View source for Myostatin

{{Infobox_gene}}
[[File:MSTN location.jpeg|thumb|In human, the MSTN gene is located on the long (q) arm of [[Chromosome 2 (human)|chromosome 2]] at position 32.2.<ref name=GHR-MSTN>{{cite web | url = https://ghr.nlm.nih.gov/gene/MSTN | title = MSTN gene | work = Genetics Home Reference | date =  28 March 2016 }}</ref>]]
'''Myostatin''' (also known as '''growth differentiation factor 8''', abbreviated '''GDF-8''') is a [[myokine]], a [[protein]] produced and released by [[myocyte]]s that acts on muscle cells' autocrine function to inhibit [[myogenesis]]: muscle cell growth and differentiation. In humans it is encoded by the ''MSTN'' [[gene]].<ref name="pmid9843994">{{cite journal | vauthors = 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 | title = Organization of the human myostatin gene and expression in healthy men and HIV-infected men with muscle wasting | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 25 | pages = 14938–43 | date = December 1998 | pmid = 9843994 | pmc = 24554 | doi = 10.1073/pnas.95.25.14938 | bibcode = 1998PNAS...9514938G }}</ref> Myostatin is a secreted [[growth differentiation factor]] that is a member of the [[transforming growth factor beta|TGF beta]] protein family.<ref name="pmid16842126">{{cite journal | vauthors = Carnac G, Ricaud S, Vernus B, Bonnieu A | title = Myostatin: biology and clinical relevance | journal = Mini Reviews in Medicinal Chemistry | volume = 6 | issue = 7 | pages = 765–70 | date = July 2006 | pmid = 16842126 | doi = 10.2174/138955706777698642 }}</ref><ref name="pmid17374508">{{cite journal | vauthors = Joulia-Ekaza D, Cabello G | title = The myostatin gene: physiology and pharmacological relevance | journal = Current Opinion in Pharmacology | volume = 7 | issue = 3 | pages = 310–5 | date = June 2007 | pmid = 17374508 | doi = 10.1016/j.coph.2006.11.011 }}</ref>

Animals either lacking myostatin or treated with substances that block the activity of myostatin have significantly more muscle mass.
Furthermore, individuals who have mutations in both copies of the myostatin gene have significantly more muscle mass and are stronger than normal. There is hope that studies into myostatin may have therapeutic application in treating muscle wasting diseases such as [[muscular dystrophy]].<ref name="pmid18600566"/>

==Discovery and sequencing==
The [[gene]] encoding myostatin was discovered in 1997 by geneticists Se-Jin Lee and Alexandra McPherron who produced a [[knockout mice|knockout]] strain of [[mus musculus|mice]] that lack the gene, and have approximately twice as much muscle as normal mice.<ref name="McPherron_1997">{{cite journal | vauthors = McPherron AC, Lawler AM, Lee SJ | title = Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member | journal = Nature | volume = 387 | issue = 6628 | pages = 83–90 | date = May 1997 | pmid = 9139826 | doi = 10.1038/387083a0 | bibcode = 1997Natur.387...83M }}</ref> These mice were subsequently named "mighty mice".

Naturally occurring deficiencies of myostatin of various sorts have been identified in some breeds of cattle,<ref name="Kambadur_1997">{{cite journal | vauthors = Kambadur R, Sharma M, Smith TP, Bass JJ | title = Mutations in myostatin (GDF8) in double-muscled Belgian Blue and Piedmontese cattle | journal = Genome Research | volume = 7 | issue = 9 | pages = 910–16 | date = September 1997 | pmid = 9314496 | doi=10.1101/gr.7.9.910}}</ref> sheep,<ref name="pmid16751773">{{cite journal | vauthors = 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 | title = A mutation creating a potential illegitimate microRNA target site in the myostatin gene affects muscularity in sheep | journal = Nature Genetics | volume = 38 | issue = 7 | pages = 813–18 | date = July 2006 | pmid = 16751773 | doi = 10.1038/ng1810 }}</ref> [[whippet]]s,<ref name=Mosher/> and humans.<ref name= avery/> In each case the result is a dramatic increase in muscle mass.

