German boy was diagnosed with a mutation in both copies of the myostatin-producing gene, making him considerably stronger than his peers. His mother, a former sprinter, has a mutation in one copy of the gene.[10][11][12][13][14][15] An American boy born in 2005 was diagnosed with the same condition.[16]

[edit] Biochemistry

Myostatin is a member of the TGF beta superfamily of proteins.

Human myostatin consists of two identical subunits, each consisting of 110 amino acid residues. Its total molecular weight is 25.0 kDa. It can be produced in genetically engineered E. coli or eukaryotic cells and the recombinant protein from both sources is commercially available. However, due to the unique manner by which the mature protein is processed, there is considerable doubt as to the effectiveness of myostatin generated in E. coli.

[edit] Performance enhancement in dogs

A "bully whippet" with a homozygous mutation in myostatin. Image from
A "bully whippet" with a homozygous mutation in myostatin. Image from[17]

A 2007 NIH study in PLOS Genetics[17] found a significant relationship in whippets between a myostatin mutation and racing performance. Whippets that were heterozygous for a 2 base pair deletion in myostatin were significantly over-represented in the top racing classes. Whippets with a homozygous deletion were apparently less able runners although their overall appearance was significantly more muscular. The 2 base pair mutation resulted in a truncated myostatin mRNA, likely resulting in an inactive form of myostatin.

Interestingly, whippets with the homozygous deletion also had an unusual body shape, with a broader head, pronounced overbite, shorter legs, and thicker tails. These whippets have also been called "bully whippets" by the breeding community due to their size, but not their temperament.

This particular mutation was not found in other muscular dog breeds such as boxers and mastiffs, nor was it found in other slight hounds such as greyhounds, Italian greyhounds, or Afghan hounds. The authors of the study suggest that myostatin mutation may not be desirable in greyhounds, the whippets' nearest relative, because greyhound racing requires more significant endurance due to the longer races (900 meters for greyhounds vs. 300 meters for whippets).

[edit] Potential clinical significance

Further research into myostatin and the myostatin gene may lead to therapies for muscular dystrophy.[18] The idea is to introduce substances that block myostatin. In 2002, researchers at the University of Pennsylvania showed that monoclonal antibody specific to myostatin improves the condition of mice with muscular dystrophy, presumably by blocking myostatin's action.

In 2005, Lee showed that a two-week treatment of normal mice with soluble activin type IIB receptor, a molecule that is normally attached to cells and binds to myostatin, leads to a significantly increased muscle mass (up to 60%).[19] It is thought that binding of myostatin to the soluble activin receptor prevents it from interacting with the cell-bound receptors.

It remains unclear whether long term treatment of muscular dystropy with myostatin inhibitors is beneficial: the depletion of muscle stem cells could worsen the disease later on.

As of 2005, no myostatin-inhibiting drugs for humans are on the market, but an antibody genetically engineered to neutralize myostatin was developed by New Jersey pharmaceutical company Wyeth.[20] The inhibitor is called MYO-029 and recently underwent testing however the results have not yet been made public.[21][22][23] Some athletes, eager to get their hands on such drugs, turn to the internet, where fake "myostatin blockers" are being sold.

Johns Hopkins University has developed a technique for detecting mutations in myostatin variants. [24]

[edit] See also

[edit] References

  1. ^ McPherron AC, Lawler AM, Lee SJ. Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member. Nature 1997;387:83-90. PMID 9139826.
  2. ^ Rodgers and Weber. "Sequence conservation among fish myostatin orthologues and the characterization of two additional cDNA clones from Morone saxatilis and Morone americana." Comp Biochem Physiol B Biochem Mol Biol 2001;129(2-3):597-603. PMID 11399495.
  3. ^ Garikipati DK, Gahr SA, Roalson EH, Rodgers BD. "Characterization of rainbow trout myostatin-2 genes (rtMSTN-2a and -2b): genomic organization, differential expression, and pseudogenization." Endocrinology 2007;148(5):2106-15. PMID 17289851.
  4. ^ Kerr T, Roalson EH, Rodgers BD. "Phylogenetic analysis of the myostatin gene sub-family and the differential expression of a novel member in zebrafish." Evol Dev 2005;7(5):390-400. PMID 16174033.
  5. ^ Rodgers BD, Roalson EH, Weber GM, Roberts SB, Goetz FW. "A proposed nomenclature consensus for the myostatin gene family." Am J Physiol Endocrinol Metab 2007;292(2):E371-2. PMID 17003236.
  6. ^ Garikipati DK, Gahr SA, Rodgers BD. "Identification, characterization, and quantitative expression analysis of rainbow trout myostatin-1a and myostatin-1b genes." J Endocrinol 2006;190(3):879-88. PMID 17003288.
  7. ^ Photos of double muscled Myostatin inhibited Belgian Blue Bulls
  8. ^ Kambadur R, Sharma M, Smith T, Bass J (1997). "Mutations in myostatin (GDF8) in double-muscled Belgian Blue and Piedmontese cattle". Genome Res 7 (9): 910-6. PMID 9314496. 
  9. ^ McPherron A, Lee S (1997). "Double muscling in cattle due to mutations in the myostatin gene". Proc Natl Acad Sci U S A 94 (23): 12457-61. doi:10.1073/pnas.94.23.12457. PMID 9356471. 
  10. ^ cevgenetica: Gene Mutation Makes German Boy Extra Strong Muscle Baby
  11. ^ Gina Kolota: A Very Muscular Baby Offers Hope Against Diseases, The New York Times, June 24, 2004. (Requires login)
  12. ^ Genetic mutation turns tot into superboy
  13. ^ Muscle Boy
  14. ^ One Strong Tyke: Gene mutation in muscular boy may hold disease clues
  15. ^ Schuelke M, Wagner K, Stolz L, Hübner C, Riebel T, Kömen W, Braun T, Tobin J, Lee S (2004). "Myostatin mutation associated with gross muscle hypertrophy in a child". N Engl J Med 350 (26): 2682-8. doi:10.1056/NEJMoa040933. PMID 15215484. 
  16. ^ "Rare condition gives toddler super strength"
  17. ^ a b Mosher DS, Quignon P, Bustamante CD, Sutter NB, Mellersh CS, et al. A Mutation in the Myostatin Gene Increases Muscle Mass and Enhances Racing Performance in Heterozygote Dogs. PLOS Genetics 2007;PLoS Genetics, e79.eor doi:10.1371/journal.pgen.0030079.eor.
  18. ^ Kate Ruder: Strong Boy Could Benefit Research on Muscular Dystrophy, Genome News Network, June 24, 2004.
  19. ^ Lee SJ et al. Regulation of muscle growth by multiple ligands signaling through activin type II receptors. Proc Natl Acad Sci U S A. Dec 5, 2005. PMID 16330774
  20. ^ 2/23/05 Wyeth MYO-029 press release
  21. ^ FDA's record on the MYO-029 Myostatin Inhibor Trial is NCT00104078
  22. ^ Medical News Today press article about the Myostatin Inhibtor trial
  23. ^ MDA Research | Wyeth Analyzing MYO-029 Results
  24. ^ http://www.patentstorm.us/patents/6673534-fulltext.html Methods for detection of mutations in myostatin variants

[edit] External links

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Cell signaling: TGF beta signaling pathway
TGF beta superfamily of ligands
TGF beta receptors
Transducers/SMAD
Ligand Inhibitors
Coreceptors
Other