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Myostatin
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<h2 id="discovery-and-sequencing">Discovery and sequencing</h2> <p>The <a href="/facts/Gene/e1swwPY6">gene</a> encoding myostatin was discovered in 1997 by geneticists Se-Jin Lee and Alexandra McPherron who produced a <a href="/facts/Knockout_mice/Aw50cobf">knockout</a> strain of <a href="/facts/Mus_musculus/A1fj6LQ2">mice</a> that lack the gene, and have approximately twice as much muscle as normal mice.<a class="footnote-ref" id="fnref:8" href="#fn:8"><sup>8</sup></a> These mice were subsequently named "mighty mice". </p><p>Naturally occurring deficiencies of myostatin of various sorts have been identified in some breeds of cattle,<a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a> sheep,<a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a> <a href="/facts/Whippet/SEwJK45b">whippets</a>,<a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a> and humans.<a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a> In each case the result is a dramatic increase in muscle mass. </p> <h2 id="structure-and-mechanism-of-action">Structure and mechanism of action</h2> <p>Human myostatin consists of two identical subunits, each consisting of 109 (NCBI database claims human myostatin is 375 residues long) <a href="/facts/Amino_acid/WDxYwBny">amino acid</a> residues [note the full length gene encodes a 375AA prepro-protein which is proteolytically processed to its shorter active form].<a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a><a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a> Its total <a href="/facts/Molecular_mass/FWueGMed">molecular weight</a> is 25.0 k<a href="/facts/Atomic_mass_unit/IMATU3vf">Da</a>. The protein is inactive until a <a href="/facts/Protease/G1ASdVat">protease</a> cleaves the <a href="/facts/NH2-terminal/yKYpuaBJ">NH2-terminal</a>, or "pro-domain" portion of the molecule, resulting in the active <a href="/facts/COOH-terminal/ws4scHgT">COOH-terminal</a> dimer. Myostatin binds to the <a href="/facts/Activin_type_2_receptors/T0dW6Ksz">activin type II receptor</a>, resulting in a recruitment of either coreceptor <a href="/facts/BMPR1A/5ACbrWpw">Alk-3</a> or <a href="/facts/ACVR1B/1ugouTel">Alk-4</a>. This coreceptor then initiates a <a href="/facts/Cell_signaling/6oYAVP9I">cell signaling</a> cascade in the <a href="/facts/Muscle/dmxrL8pH">muscle</a> that includes the activation of <a href="/facts/Transcription_factor/wro0DPHe">transcription factors</a> in the <a href="/facts/SMAD_(protein)/aIWIB7Nq">SMAD</a> family—<a href="/facts/SMAD2/xlS5oygm">SMAD2</a> and <a href="/facts/SMAD3/6j6Go6va">SMAD3</a>. These factors then induce myostatin-specific <a href="/facts/Regulation_of_gene_expression/9N4G341I">gene regulation</a>. When applied to <a href="/facts/Myoblasts/cP7Jea3q">myoblasts</a>, myostatin inhibits their proliferation and either initiates differentiation or stimulates quiescence. </p><p>In mature muscle, myostatin inhibits <a href="/facts/AKT/odL6duk1">Akt</a>, a kinase that is sufficient to cause <a href="/facts/Muscle_hypertrophy/6aAUF7Ma">muscle hypertrophy</a>, in part through the activation of <a href="/facts/Protein_biosynthesis/P4IcGjPd">protein synthesis</a> while stimulating the production of ubiquitin ligases, proteins that regulate muscle protein breakdown. However, Akt is not responsible for all of the observed muscle hypertrophic effects, which are mediated by myostatin inhibition.<a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a> Thus myostatin acts in two ways: by inhibiting Akt-induced protein synthesis and stimulating ubiquitin-regulated protein degradation. </p> <h2 id="biological-advantage">Biological advantage</h2> <p>Many different mammalian and avian species produce myostatin, indicating that the ability to produce myostatin was positively selected for.