==Structure and mechanism of action==
{{one source|section|date=October 2015}}
Human myostatin consists of two identical subunits, each consisting of 109 (NCBI database claims human myostatin is 375 residues long) [[amino acid]] residues [note the full length gene encodes a 375AA prepro-protein which is proteolytically processed to its shorter active form].<ref>https://www.ncbi.nlm.nih.gov/protein/NP_005250.1{{full citation needed|date=January 2017}}</ref><ref>{{cite journal |vauthors=Ge G, Greenspan DS |title=Developmental roles of the BMP1/TLD metalloproteinases |journal=Birth Defects Research. Part C, Embryo Today |volume=78 |issue=1 |pages=47–68 |year=2006 |pmid=16622848 |doi=10.1002/bdrc.20060 }}</ref> Its total [[molecular mass|molecular weight]] is 25.0 k[[atomic mass unit|Da]]. The protein is inactive until a [[protease]] cleaves the NH2-terminal, or "pro-domain" portion of the molecule, resulting in the active COOH-terminal dimer. Myostatin binds to the [[Activin type 2 receptors|activin type II receptor]], resulting in a recruitment of either coreceptor  [[BMPR1A|Alk-3]] or [[ACVR1B|Alk-4]]. This coreceptor then initiates a [[cell signaling]] cascade in the [[muscle]], which includes the activation of [[transcription factor]]s in the [[SMAD (protein)|SMAD]] family - [[SMAD2]] and [[SMAD3]]. These factors then induce myostatin-specific [[regulation of gene expression|gene regulation]]. When applied to [[myoblasts]], myostatin inhibits their [[Cellular differentiation|differentiation]] into mature [[muscle fiber]]s.{{citation needed|date=October 2015}}

Myostatin also inhibits [[AKT|Akt]], a kinase that is sufficient to cause [[muscle hypertrophy]], in part through the activation of [[protein biosynthesis|protein synthesis]]. However, Akt is not responsible for all of the observed muscle hyperthrophic effects which are mediated by myostatin inhibition<ref>{{cite journal | vauthors = Sartori R, Gregorevic P, Sandri M | title = TGFβ and BMP signaling in skeletal muscle: potential significance for muscle-related disease | journal = Trends in Endocrinology and Metabolism | volume = 25 | issue = 9 | pages = 464–71 | date = September 2014 | pmid = 25042839 | doi = 10.1016/j.tem.2014.06.002 }}</ref> Thus myostatin acts in two ways: by inhibiting [[muscle]] [[cellular differentiation|differentiation]], and by inhibiting Akt-induced protein synthesis.

==Effects in animals==

===Double muscled cattle===
[[File:BlancBleuBelge.jpg|thumb|[[Belgian Blue]] 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 (cattle)|Piedmontese]]. They found mutations in the myostatin gene (various mutations in each breed) which in one way or another lead to absence of functional myostatin.<ref name="McPherron_1997"/><ref name="Kambadur_1997"/><ref name="Grobet_1997">{{cite journal | vauthors = Grobet L, Martin LJ, Poncelet D, Pirottin D, Brouwers B, Riquet J, Schoeberlein A, Dunner S, Ménissier F, Massabanda J, Fries R, Hanset R, Georges M | title = A deletion in the bovine myostatin gene causes the double-muscled phenotype in cattle | journal = Nature Genetics | volume = 17 | issue = 1 | pages = 71–74 | date = September 1997 | pmid = 9288100 | doi = 10.1038/ng0997-71 }}</ref> 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%.<ref name="Kambadur_1997"/><ref>[http://www.builtreport.com/bovine.html  Photos of double-muscled Myostatin-inhibited Belgian Blue bulls]</ref><ref>{{cite journal | vauthors = McPherron AC, Lee SJ | title = Double muscling in cattle due to mutations in the myostatin gene | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 94 | issue = 23 | pages = 12457–61 | date = November 1997 | pmid = 9356471 | pmc = 24998 | doi = 10.1073/pnas.94.23.12457 | bibcode = 1997PNAS...9412457M }}</ref>

Animals lacking myostatin or animals treated with substances such as [[follistatin]] that block the binding of myostatin to its receptor have significantly larger muscles. Thus, reduction of myostatin could potentially benefit the [[livestock|livestock industry]], with even a 20 percent reduction in myostatin levels potentially having a large effect on the development of muscles.<ref name="Kota_2009"/>

However, the animal breeds developed as [[homozygous]] for myostatin deficiency have [[Belgian Blue#Breed issues|reproduction issues]] due to their unusually heavy and bulky offspring, and require special care and a more expensive diet to achieve a superior yield. This negatively affects economics of myostatin-deficient breeds to the point where they do not usually offer an obvious advantage. While hypertrophic meat (e.g. from [[Piedmontese (cattle)#Piedmontese beef|Piedmontese beef]]) has a place on the specialist market due to its unusual properties, at least for purebred myostatin-deficient strains the expenses and (especially in cattle) necessity of veterinary supervision place them at a disadvantage in the bulk market.<ref name="De_Smet_2004">{{cite journal|vauthors=De Smet S|title=Double-Muscled Animals|year=2004|journal=Encyclopedia of Meat Sciences|pages=396–402|doi=10.1016/B0-12-464970-X/00260-9|editor=Jensen WK|publisher=Elsevier|location=Oxford, UK}}</ref>

===Whippets{{anchor|Whippets}}===
[[Image:MyostatinMutantWhippet.jpg|thumb|A "bully whippet" with a [[homozygous]] mutation in myostatin.<ref name="Mosher">{{cite journal | vauthors = Mosher DS, Quignon P, Bustamante CD, Sutter NB, Mellersh CS, Parker HG, Ostrander EA | title = A mutation in the myostatin gene increases muscle mass and enhances racing performance in heterozygote dogs | journal = PLoS Genetics | volume = 3 | issue = 5 | page = e79 | date = May 2007 | pmid = 17530926 | pmc = 1877876 | doi = 10.1371/journal.pgen.0030079 }}</ref>]]
 
[[Whippets]] can have a mutation of the myostatin which involves a two-base-pair deletion, and results in a truncated, and likely inactive, myostatin [[protein]].

