- Myostatin
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Myostatin (also known as growth differentiation factor 8, abbreviated "GDF8") is a secreted TGF beta protein family member that inhibits muscle differentiation and growth. Myostatin is produced primarily in skeletal muscle cells, circulates in the blood and acts on muscle tissue, by binding a cell-bound receptor called the activin type II receptor.[1][2] In humans, myostatin is encoded by the MSTN gene.[3]
Animals lacking myostatin or animals treated with substances such as follistatin that block the binding of myostatin to its receptor have significantly larger muscles.[4]
Contents
Discovery and sequencing
The gene encoding myostatin was discovered in 1997 by geneticists Alexandra McPherron and Se-Jin Lee who also produced a strain of mutant mice that lack the gene. These myostatin "knockout" mice have approximately twice as much muscle as normal mice.[5] These mice were subsequently named "mighty mice".
Naturally occurring myostatin "nulls" have been identified in cattle, whippets, and humans; in each case the result is a dramatic increase in muscle mass. A mutation in the 3' UTR of the myostatin gene in Texel sheep creates target sites for the microRNAs miR-1 and miR-206. This is likely to cause the muscular phenotype of this breed of sheep.[6]
Effects of inactivated myostatin in cattle
After that discovery, several laboratories cloned and established the nucleotide sequence of a myostatin gene in two breeds of cattle Belgian Blue and Piedmontese, and found that these animals have mutations in that myostatin gene (various mutations in each breed) which in one way or another lead to absence of functional myostatin.[7] Unlike mice with a damaged myostatin gene, in these cattle breeds the muscle cells multiply rather than enlarge. People describe these cattle breeds as "double muscled", but the total increase in all muscles is no more than 40%.[8][9][10]
The double-muscle mutation in humans
Myostatin is active in muscles used for movement (skeletal muscles) both before and after birth. This protein normally restrains muscle growth, ensuring that muscles do not grow too large. Mutations that reduce the production of functional myostatin lead to an overgrowth of muscle tissue. Myostatin-related muscle hypertrophy has a pattern of inheritance known as incomplete autosomal dominance. People with a mutation in both copies of the MSTN gene in each cell (homozygotes) have significantly increased muscle mass and strength. People with a mutation in one copy of the MSTN gene in each cell (heterozygotes) also have increased muscle bulk, but to a lesser degree.
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.[11][12][13][14][15][16]
An American boy born in 2005 (Liam Hoekstra) was diagnosed with a clinically similar condition but with a somewhat different cause:[17] his body produces a normal level of functional myostatin, but because he is stronger and more muscular than most others his age, his doctor believes that a defect in his myostatin receptors prevents his muscle cells from responding normally to myostatin. Liam appeared on the television show World's Strongest Toddler.
Performance enhancement in dogs
A 2007 NIH study in PLOS Genetics[18] found a significant relationship in whippets between a myostatin mutation and racing performance. Whippets that were heterozygous for a 2 base pair deletion in the myostatin gene were significantly over-represented in the top racing classes. The mutation resulted in a truncated myostatin protein, likely resulting in an inactive form of myostatin.
Whippets with a homozygous deletion were apparently less able runners although their overall appearance was significantly more muscular. 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 sighthounds 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).
Biochemistry
Myostatin is a member of the TGF beta superfamily of proteins.
Human myostatin consists of two identical subunits, each consisting of 109 amino acid residues. Its total molecular weight is 25.0 kDa. The protein is made in an inactive form. For it to be activated, a protease cleaves the NH2-terminal, or "pro-domain" portion of the molecule, resulting in the now-active COOH-terminal dimer.
Myostatin binds to the activin type II receptor, resulting in a recruitment of a coreceptor called Alk-3 or Alk-4. This coreceptor then initiates a cell signaling cascade in the muscle, which includes the activation of transcription factors in the SMAD family - SMAD2 and SMAD3. These factors then induce myostatin-specific gene regulation. When applied to myoblasts, myostatin inhibits their differentiation into mature muscle fibers.
Recently, myostatin has also been shown to inhibit Akt, a kinase that is sufficient to cause muscle hypertrophy, in part through the activation of protein synthesis.