<a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a> </p> <h2 id="effects-in-animals">Effects in animals</h2> <h3>Mutations</h3> <p>Mutations in myostatin do more than just affect the amount of muscle mass an organism can produce; they also have variable effects on other phenotypes for different species.<a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a>For example, a Belgian Blue bovine with a mutation that inhibits myostatin production will exhibit a dramatic increase in muscle mass but will also lead to <a href="/facts/Dystocia/8VJ5taCW">dystocia</a>.<a class="footnote-ref" id="fnref:18" href="#fn:18"><sup>18</sup></a> Other species with myostatin deficiency mutation such as humans or Whippet dogs do not get obstructed labor.<a class="footnote-ref" id="fnref:19" href="#fn:19"><sup>19</sup></a> </p> <h3>Double-muscled cattle</h3> <p class="note">Main article: <a href="/facts/Double-muscled_cattle/RXtnqr6t">Double-muscled cattle</a></p> <p>After the discovery of the gene encoding myostatin in 1997, several laboratories cloned and established the <a href="/facts/Nucleotide/pQKEwlJI">nucleotide</a> sequence of a myostatin gene in two breeds of cattle, <a href="/facts/Belgian_Blue/WzT4nPTD">Belgian Blue</a> and <a href="/facts/Piedmontese_(cattle)/MGrMW6AT">Piedmontese</a>. They found mutations in the myostatin gene (various mutations in each breed) which in one way or another lead to absence of functional myostatin.<a class="footnote-ref" id="fnref:20" href="#fn:20"><sup>20</sup></a><a class="footnote-ref" id="fnref:21" href="#fn:21"><sup>21</sup></a><a class="footnote-ref" id="fnref:22" href="#fn:22"><sup>22</sup></a> Unlike mice with a damaged myostatin gene, in these cattle breeds, 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%.<a class="footnote-ref" id="fnref:23" href="#fn:23"><sup>23</sup></a><a class="footnote-ref" id="fnref:24" href="#fn:24"><sup>24</sup></a><a class="footnote-ref" id="fnref:25" href="#fn:25"><sup>25</sup></a> </p><p>Animals lacking myostatin or animals treated with substances such as <a href="/facts/Follistatin/ftC2rvsf">follistatin</a> that block the binding of myostatin to its receptor have significantly larger muscles. Thus, reduction of myostatin could potentially benefit the <a href="/facts/Livestock_industry/Quhv6GvP">livestock industry</a>, with even a 20 percent reduction in myostatin levels potentially having a large effect on the development of muscles.<a class="footnote-ref" id="fnref:26" href="#fn:26"><sup>26</sup></a> </p><p>However, the animal breeds developed as <a href="/facts/Homozygous/XzEJ5gPp">homozygous</a> for myostatin deficiency have <a href="/facts/Belgian_Blue/WzT4nPTD">reproduction issues</a> 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 <a href="/facts/Piedmontese_(cattle)/MGrMW6AT">Piedmontese beef</a>) has a place on the specialist market due to its high palatability and tenderness, 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.<a class="footnote-ref" id="fnref:27" href="#fn:27"><sup>27</sup></a> </p> <h3>Whippets</h3> <p><a href="/facts/Whippets/SEwJK45b">Whippets</a> can have a mutation of the myostatin which involves a two-base-pair deletion, and results in a truncated, and likely inactive, myostatin <a href="/facts/Protein/Jxmagu3E">protein</a>. </p><p>Animals with a <a href="/facts/Homozygous/XzEJ5gPp">homozygous</a> 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 <a href="/facts/Heterozygous/XzEJ5gPp">heterozygous</a> for the mutation were significantly over-represented in the top racing classes.<a class="footnote-ref" id="fnref:28" href="#fn:28"><sup>28</sup></a> In 2015 scientist used <a href="/facts/CRISPR%2fCas9/gDhwlw7I">CRISPR/Cas9</a> to have the same homozygous deletion in <a href="/facts/Beagle/gp6A3qFk">Beagles</a> that appears in "bully whippets".<a class="footnote-ref" id="fnref:29" href="#fn:29"><sup>29</sup></a><a class="footnote-ref" id="fnref:30" href="#fn:30"><sup>30</sup></a> </p> <h3>Mice</h3> <p>Mice that produce large amounts of myostatin exhibit a significant loss of skeletal muscle and body fat compared to normal mice.