Animals with a [[homozygous]] deletion have an unusual body shape, with a broader head, pronounced overbite, shorter legs, and thicker tails, and are called "bully whippets" by the breeding community. Although significantly more muscular, they are less able runners than other whippets. However, whippets that were [[heterozygous]] for the mutation were significantly over-represented in the top racing classes.<ref name=Mosher/>

=== Rabbits and Goats ===
In 2016, the CRISPR/Cas9 system was used to genetically engineer rabbits and goats with no functional copies of the myostatin gene.<ref>{{cite journal | vauthors = Guo R, Wan Y, Xu D, Cui L, Deng M, Zhang G, Jia R, Zhou W, Wang Z, Deng K, Huang M, Wang F, Zhang Y | title = Generation and evaluation of Myostatin knock-out rabbits and goats using CRISPR/Cas9 system | journal = Scientific Reports | volume = 6 | pages = 29855 | date = 2016-01-01 | pmid = 27417210 | pmc = 4945924 | doi = 10.1038/srep29855 | bibcode = 2016NatSR...629855G }}</ref>  In both cases the resulting animals were significantly more muscular.  However, rabbits without myostatin also exhibited an enlarged tongue, a higher rate of still births, and a reduced lifespan.

==Clinical significance==

===Mutations===
A technique for detecting mutations in myostatin variants has been developed.<ref>{{cite patent|country=US|number=6673534|status=patent|title=Methods for detection of mutations in myostatin variants|gdate=2004-01-06|inventor=Lee S-J, McPherron AC|assign1=The Johns Hopkins University School of Medicine}}</ref> Mutations that reduce the production of functional myostatin lead to an overgrowth of muscle tissue. Myostatin-related muscle hypertrophy has an incomplete autosomal [[Dominance (genetics)|dominance]] pattern of inheritance. People with a mutation in both copies of the ''MSTN'' gene in each [[Cell (biology)|cell]] ([[homozygote]]s) have significantly increased muscle mass and strength. People with a mutation in one copy of the ''MSTN'' gene in each cell ([[heterozygote]]s) have increased muscle bulk, but to a lesser degree.{{citation needed|date=October 2015}}

===In humans===
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 has a mutation in one copy of the gene.<ref name=avery>Gina Kolota. [https://www.nytimes.com/2004/06/24/science/24muscle.html "A Very Muscular Baby Offers Hope Against Diseases"], nytimes.com, June 24, 2004; accessed October 25, 2015.</ref><ref>[http://www.msnbc.msn.com/id/5278028 Genetic mutation turns tot into superboy], msnbc.msn.com; accessed October 25, 2015.</ref><ref>{{cite journal | vauthors = Schuelke M, Wagner KR, Stolz LE, Hübner C, Riebel T, Kömen W, Braun T, Tobin JF, Lee SJ | title = Myostatin mutation associated with gross muscle hypertrophy in a child | journal = The New England Journal of Medicine | volume = 350 | issue = 26 | pages = 2682–88 | date = June 2004 | pmid = 15215484 | doi = 10.1056/NEJMoa040933 }}</ref>

An American boy born in 2005 was diagnosed with a clinically similar condition, but with a somewhat different cause:<ref name="urlCTV.ca|Rare condition gives toddler super strength">{{cite web|url=http://www.ctv.ca/servlet/ArticleNews/story/CTVNews/20070530/strong_toddler_070530/20070530|title=Rare condition gives toddler super strength|author=Associated Press|date=2007-05-30|publisher=CTVglobemedia|accessdate=2009-01-21|deadurl=yes|archiveurl=https://web.archive.org/web/20090118080725/http://www.ctv.ca/servlet/ArticleNews/story/CTVNews/20070530/strong_toddler_070530/20070530|archivedate=2009-01-18|df=}}</ref> his body produces a normal level of functional myostatin, but because he is stronger and more muscular than most others his age, a defect in his [[activin type IIB receptor|myostatin receptor]]s is thought to prevent his muscle cells from responding normally to myostatin. He appeared on the television show ''World's Strongest Toddler''.{{citation needed|date=October 2015}} [https://www.google.com/search?q=%22World%27s+Strongest+Toddler%22&ie=utf-8&oe=utf-8&client=firefox-b Google search]