Therefore, myostatin acts in two ways, by inhibiting muscle differentiation and by inhibiting Akt-induced protein synthesis.
Clinical significance
Further research into myostatin and the myostatin gene may lead to therapies for muscular dystrophy.[19] 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, it is presumed, by blocking myostatin's action. Similar results in monkeys were published in 2009.[20]
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%).[21] It is thought that binding of myostatin to the soluble activin receptor prevents it from interacting with the cell-bound receptors.
It remains unclear as to whether long-term treatment of muscular dystrophy with myostatin inhibitors is beneficial: The depletion of muscle stem cells could worsen the disease later on.
As of 2009[update], 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.[22] The inhibitor is called MYO-029, but, after an initial clinical trial, Wyeth says they will not be developing the drug.[23] Some athletes, eager to get their hands on such drugs, turn to the internet, where fake "myostatin blockers" are being sold.[19]
Myostatin levels are effectively decreased by creatine supplementation.[24]
A technique for detecting mutations in myostatin variants has been developed.[25]
In fiction
A fictional drug called myostatin is featured in the TV series The Incredible Hulk episode "A Death in the Family" (Season 1, Episode 2). This episode came out about 20 years before real myostatin was discovered.
In the Japanese manga Air Gear, the two characters Akira Udou and Mitsuru Bandou have this condition.
See also
References
- ^ Carnac G, Ricaud S, Vernus B, Bonnieu A (July 2006). "Myostatin: biology and clinical relevance". Mini Rev Med Chem 6 (7): 765–70. doi:10.2174/138955706777698642. PMID 16842126.
- ^ Joulia-Ekaza D, Cabello G (June 2007). "The myostatin gene: physiology and pharmacological relevance". Curr Opin Pharmacol 7 (3): 310–5. doi:10.1016/j.coph.2006.11.011. PMID 17374508.
- ^ Gonzalez-Cadavid NF, Taylor WE, Yarasheski K, Sinha-Hikim I, Ma K, Ezzat S, Shen R, Lalani R, Asa S, Mamita M, Nair G, Arver S, Bhasin S (December 1998). "Organization of the human myostatin gene and expression in healthy men and HIV-infected men with muscle wasting". Proc. Natl. Acad. Sci. U.S.A. 95 (25): 14938–43. Bibcode 1998PNAS...9514938G. doi:10.1073/pnas.95.25.14938. PMC 24554. PMID 9843994. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=24554.
- ^ Kota J, Handy CR, Haidet AM, Montgomery CL, Eagle A, Rodino-Klapac LR, Tucker D, Shilling CJ, Therlfall WR, Walker CM, Weisbrode SE, Janssen PML, Clark KR, Sahenk Z, Mendell JR, Kaspar BK (2009). "Follistatin Gene Delivery Enhances Muscle Growth and Strength in Nonhuman Primates". Science Translational Medicine 1 (6): 6ra15–6ra15. doi:10.1126/scitranslmed.3000112. PMC 2852878. PMID 20368179. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2852878.
- ^ McPherron AC, Lawler AM, Lee SJ (May 1997). "Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member". Nature 387 (6628): 83–90. Bibcode 1997Natur.387...83M. doi:10.1038/387083a0. PMID 9139826.
- ^ Clop A, Marcq F, Takeda H, Pirottin D, Tordoir X, Bibé B, Bouix J, Caiment F, Elsen JM, Eychenne F, Larzul C, Laville E, Meish F, Milenkovic D, Tobin J, Charlier C, Georges M (2006). "A mutation creating a potential illegitimate microRNA target site in the myostatin gene affects muscularity in sheep". Nat Genet 38 (7): 813–8. doi:10.1038/ng1810. PMID 16751773.
- ^ McPherron A., Lee S-J., 1997; Grobet L. et al., 1997; Kambadur R. et al., 1997
- ^ Photos of double muscled Myostatin, inhibited Belgian Blue Bulls
- ^ 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.
- ^ McPherron A, Lee S (1997). "Double muscling in cattle due to mutations in the myostatin gene". Proc Natl Acad Sci USA 94 (23): 12457–61. Bibcode 1997PNAS...9412457M. doi:10.1073/pnas.94.23.12457. PMC 24998. PMID 9356471. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=24998.