<a class="footnote-ref" id="fnref:31" href="#fn:31"><sup>31</sup></a> Comparatively, mice that produced decreased levels of myostatin had more muscle mass, less adipose tissue, and were double the size of wild type mice.<a class="footnote-ref" id="fnref:32" href="#fn:32"><sup>32</sup></a> </p> <h3>Rabbits and goats</h3> <p>In 2016, the CRISPR/Cas9 system was used to genetically engineer rabbits and goats with no functional copies of the myostatin gene.<a class="footnote-ref" id="fnref:33" href="#fn:33"><sup>33</sup></a> 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. </p> <h3>Pigs</h3> <p>A <a href="/facts/South_Korea/pCobAaVw">South Korean</a>-<a href="/facts/China/lTjIXY5p">Chinese</a> team has engineered "double muscle" pigs, as with cattle, aiming for cheaper breeds for the meat market.<a class="footnote-ref" id="fnref:34" href="#fn:34"><sup>34</sup></a> Similar health problems have resulted as with other mammals, such as birthing difficulties due to excessive size.<a class="footnote-ref" id="fnref:35" href="#fn:35"><sup>35</sup></a> </p> <h3>Fish</h3> <p>Myostatin-disabled <a href="/facts/Pagrus_major/5T6J6ILz">red sea breams</a> grow to 1.2 the natural average size with the same amount of food and are sold as food in Japan by a startup.<a class="footnote-ref" id="fnref:36" href="#fn:36"><sup>36</sup></a><a class="footnote-ref" id="fnref:37" href="#fn:37"><sup>37</sup></a><a class="footnote-ref" id="fnref:38" href="#fn:38"><sup>38</sup></a> </p> <h2 id="clinical-significance">Clinical significance</h2> <h3>Mutations</h3> <p>A technique for detecting mutations in myostatin variants has been developed.<a class="footnote-ref" id="fnref:39" href="#fn:39"><sup>39</sup></a> Mutations that reduce the production of functional myostatin lead to an overgrowth of muscle tissue. Myostatin-related muscle hypertrophy has an incomplete autosomal <a href="/facts/Dominance_(genetics)/DsvtPyQU">dominance</a> pattern of inheritance. People with a mutation in both copies of the <i>MSTN</i> gene in each <a href="/facts/Cell_(biology)/bLM9UQvy">cell</a> (<a href="/facts/Homozygote/XzEJ5gPp">homozygotes</a>) have significantly increased muscle mass and strength. People with a mutation in one copy of the <i>MSTN</i> gene in each cell (<a href="/facts/Heterozygote/XzEJ5gPp">heterozygotes</a>) have increased muscle bulk, but to a lesser degree. </p> <h3>In humans</h3> <p>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.<a class="footnote-ref" id="fnref:40" href="#fn:40"><sup>40</sup></a><a class="footnote-ref" id="fnref:41" href="#fn:41"><sup>41</sup></a><a class="footnote-ref" id="fnref:42" href="#fn:42"><sup>42</sup></a> </p><p>An American boy born in 2005 was diagnosed with a clinically similar condition, but with a somewhat different cause:<a class="footnote-ref" id="fnref:43" href="#fn:43"><sup>43</sup></a> 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 <a href="/facts/Activin_type_IIB_receptor/T0dW6Ksz">myostatin receptors</a> is thought to prevent his muscle cells from responding normally to myostatin. He appeared on the television show <i>World's Strongest Toddler</i>.<a class="footnote-ref" id="fnref:44" href="#fn:44"><sup>44</sup></a> </p> <h3>Therapeutic potential</h3> <p>Further research into myostatin and the myostatin gene may lead to therapies for <a href="/facts/Muscular_dystrophy/uU5xD0h8">muscular dystrophy</a>.<a class="footnote-ref" id="fnref:45" href="#fn:45"><sup>45</sup></a><a class="footnote-ref" id="fnref:46" href="#fn:46"><sup>46</sup></a> The idea is to introduce substances that block myostatin. A <a href="/facts/Monoclonal_antibody/4rUBWB87">monoclonal antibody</a> specific to myostatin increases muscle mass in mice<a class="footnote-ref" id="fnref:47" href="#fn:47"><sup>47</sup></a> and monkeys.