===Therapeutic potential===
Further research into myostatin and the myostatin gene may lead to therapies for [[muscular dystrophy]].<ref name="pmid18600566">{{cite journal | vauthors = Tsuchida K | title = Targeting myostatin for therapies against muscle-wasting disorders | journal = Current Opinion in Drug Discovery & Development | volume = 11 | issue = 4 | pages = 487–94 | date = July 2008 | pmid = 18600566 }}</ref><ref name="pmid15215484">{{cite journal | vauthors = Schuelke M, Wagner KR, Stolz LE, Hübner C, Riebel T, Kömen W, Braun T, Tobin JF, Lee SJ | title = Myostatin mutation associated with gross muscle hypertrophy in a child | journal = The New England Journal of Medicine | volume = 350 | issue = 26 | pages = 2682–88 | date = June 2004 | pmid = 15215484 | doi = 10.1056/NEJMoa040933 | laysummary = http://www.genomenewsnetwork.org/articles/2004/06/24/musclegene.php | laysource = Genome News Network }}</ref> The idea is to introduce substances that block myostatin. A [[monoclonal antibody]] specific to myostatin increases muscle mass in mice<ref name="pmid12559968">{{cite journal | vauthors = Whittemore LA, Song K, Li X, Aghajanian J, Davies M, Girgenrath S, Hill JJ, Jalenak M, Kelley P, Knight A, Maylor R, O'Hara D, Pearson A, Quazi A, Ryerson S, Tan XY, Tomkinson KN, Veldman GM, Widom A, Wright JF, Wudyka S, Zhao L, Wolfman NM | title = Inhibition of myostatin in adult mice increases skeletal muscle mass and strength | journal = Biochemical and Biophysical Research Communications | volume = 300 | issue = 4 | pages = 965–71 | date = January 2003 | pmid = 12559968 | doi = 10.1016/s0006-291x(02)02953-4 }}</ref> and monkeys.<ref name="Kota_2009">{{cite journal | vauthors = Kota J, Handy CR, Haidet AM, Montgomery CL, Eagle A, Rodino-Klapac LR, Tucker D, Shilling CJ, Therlfall WR, Walker CM, Weisbrode SE, Janssen PM, Clark KR, Sahenk Z, Mendell JR, Kaspar BK | title = Follistatin gene delivery enhances muscle growth and strength in nonhuman primates | journal = Science Translational Medicine | volume = 1 | issue = 6 | pages = 6ra15 | date = November 2009 | pmid = 20368179 | pmc = 2852878 | doi = 10.1126/scitranslmed.3000112 | laysummary = https://www.npr.org/templates/story/story.php?storyId=120316010 | laysource = National Public Radio }}</ref>

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%).<ref name="pmid16330774">{{cite journal | vauthors = 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 | title = Regulation of muscle growth by multiple ligands signaling through activin type II receptors | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 102 | issue = 50 | pages = 18117–22 | date = December 2005 | pmid = 16330774 | pmc = 1306793 | doi = 10.1073/pnas.0505996102 | bibcode = 2005PNAS..10218117L }}</ref> It is thought that binding of myostatin to the soluble activin receptor prevents it from interacting with the cell-bound receptors.{{citation needed|date=October 2015}}

It remains unclear as to whether long-term treatment of muscular dystrophy with myostatin inhibitors is beneficial, as the depletion of muscle [[Satellite cell|stem cells]] could worsen the disease later on. {{As of|2012}}, no myostatin-inhibiting drugs for humans are on the market. An antibody genetically engineered to neutralize myostatin, [[stamulumab]], which was under development by pharmaceutical company [[Wyeth]],<ref>[http://static.mda.org/research/051014bmd_myo-029.html MYO-029 press release], mda.org, February 23, 2005.</ref> is no longer under development.<ref>[http://static.mda.org/research/080311md_myo-029.html Wyeth Won't Develop MYO-029 for MD], mda.org, March 11, 2008.</ref> Some athletes, eager to get their hands on such drugs, turn to the internet where [[fake medicine|fake]] "myostatin blockers" are being sold.<ref name="Kota_2009"/>

Myostatin levels are effectively decreased by [[creatine]] supplementation.<ref name="pmid20026378">{{cite journal | vauthors = Saremi A, Gharakhanloo R, Sharghi S, Gharaati MR, Larijani B, Omidfar K | title = Effects of oral creatine and resistance training on serum myostatin and GASP-1 | journal = Molecular and Cellular Endocrinology | volume = 317 | issue = 1-2 | pages = 25–30 | date = April 2010 | pmid = 20026378 | doi = 10.1016/j.mce.2009.12.019 }}</ref>

Myostatin levels can be temporarily reduced using a cholesterol-conjugated siRNA gene knockdown.<ref>{{cite journal | vauthors = Khan T, Weber H, DiMuzio J, Matter A, Dogdas B, Shah T, Thankappan A, Disa J, Jadhav V, Lubbers L, Sepp-Lorenzino L, Strapps WR, Tadin-Strapps M | title = Silencing Myostatin Using Cholesterol-conjugated siRNAs Induces Muscle Growth | journal = Molecular Therapy: Nucleic Acids | volume = 5 | issue = 8 | pages = e342 | date = 2016-01-01 | pmid = 27483025 | doi = 10.1038/mtna.2016.55 | pmc=5023400}}</ref>