- ^ cevgenetica: Gene Mutation Makes German Boy Extra Strong Muscle Baby
- ^ Gina Kolota: A Very Muscular Baby Offers Hope Against Diseases, The New York Times, June 24, 2004. (Requires login)
- ^ Genetic mutation turns tot into superboy
- ^ Muscle Boy
- ^ One Strong Tyke: Gene mutation in muscular boy may hold disease clues
- ^ 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.
- ^ Associated Press (2007-05-30). "CTV.ca | Rare condition gives toddler super strength". CTVglobemedia. http://www.ctv.ca/servlet/ArticleNews/story/CTVNews/20070530/strong_toddler_070530/20070530. Retrieved 2009-01-21.
- ^ a b Mosher DS, Quignon P, Bustamante CD, Sutter NB, Mellersh CS, Parker HG, Ostrander EA (May 2007). "A Mutation in the Myostatin Gene Increases Muscle Mass and Enhances Racing Performance in Heterozygote Dogs". PLoS Genet. 3 (5): e79. doi:10.1371/journal.pgen.0030079. PMC 1877876. PMID 17530926. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1877876.
- ^ a b Kate Ruder: Strong Boy Could Benefit Research on Muscular Dystrophy, Genome News Network, June 24, 2004.
- ^ http://www.npr.org/templates/story/story.php?storyId=120316010
- ^ Lee SJ, Reed LA, Davies MV, Girgenrath S, Goad ME, Tomkinson KN, Wright JF, Barker C, Ehrmantraut G, Holmstrom J, Trowell B, Gertz B, Jiang MS, Sebald SM, Matzuk M, Li E, Liang LF, Quattlebaum E, Stotish RL, Wolfman NM (December 2005). "Regulation of muscle growth by multiple ligands signaling through activin type II receptors". Proc. Natl. Acad. Sci. U.S.A. 102 (50): 18117–22. Bibcode 2005PNAS..10218117L. doi:10.1073/pnas.0505996102. PMC 1306793. PMID 16330774. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1306793.
- ^ 2/23/05 Wyeth MYO-029 press release
- ^ 3/11/2008 Wyeth Won't Develop MYO-029 for MD
- ^ Saremi A, Gharakhanloo R, Sharghi S, Gharaati MR, Larijani B, Omidfar K (April 2010). "Effects of oral creatine and resistance training on serum myostatin and GASP-1". Mol. Cell. Endocrinol. 317 (1–2): 25–30. doi:10.1016/j.mce.2009.12.019. PMID 20026378.
- ^ US granted 6673534, Lee S-J, McPherron AC, "Methods for detection of mutations in myostatin variants", issued 2004-01-06, assigned to The Johns Hopkins University School of Medicine
External links
- GeneReviews profile
- NPR.org: Myostatin Therapies Hold Hope for Muscle Diseases by Jon Hamilton
- Times Colonist Big Wendy the muscular whippet
- MeSH myostatin
Cell signaling: TGF beta signaling pathway TGF beta superfamily of ligands TGF beta family (TGF-β1, TGF-β2, TGF-β3)
Bone morphogenetic proteins (BMP2, BMP3, BMP4, BMP5, BMP6, BMP7, BMP8a, BMP8b, BMP10 , BMP15)
Growth differentiation factors (GDF1, GDF2, GDF3, GDF5, GDF6, GDF7, Myostatin/GDF8, GDF9, GDF10, GDF11, GDF15)
Other (Activin and inhibin, Anti-müllerian hormone, Nodal)TGF beta receptors
(Activin, BMP)TGFBR1: Activin type 1 receptors (ACVR1, ACVR1B, ACVR1C) · ACVRL1 · BMPR1 (BMPR1A · BMPR1B)
TGFBR2: Activin type 2 receptors (ACVR2A, ACVR2B) · AMHR2 · BMPR2
TGFBR3: betaglycanTransducers/SMAD Ligand inhibitors Coreceptors Other SARACategories:- Human proteins
- Growth factors
- Muscular dystrophy
- TGFβ domain
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