<a class="footnote-ref" id="fnref:48" href="#fn:48"><sup>48</sup></a> </p><p>A two-week treatment of normal mice with soluble <a href="/facts/Activin_type_IIB_receptor/T0dW6Ksz">activin type IIB receptor</a>, a molecule that is normally attached to cells and binds to myostatin, leads to a significantly increased muscle mass (up to 60%).<a class="footnote-ref" id="fnref:49" href="#fn:49"><sup>49</sup></a> It is thought that binding of myostatin to the soluble activin receptor prevents it from interacting with the cell-bound receptors. In September 2020 scientists reported that suppressing <a href="/facts/Activin_type_2_receptors/T0dW6Ksz">activin type 2 receptors</a>-signalling proteins myostatin and <a href="/facts/Activin_A/jLwLmlGs">activin A</a> via activin A/<a href="/facts/Myostatin_inhibitor/q9utY19J">myostatin inhibitor</a> <a href="/facts/ACVR2B/fXxR2cwg">ACVR2B</a> – tested preliminarily in humans in the form of <a href="/facts/ACE-031/FRH2AIdM">ACE-031</a> in the early 2010s<a class="footnote-ref" id="fnref:50" href="#fn:50"><sup>50</sup></a><a class="footnote-ref" id="fnref:51" href="#fn:51"><sup>51</sup></a> – can protect against both <a href="/facts/Atrophy/QNxSoxDV">muscle</a> and <a href="/facts/Bone_density/poUvLR69">bone loss</a> in mice. The mice were sent to the International Space Station and could largely maintain their muscle weights – about twice those of wild type due to <a href="/facts/Genetic_engineering/vwdlDR61">genetic engineering</a> for targeted deletion of the myostatin gene – <a href="/facts/Effect_of_spaceflight_on_the_human_body/fjXCjCXH">under microgravity</a>.<a class="footnote-ref" id="fnref:52" href="#fn:52"><sup>52</sup></a><a class="footnote-ref" id="fnref:53" href="#fn:53"><sup>53</sup></a> Treating <a href="/facts/Progeric/fT26dA0o">progeric</a> mice with soluble activin receptor type IIB before the onset of premature ageing signs appear to protects against muscle loss and delay age related signs in other organs.<a class="footnote-ref" id="fnref:54" href="#fn:54"><sup>54</sup></a> </p><p>It remains unclear as to whether long-term treatment of muscular dystrophy with myostatin inhibitors is beneficial, as the depletion of muscle <a href="/facts/Satellite_cell/SGdgVX0m">stem cells</a> 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, <a href="/facts/Stamulumab/M4M53nFa">stamulumab</a>, which was under development by pharmaceutical company <a href="/facts/Wyeth/oaUm9fwY">Wyeth</a>,<a class="footnote-ref" id="fnref:55" href="#fn:55"><sup>55</sup></a> is no longer under development.<a class="footnote-ref" id="fnref:56" href="#fn:56"><sup>56</sup></a> Some athletes, eager to get their hands on such drugs, turn to the internet where <a href="/facts/Fake_medicine/a1bqeWde">fake</a> "myostatin blockers" are being sold.<a class="footnote-ref" id="fnref:57" href="#fn:57"><sup>57</sup></a> </p><p><a href="/facts/Resistance_exercise/G5u5cBH0">Resistance exercise</a> and <a href="/facts/Creatine/xhBTBard">creatine</a> supplementation lead to greater decreases in myostatin levels.<a class="footnote-ref" id="fnref:58" href="#fn:58"><sup>58</sup></a> </p><p>Myostatin levels can be temporarily reduced using a cholesterol-conjugated siRNA gene knockdown.<a class="footnote-ref" id="fnref:59" href="#fn:59"><sup>59</sup></a> </p> <h3>Athletic use</h3> <p>Inhibition of myostatin leads to muscle <a href="/facts/Hypertrophy/4JolPfnS">hypertrophy</a>. Myostatin inhibitors can improve athletic performance and therefore there is a concern these inhibitors might be abused in the field of sports.<a class="footnote-ref" id="fnref:60" href="#fn:60"><sup>60</sup></a> However, studies in mice suggest that myostatin inhibition does not directly increase the strength of individual muscle fibers.<a class="footnote-ref" id="fnref:61" href="#fn:61"><sup>61</sup></a> Myostatin inhibitors are specifically banned by the World Anti-Doping Agency (WADA).