=== Athletic use ===
Inhibition of myostatin leads to muscle [[hyperplasia]] and [[hypertrophy]]. Myostatin inhibitors can improve athletic performance and therefore there is a concern these inhibitors might be abused in the field of sports.<ref name= "Haisma_2006">{{cite journal | vauthors = Haisma HJ, de Hon O | title = Gene doping | journal = International Journal of Sports Medicine | volume = 27 | issue = 4 | pages = 257–66 | date = April 2006 | pmid = 16572366 | doi = 10.1055/s-2006-923986 }}</ref> However, studies in mice suggest that myostatin inhibition does not directly increase the strength of individual muscle fibers.<ref name="pmid21565991">{{cite journal | vauthors = Mendias CL, Kayupov E, Bradley JR, Brooks SV, Claflin DR | title = Decreased specific force and power production of muscle fibers from myostatin-deficient mice are associated with a suppression of protein degradation | journal = Journal of Applied Physiology | volume = 111 | issue = 1 | pages = 185–91 | date = July 2011 | pmid = 21565991 | pmc = 3137541 | doi = 10.1152/japplphysiol.00126.2011 }}</ref> Myostatin inhibitors are specifically banned by the World Anti-Doping Agency (WADA).<ref>http://list.wada-ama.org/list/s4-hormone-and-metabolic-modulators/#myostatin%20inhibitors</ref> In an August 12, 2012 interview with [[National Public Radio]], [[Carlon Colker]] stated “when the myostatin inhibitors come along, they'll be abused. There's no question in my mind.”<ref>{{cite web|url=https://www.npr.org/sections/health-shots/2013/08/12/210487410/new-muscle-drugs-could-be-the-next-big-thing-in-sports-doping|title=New Muscle Drugs Could Be The Next Big Thing In Sports Doping|author=|date=|website=npr.org}}</ref>

== Effects ==
=== On bone formation ===
Due to myostatin’s ability to inhibit muscle growth, it can indirectly inhibit bone formation by decreasing the load on the bone.<ref>{{cite journal | vauthors = Hamrick MW | title = Increased bone mineral density in the femora of GDF8 knockout mice| journal = The Anatomical Record Part A: Discoveries in Molecular, Cellular, and Evolutionary Biology | volume = 272 | issue = 1 | pages = 388–91 | date = May 2003 | pmid = 12704695 | doi = 10.1002/ar.a.10044 }}</ref><ref name="Tarantino_2015">{{cite journal | vauthors = Tarantino U, Scimeca M, Piccirilli E, Tancredi V, Baldi J, Gasbarra E, Bonanno E | title = Sarcopenia: a histological and immunohistochemical study on age-related muscle impairment| journal = Aging Clinical and Experimental Research | volume = 27 Suppl 1 | issue = 1 | pages = S51-60 | date = October 2015 | pmid = 26197719 | doi = 10.1007/s40520-015-0427-z }}</ref> It has a direct signalling effect on bone formation<ref>{{cite journal | vauthors = Oestreich AK, Carleton SM, Yao X, Gentry BA, Raw CE, Brown M, Pfeiffer FM, Wang Y, Phillips CL | title = Myostatin deficiency partially rescues the bone phenotype of osteogenesis imperfecta model mice| journal = Osteoporosis International | volume = 27 | issue = 1 | pages = 161–70 | date = January 2016 | pmid = 26179666 | doi = 10.1007/s00198-015-3226-7 }}</ref> as well as degradation.<ref name="Dankbar_2015">{{cite journal | vauthors = Dankbar B, Fennen M, Brunert D, Hayer S, Frank S, Wehmeyer C, Beckmann D, Paruzel P, Bertrand J, Redlich K, Koers-Wunrau C, Stratis A, Korb-Pap A, Pap T | title = Myostatin is a direct regulator of osteoclast differentiation and its inhibition reduces inflammatory joint destruction in mice | journal = Nature Medicine | volume = 21 | issue = 9 | pages = 1085–90 | date = September 2015 | pmid = 26236992 | doi = 10.1038/nm.3917 }}</ref><ref name="Tarantino_2015" />  Knockdown of myostatin has been shown to reduce formation of osteoclasts (multinucleated cells responsible for the breakdown of bone tissue) in mice modeling rheumatoid arthritis.<ref name="Dankbar_2015" /> Rheumatoid arthritis is an autoimmune disorder that, among other effects, leads to the degradation of the bone tissue in affected joints. Myostatin has not, however, been shown to be solely sufficient for the formation of mature osteoclasts from macrophages, only an enhancer.

