|Symbols||; GDF8; MSLHP|
Myostatin (also known as growth differentiation factor 8, abbreviated GDF-8) is a protein that in humans is encoded by the MSTN gene. Myostatin is a secreted growth differentiation factor that is a member of the TGF beta protein family that inhibits muscle differentiation and growth in the process known as myogenesis. 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.
Animals lacking myostatin or animals treated with substances that block the activity of myostatin have significantly larger muscles. This could be of economic benefit to the livestock industry. However these animals require special care and feeding which offsets the potential economic advantage.
Mutations in both copies of the human myostatin gene results in individuals that have significantly more muscle mass and hence are considerably stronger than normal. However, because this added muscle mass is not necessarily the product of exercise-mediated growth, it may not form with the same level of useful and purposeful tone and structure as normal muscle growth, as is seen in the relationship between cardiac muscle growth and cardiomyopathy. Furthermore, blocking the activity of myostatin may have therapeutic application in treating muscle wasting diseases such as muscular dystrophy.
Discovery and sequencing
The gene encoding myostatin was discovered in 1997 by geneticists Dr. Se-Jin Lee and Alexandra McPherron 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. These mice were subsequently named "mighty mice".
Naturally occurring lacks of myostatin have been identified in cattle by Dr. Ravi Kambadur, 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.
Structure and mechanism of action
Myostatin is a member of the TGF beta superfamily of proteins.
Human myostatin consists of two identical subunits, each consisting of 109 (NCBI database claims human myostatin is 375 residues long) 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. However, it is notable that Akt does not responsible for all of the observed muscle hyperthrophic effects which are mediated by myostatin inhibition
Myostatin is also classed as a myokine, and is in fact considered the first myokine to have been characterized.
Effects in animals
Double muscled 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. 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%.
Animals lacking myostatin or