<a class="footnote-ref" id="fnref:62" href="#fn:62"><sup>62</sup></a> In an August 12, 2012, interview with <a href="/facts/National_Public_Radio/BohIW9Xg">NPR</a>, <a href="/facts/Carlon_Colker/Jd89Yv6T">Carlon Colker</a> stated "when the myostatin inhibitors come along, they'll be abused. There's no question in my mind."<a class="footnote-ref" id="fnref:63" href="#fn:63"><sup>63</sup></a> </p> <h3>Lifestyle effects on myostatin</h3> <p>Myostatin expression is decreased in physically active individuals, while obesity is linked to having a higher level myostatin as well as plasma in circulation.<a class="footnote-ref" id="fnref:64" href="#fn:64"><sup>64</sup></a> </p> <h2 id="effects">Effects</h2> <h3>On bone formation</h3> <p>Due to myostatin's ability to inhibit muscle growth, it can indirectly inhibit bone formation by decreasing the load on the bone.<a class="footnote-ref" id="fnref:65" href="#fn:65"><sup>65</sup></a><a class="footnote-ref" id="fnref:66" href="#fn:66"><sup>66</sup></a> It has a direct signalling effect on bone formation<a class="footnote-ref" id="fnref:67" href="#fn:67"><sup>67</sup></a> as well as degradation.<a class="footnote-ref" id="fnref:68" href="#fn:68"><sup>68</sup></a><a class="footnote-ref" id="fnref:69" href="#fn:69"><sup>69</sup></a> 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.<a class="footnote-ref" id="fnref:70" href="#fn:70"><sup>70</sup></a> 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. </p><p>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<a class="footnote-ref" id="fnref:71" href="#fn:71"><sup>71</sup></a> 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).<a class="footnote-ref" id="fnref:72" href="#fn:72"><sup>72</sup></a><a class="footnote-ref" id="fnref:73" href="#fn:73"><sup>73</sup></a> </p><p>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.<a class="footnote-ref" id="fnref:74" href="#fn:74"><sup>74</sup></a> Whether this link is a result of direct regulation or a secondary effect through muscle mass is not known. </p><p>A link in mice between the concentration of myostatin in the prenatal environment and the strength of offspring's bones, partially counteracting the effects of osteogenesis imperfecta (brittle bone disease) has been found.<a class="footnote-ref" id="fnref:75" href="#fn:75"><sup>75</sup></a> 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.<a class="footnote-ref" id="fnref:76" href="#fn:76"><sup>76</sup></a> </p> <h3>On the heart</h3> <p>Myostatin is expressed at very low levels in cardiac myocytes.<a class="footnote-ref" id="fnref:77" href="#fn:77"><sup>77</sup></a><a class="footnote-ref" id="fnref:78" href="#fn:78"><sup>78</sup></a> Although its presence has been noted in <a href="/facts/Cardiomyocytes/fE40oTQz">cardiomyocytes</a> of both fetal and adult mice,<a class="footnote-ref" id="fnref:79" href="#fn:79"><sup>79</sup></a> its physiological function remains uncertain.<a class="footnote-ref" id="fnref:80" href="#fn:80"><sup>80</sup></a> However, it has been suggested that fetal cardiac myostatin may play a role in early heart development.<a class="footnote-ref" id="fnref:81" href="#fn:81"><sup>81</sup></a> </p><p>Myostatin is produced as promyostatin, a precursor protein kept inactive by the latent <a href="/facts/LTBP3/5T0yqvU6">TGF-β binding protein 3</a> (LTBP3).<a class="footnote-ref" id="fnref:82" href="#fn:82"><sup>82</sup></a> Pathological cardiac stress promotes N-terminal cleavage by <a href="/facts/Furin/0U9X0rKX">furin</a> convertase to create a biologically active C-terminal fragment. The mature myostatin is then segregated from the latent complex via proteolytic cleavage by <a href="/facts/Bone_morphogenetic_protein_1/swjk2ULy">BMP-1</a> and <a href="/facts/TLL1/e4TWYczV">tolloid metalloproteinases</a>.<a class="footnote-ref" id="fnref:83" href="#fn:83"><sup>83</sup></a> Free myostatin is able to bind its receptor, ActRIIB, and increase <a href="/facts/SMAD2/xlS5oygm">SMAD2/3</a> phosphorylation.