Myostatin expression is increased around the site of a fracture. Suppression of myostatin at the fracture site leads to increased callus and overall bone size, further supporting the inhibitory effect of myostatin on bone formation. One study<ref name="Dankbar_2015" /> by Berno Dankbar et al., 2015 found that myostatin deficiency leads to a notable reduction in inflammation around a fracture site.  Myostatin affects osteoclastogenesis by binding to receptors on osteoclastic macrophages and causing a signalling cascade. The downstream signalling cascade enhances the expression of RANKL-dependent integrin αvβ3, DC-STAMP, calcitonin receptors, and NFATc1 (which is part of the initial intracellular complex that starts the  signaling cascade, along with R-Smad2 and ALK4 or ALK5).<ref name="Dankbar_2015" /><ref name="Tarantino_2015" />

An association between osteoporosis, another disease characterized by the degradation of bony tissue, and sarcopenia, the age-related degeneration of muscle mass and quality have also been found.<ref name="Tarantino_2015" /> Whether this link is a result of direct regulation or a secondary effect through muscle mass is not known.

A link in mice between the concentration of myostatin in the prenatal environment and the strength of offsprings’ bones, partially counteracting the effects of osteogenesis imperfecta (brittle bone disease) has been found.<ref name="Oestreich_2016">{{cite journal | vauthors = Oestreich AK, Kamp WM, McCray MG, Carleton SM, Karasseva N, Lenz KL, Jeong Y, Daghlas SA, Yao X, Wang Y, Pfeiffer FM, Ellersieck MR, Schulz LC, Phillips CL | display-authors = 6 | title = Decreasing maternal myostatin programs adult offspring bone strength in a mouse model of osteogenesis imperfecta| journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 113 | issue = 47 | pages = 13522–13527 | date = November 2016 | pmid = 27821779 | pmc = 5127318 | doi = 10.1073/pnas.1607644113 }}</ref> Osteogenesis imperfecta is due to a mutation that causes the production of abnormal Type I collagen. Mice with defective myostatin were created by replacing sequences coding for the C-terminal region of myostatin with a neomycin cassette, rendering the protein nonfunctional. By crossbreeding mice with the abnormal Type I collagen and those with the knockout myostatin, the offspring had “a 15% increase in torsional ultimate strength, a 29% increase in tensile strength, and a 24% increase in energy to failure” of their femurs as compared to the other mice with osteogenesis imperfecta, showing the positive effects of decreased myostatin on bone strength and formation.<ref>{{cite journal | vauthors = Kawao N, Kaji H | title = Interactions between muscle tissues and bone metabolism| journal = Journal of Cellular Biochemistry | volume = 116 | issue = 5 | pages = 687–95 | date = May 2015 | pmid = 25521430 | doi = 10.1002/jcb.25040 }}</ref>

=== On the heart ===
Myostatin is expressed at very low levels in cardiac myocytes.<ref name="Breitbart_2011">{{cite journal | vauthors = Breitbart A, Auger-Messier M, Molkentin JD, Heineke J | title = Myostatin from the heart: local and systemic actions in cardiac failure and muscle wasting | journal = American Journal of Physiology. Heart and Circulatory Physiology | volume = 300 | issue = 6 | pages = H1973-82 | date = June 2011 | pmid = 21421824 | pmc = 3119101 | doi = 10.1152/ajpheart.00200.2011 }}</ref><ref name="Heineke_2010">{{cite journal | vauthors = Heineke J, Auger-Messier M, Xu J, Sargent M, York A, Welle S, Molkentin JD | title = Genetic deletion of myostatin from the heart prevents skeletal muscle atrophy in heart failure | journal = Circulation | volume = 121 | issue = 3 | pages = 419–25 | date = January 2010 | pmid = 20065166 | pmc = 2823256 | doi = 10.1161/CIRCULATIONAHA.109.882068 }}</ref> Although its presence has been noted in [[cardiomyocytes]] of both fetal and adult mice,<ref name="Sharma_1999">{{cite journal | vauthors = Sharma M, Kambadur R, Matthews KG, Somers WG, Devlin GP, Conaglen JV, Fowke PJ, Bass JJ | title = Myostatin, a transforming growth factor-beta superfamily member, is expressed in heart muscle and is upregulated in cardiomyocytes after infarct | journal = Journal of Cellular Physiology | volume = 180 | issue = 1 | pages = 1–9 | date = July 1999 | pmid = 10362012 | doi = 10.1002/(SICI)1097-4652(199907)180:1<1::AID-JCP1>3.0.CO;2-V }}</ref> its physiological function remains uncertain.<ref name="Heineke_2010"/> However, it has been suggested that fetal cardiac myostatin may play a role in early heart development.<ref name="Sharma_1999"/>