<a class="footnote-ref" id="fnref:84" href="#fn:84"><sup>84</sup></a> The latter produces a heteromeric complex with <a href="/facts/SMAD4/cgvz1vKP">SMAD4</a>, inducing myostatin translocation into the cardiomyocyte nucleus to modulate transcription factor activity.<a class="footnote-ref" id="fnref:85" href="#fn:85"><sup>85</sup></a> Manipulating the muscle <a href="/facts/Creatinine_kinase_convertase/vq9JG5pz">creatinine kinase</a> promoter can modulate myostatin expression, although it has only been observed in male mice thus far.<a class="footnote-ref" id="fnref:86" href="#fn:86"><sup>86</sup></a><a class="footnote-ref" id="fnref:87" href="#fn:87"><sup>87</sup></a> </p><p>Myostatin may inhibit <a href="/facts/Cardiomyocyte_proliferation/4kEBBlTX">cardiomyocyte proliferation</a> and <a href="/facts/Cellular_differentiation/bCVqUG7w">differentiation</a> by manipulating cell cycle progression.<a class="footnote-ref" id="fnref:88" href="#fn:88"><sup>88</sup></a> This argument is supported by the fact that myostatin mRNA is poorly expressed in proliferating fetal cardiomyocytes.<a class="footnote-ref" id="fnref:89" href="#fn:89"><sup>89</sup></a><a class="footnote-ref" id="fnref:90" href="#fn:90"><sup>90</sup></a> <i>In vitro </i>studies indicate that myostatin promotes <a href="/facts/SMAD2/xlS5oygm">SMAD2</a> phosphorylation to inhibit cardiomyocyte proliferation. Furthermore, myostatin has been shown to directly prevent <a href="/facts/Cell_Cycle_(journal)/KdTr9qCc">cell cycle</a> G1 to S phase transition by decreasing levels of <a href="/facts/CDK2/ga3e7mvK">cyclin-dependent kinase complex 2</a> (CDK2) and by increasing <a href="/facts/P21/gb0VLtY8">p21</a> levels.<a class="footnote-ref" id="fnref:91" href="#fn:91"><sup>91</sup></a> </p><p>Growth of cardiomyocytes may also be hindered by myostatin-regulated inhibition of protein kinase <a href="/facts/P38_mitogen-activated_protein_kinases/oodDxsQK">p38</a> and the serine-threonine protein kinase <a href="/facts/Akt/odL6duk1">Akt</a>, which typically promote cardiomyocyte <a href="/facts/Hypertrophy/4JolPfnS">hypertrophy</a>.<a class="footnote-ref" id="fnref:92" href="#fn:92"><sup>92</sup></a> However, increased myostatin activity only occurs in response to specific stimuli,<a class="footnote-ref" id="fnref:93" href="#fn:93"><sup>93</sup></a><a class="footnote-ref" id="fnref:94" href="#fn:94"><sup>94</sup></a> such as in pressure stress models, in which cardiac myostatin induces whole-body muscular <a href="/facts/Atrophy/QNxSoxDV">atrophy</a>.<a class="footnote-ref" id="fnref:95" href="#fn:95"><sup>95</sup></a><a class="footnote-ref" id="fnref:96" href="#fn:96"><sup>96</sup></a> </p><p>Physiologically, minimal amounts of cardiac myostatin are secreted from the myocardium into serum, having a limited effect on muscle growth.<a class="footnote-ref" id="fnref:97" href="#fn:97"><sup>97</sup></a> However, increases in cardiac myostatin can increase its serum concentration, which may cause skeletal muscle atrophy.<a class="footnote-ref" id="fnref:98" href="#fn:98"><sup>98</sup></a><a class="footnote-ref" id="fnref:99" href="#fn:99"><sup>99</sup></a> Pathological states that increase cardiac stress and promote <a href="/facts/Heart_failure/7fckX3Jm">heart failure</a> can induce a rise in both cardiac myostatin mRNA and protein levels within the heart.<a class="footnote-ref" id="fnref:100" href="#fn:100"><sup>100</sup></a><a class="footnote-ref" id="fnref:101" href="#fn:101"><sup>101</sup></a> In ischemic or <a href="/facts/Dilated_cardiomyopathy/GlmnXCYU">dilated cardiomyopathy</a>, increased levels of myostatin mRNA have been detected within the left ventricle.<a class="footnote-ref" id="fnref:102" href="#fn:102"><sup>102</sup></a><a class="footnote-ref" id="fnref:103" href="#fn:103"><sup>103</sup></a> </p><p>As a member of the TGF-β family, myostatin may play a role in post-infarct recovery.