Myostatin is produced as promyostatin, a precursor protein kept inactive by the latent [[LTBP3|TGF-β binding protein 3]] (LTBP3).<ref name="Breitbart_2011"/> Pathological cardiac stress promotes N-terminal cleavage by [[furin]] convertase to create a biologically active C-terminal fragment. The mature myostatin is then segregated from the latent complex via proteolytic cleavage by [[BMP-1]] and [[TLL1|tolloid metallopreoteinases]].<ref name="Breitbart_2011"/> Free myostatin is able to bind its receptor, ActRIIB, and increase [[SMAD2|SMAD2/3]] phosphorylation.<ref name="Breitbart_2011"/> The latter produces a heteromeric complex with [[SMAD4]], inducing myostatin translocation into the cardiomyocyte nucleus to modulate transcription factor activity.<ref name="McKoy_2007">{{cite journal | vauthors = McKoy G, Bicknell KA, Patel K, Brooks G | title = Developmental expression of myostatin in cardiomyocytes and its effect on foetal and neonatal rat cardiomyocyte proliferation | journal = Cardiovascular Research | volume = 74 | issue = 2 | pages = 304–12 | date = May 2007 | pmid = 17368590 | doi = 10.1016/j.cardiores.2007.02.023 }}</ref> Manipulating the muscle [[Creatinine kinase convertase|creatinine kinase]] promoter can modulate myostatin expression, although it has only been observed in male mice thus far.<ref name="Breitbart_2011"/><ref name="Heineke_2010"/>

Myostatin may inhibit cardiomyocyte proliferation and [[Cellular differentiation|differentiation]] by manipulating cell cycle progression.<ref name="Sharma_1999"/> This argument is supported by the fact that myostatin mRNA is poorly expressed in proliferating fetal cardiomyocytes.<ref name="Breitbart_2011"/><ref name="McKoy_2007"/> ''In vitro ''studies indicate that myostatin promotes [[SMAD2]] phosphorylation to inhibit cardiomyocyte proliferation. Furthermore, myostatin has been shown to directly prevent [[Cell Cycle (journal)|cell cycle]] G1 to S phase transition by decreasing levels of [[CDK2|cyclin-dependent kinase complex 2]] (CDK2) and by increasing [[p21]] levels.<ref name="McKoy_2007"/>

Growth of cardiomyocytes may also be hindered by myostatin-regulated inhibition of protein kinase [[P38 mitogen-activated protein kinases|p38]] and the serine-threonine protein kinase [[Akt]], which typically promote cardiomyocyte [[hypertrophy]].<ref name="Morissette_2006">{{cite journal | vauthors = Morissette MR, Cook SA, Foo S, McKoy G, Ashida N, Novikov M, Scherrer-Crosbie M, Li L, Matsui T, Brooks G, Rosenzweig A | title = Myostatin regulates cardiomyocyte growth through modulation of Akt signaling | journal = Circulation Research | volume = 99 | issue = 1 | pages = 15–24 | date = July 2006 | pmid = 16763166 | pmc = 2901846 | doi = 10.1161/01.RES.0000231290.45676.d4 }}</ref> However, increased myostatin activity only occurs in response to specific stimuli,<ref name="Breitbart_2011"/><ref name="Morissette_2006"/> such as in pressure stress models, in which cardiac myostatin induces whole-body muscular [[atrophy]].<ref name="Breitbart_2011"/><ref name="Sharma_1999"/>

Physiologically, minimal amounts of cardiac myostatin are secreted from the myocardium into serum, having a limited effect on muscle growth.<ref name="Heineke_2010"/> However, increases in cardiac myostatin can increase its serum concentration, which may cause skeletal muscle atrophy.<ref name="Breitbart_2011"/><ref name="Heineke_2010"/> Pathological states that increase cardiac stress and promote [[heart failure]] can induce a rise in both cardiac myostatin mRNA and protein levels within the heart.<ref name="Breitbart_2011"/><ref name="Heineke_2010"/> In ischemic or [[dilated cardiomyopathy]], increased levels of myostatin mRNA have been detected within the left ventricle.<ref name="Breitbart_2011"/><ref name="Torrado_2010">{{cite journal | vauthors = Torrado M, Iglesias R, Nespereira B, Mikhailov AT | title = Identification of candidate genes potentially relevant to chamber-specific remodeling in postnatal ventricular myocardium | journal = Journal of Biomedicine & Biotechnology | volume = 2010 | page = 603159 | year = 2010 | pmid = 20368782 | pmc = 2846348 | doi = 10.1155/2010/603159 }}</ref>

As a member of the TGF-β family, myostatin may play a role in post-infarct recovery.<ref name="Heineke_2010"/><ref name="Sharma_1999"/> It has been hypothesized that hypertrophy of the heart induces an increase in myostatin as a [[Negative feedback amplifier|negative feedback]] mechanism in an attempt to limit further myocyte growth.<ref name="Wang_2008">{{cite journal | vauthors = Wang BW, Chang H, Kuan P, Shyu KG | title = Angiotensin II activates myostatin expression in cultured rat neonatal cardiomyocytes via p38 MAP kinase and myocyte enhance factor 2 pathway | journal = The Journal of Endocrinology | volume = 197 | issue = 1 | pages = 85–93 | date = April 2008 | pmid = 18372235 | doi = 10.1677/JOE-07-0596 }}</ref><ref name="Shyu_2005">{{cite journal | vauthors = Shyu KG, Ko WH, Yang WS, Wang BW, Kuan P | title = Insulin-like growth factor-1 mediates stretch-induced upregulation of myostatin expression in neonatal rat cardiomyocytes | journal = Cardiovascular Research | volume = 68 | issue = 3 | pages = 405–14 | date = December 2005 | pmid = 16125157 | doi = 10.1016/j.cardiores.2005.06.028 }}</ref> This process includes mitogen-activated protein kinases and binding of the [[Mef2|MEF2]] transcription factor within the promoter region of the myostatin gene. Increases in myostatin levels during [[chronic heart failure]] have been shown to cause cardiac [[cachexia]].<ref name="Breitbart_2011"/><ref name="Heineke_2010"/><ref name="Anker_2003">{{cite journal | vauthors = Anker SD, Negassa A, Coats AJ, Afzal R, Poole-Wilson PA, Cohn JN, Yusuf S | title = Prognostic importance of weight loss in chronic heart failure and the effect of treatment with angiotensin-converting-enzyme inhibitors: an observational study | journal = Lancet | volume = 361 | issue = 9363 | pages = 1077–83 | date = March 2003 | pmid = 12672310 | doi = 10.1016/S0140-6736(03)12892-9 }}</ref> Systemic inhibition of cardiac myostatin with the JA-16 antibody maintains overall muscle weight in experimental models with pre-existing heart failure.<ref name="Heineke_2010"/>

Myostatin also alters [[EC coupling|excitation-contraction (EC) coupling]] within the heart.<ref name="Rodgers_2009">{{cite journal | vauthors = Rodgers BD, Interlichia JP, Garikipati DK, Mamidi R, Chandra M, Nelson OL, Murry CE, Santana LF | title = Myostatin represses physiological hypertrophy of the heart and excitation-contraction coupling | journal = The Journal of Physiology | volume = 587 | issue = Pt 20 | pages = 4873–86 | date = October 2009 | pmid = 19736304 | pmc = 2770153 | doi = 10.1113/jphysiol.2009.172544 }}</ref> A reduction in cardiac myostatin induces eccentric hypertrophy of the heart, and increases its sensitivity to beta-adrenergic stimuli by enhancing Ca<sup>2+</sup> release from the SR during EC coupling. Also, [[phospholamban]] phosphorylation is increased in myostatin-knockout mice, leading to an increase in Ca<sup>2+</sup> release into the cytosol during systole.<ref name="Breitbart_2011"/> Therefore, minimizing cardiac myostatin may improve cardiac output.<ref name="Rodgers_2009"/>

==In popular culture==

===Television===
In ''[[The Incredible Hulk (1978 TV series)|The Incredible Hulk]]'' episode "Death In The Family" a nurse gives a patient a dose of myostatin, but Dr. David Banner recognizes that it is not true myostatin because the liquid is red not clear.

=== Novels ===
Myostatin gene mutations are cited by a [[Stanford University]] scientist in the novel ''Performance Anomalies'',<ref>{{Cite web|url=http://www.readinggroupguides.com/reviews/performance-anomalies/guide|title=Performance Anomalies  by Victor Robert  Lee  {{!}} Book Club Discussion Questions {{!}} ReadingGroupGuides.com|website=www.readinggroupguides.com|language=en|access-date=2017-05-09}}</ref><ref>{{cite web|url=https://books.google.com/books?id=R4xrWxfC_DUC&pg=PT83&lpg=PT83&dq=performance+anomalies+myostatin&source=bl&ots=YorVMautqk&sig=Ii0-FxbqDRro0vVIp9CLGLrDKIw&hl=en&sa=X&ved=0ahUKEwi_kN7ulObTAhWR14MKHcKwBmQQ6AEIRzAF#v=onepage&q=performance+anomalies+myos|title=Performance Anomalies: A Novel|first=Victor Robert|last=Lee|date=15 January 2013|publisher=Perimeter Six Press|via=Google Books}}</ref> as the scientist evaluates mutations that may account for the accelerated nervous system of the espionage protagonist Cono 7Q.

==See also==
* [[Muscular dystrophy]]
* [[Muscle hypertrophy]]
* [[Myostatin-related muscle hypertrophy]]
* [[Superhuman strength]]

==References==
{{Reflist|33em}}

==External links==
{{Commons category}}
*[https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=mstn GeneReviews profile]
*[https://www.npr.org/templates/story/story.php?storyId=6479550 NPR.org: Myostatin Therapies Hold Hope for Muscle Diseases by Jon Hamilton]
*Times Colonist [https://web.archive.org/web/20070702162109/http://www.canada.com/victoriatimescolonist/news/story.html?id=67f15c17-2717-4022-bb76-1b982456e793 Big Wendy the muscular whippet]
*{{MeshName|myostatin}}

{{TGF beta signaling}}
{{TGFβ receptor superfamily modulators}}

[[Category:Growth factors]]
[[Category:Muscular dystrophy]]
[[Category:TGFβ domain]]
[[Category:Human proteins]]
[[Category:Genes mutated in mice]]
[[Category:Genes on human chromosome 2]]