<a class="footnote-ref" id="fnref:104" href="#fn:104"><sup>104</sup></a><a class="footnote-ref" id="fnref:105" href="#fn:105"><sup>105</sup></a> It has been hypothesized that hypertrophy of the heart induces an increase in myostatin as a <a href="/facts/Negative_feedback/G9byVgpN">negative feedback</a> mechanism in an attempt to limit further myocyte growth.<a class="footnote-ref" id="fnref:106" href="#fn:106"><sup>106</sup></a><a class="footnote-ref" id="fnref:107" href="#fn:107"><sup>107</sup></a> This process includes mitogen-activated protein kinases and binding of the <a href="/facts/Mef2/YWSgYhtY">MEF2</a> transcription factor within the promoter region of the myostatin gene. Increases in myostatin levels during <a href="/facts/Chronic_heart_failure/7fckX3Jm">chronic heart failure</a> have been shown to cause cardiac <a href="/facts/Cachexia/S8wYz0mm">cachexia</a>.<a class="footnote-ref" id="fnref:108" href="#fn:108"><sup>108</sup></a><a class="footnote-ref" id="fnref:109" href="#fn:109"><sup>109</sup></a><a class="footnote-ref" id="fnref:110" href="#fn:110"><sup>110</sup></a> Systemic inhibition of cardiac myostatin with the JA-16 antibody maintains overall muscle weight in experimental models with pre-existing heart failure.<a class="footnote-ref" id="fnref:111" href="#fn:111"><sup>111</sup></a> </p><p>Myostatin also alters <a href="/facts/EC_coupling/EbloCYfV">excitation-contraction (EC) coupling</a> within the heart.<a class="footnote-ref" id="fnref:112" href="#fn:112"><sup>112</sup></a> A reduction in cardiac myostatin induces eccentric hypertrophy of the heart, and increases its sensitivity to beta-adrenergic stimuli by enhancing Ca2+ release from the SR during EC coupling. Also, <a href="/facts/Phospholamban/XwAbNwxo">phospholamban</a> phosphorylation is increased in myostatin-knockout mice, leading to an increase in Ca2+ release into the cytosol during systole.<a class="footnote-ref" id="fnref:113" href="#fn:113"><sup>113</sup></a> Therefore, minimizing cardiac myostatin may improve cardiac output.<a class="footnote-ref" id="fnref:114" href="#fn:114"><sup>114</sup></a> </p> <h2 id="see-also">See also</h2> <ul><li><a href="/facts/Muscular_dystrophy/uU5xD0h8">Muscular dystrophy</a></li> <li><a href="/facts/Muscle_hypertrophy/6aAUF7Ma">Muscle hypertrophy</a></li> <li><a href="/facts/Myostatin-related_muscle_hypertrophy/XVB1Qj1p">Myostatin-related muscle hypertrophy</a></li> <li><a href="/facts/Superhuman_strength/0KwV3Aqy">Superhuman strength</a></li></ul> <h2 id="external-links">External links</h2> Wikimedia Commons has media related to Myostatin. <ul><li><a href="https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=mstn">GeneReviews profile</a></li> <li><a href="https://www.npr.org/templates/story/story.php?storyId=6479550">NPR.org: Myostatin Therapies Hold Hope for Muscle Diseases by Jon Hamilton</a></li> <li>Times Colonist <a href="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</a></li> <li><a href="https://meshb.nlm.nih.gov/record/ui?name=myostatin">myostatin</a> at the U.S. National Library of Medicine <a href="/facts/Medical_Subject_Headings/C57g2JuF">Medical Subject Headings</a> (MeSH)</li> <li>Overview of all the structural information available in the <a href="/facts/Protein_Data_Bank/oUhq4ABD">PDB</a> for <a href="/facts/UniProt/lfDDHjAl">UniProt</a>: <i><a href="https://www.ebi.ac.uk/pdbe/pdbe-kb/proteins/O14793">O14793</a></i> (Human Growth/differentiation factor 8) at the <a href="/facts/PDBe-KB/p1WX7lPH">PDBe-KB</a>.</li> <li>Overview of all the structural information available in the <a href="/facts/Protein_Data_Bank/oUhq4ABD">PDB</a> for <a href="/facts/UniProt/lfDDHjAl">UniProt</a>: <i><a href="https://www.ebi.ac.uk/pdbe/pdbe-kb/proteins/O08689">O08689</a></i> (Mouse Growth/differentiation factor 8) at the <a href="/facts/PDBe-KB/p1WX7lPH">PDBe-KB</a>.</li></ul> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>Gonzalez-Cadavid NF, Taylor WE, Yarasheski K, Sinha-Hikim I, Ma K, Ezzat S, et al. 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