MSTN

Myostatin (also known as growth differentiation factor 8, abbreviated GDF8) is a protein that in humans is encoded by the ''MSTN'' gene. Myostatin is a myokine that is produced and released by myocytes and acts on muscle cells to inhibit muscle growth. Myostatin is a secreted growth differentiation factor that is a member of the TGF beta protein family.

Myostatin is assembled and produced in skeletal muscle before it is released into the blood stream. Most of the data regarding the effects of myostatin comes from studies performed on mice.

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 (popularly called the "Hercules 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.

Discovery and sequencing

The gene encoding myostatin was discovered in 1997 by geneticists Se-Jin Lee and Alexandra McPherron who produced a knockout strain of mice that lack the gene, and have approximately twice as much muscle as normal mice. These mice were subsequently named "mighty mice".

Naturally occurring deficiencies of myostatin of various sorts have been identified in some breeds of cattle, sheep, whippets, and humans. In each case the result is a dramatic increase in muscle mass.

Structure and mechanism of action

Human myostatin consists of two identical subunits, each consisting of 109 (NCBI database claims human myostatin is 375 residues long) amino acid residues ote the full length gene encodes a 375AA prepro-protein which is proteolytically processed to its shorter active form Its total molecular weight is 25.0 k 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 II receptor, resulting in a recruitment of either coreceptor Alk-3 or Alk-4. This coreceptor then initiates a cell signaling cascade in the muscle that 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 proliferation and either initiates differentiation or stimulates quiescence.

In mature muscle, myostatin inhibits Akt, a kinase that is sufficient to cause muscle hypertrophy, in part through the activation of protein synthesis 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. Thus myostatin acts in two ways: by inhibiting Akt-induced protein synthesis and stimulating ubiquitin-regulated protein degradation.

Biological advantage

Many different mammalian and avian species produce myostatin, indicating that the ability to produce myostatin was positively selected for.

Effects in animals

Mutations

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.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 dystocia. Other species with myostatin deficiency mutation such as humans or Whippet dogs do not get obstructed labor.

Double-muscled cattle

After the discovery of the gene encoding myostatin in 1997, several laboratories cloned and established the nucleotide sequence of a myostatin gene in two breeds of cattle, Belgian Blue and 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. 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%.

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 industry, with even a 20 percent reduction in myostatin levels potentially having a large effect on the development of muscles.

However, the animal breeds developed as homozygous for myostatin deficiency have 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 beef) 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.

Whippets

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. In 2015 scientist used CRISPR/Cas9 to have the same homozygous deletion in Beagles that appears in "bully whippets".

Mice

Mice that produce large amounts of myostatin exhibit a significant loss of skeletal muscle and body fat compared to normal mice. Comparatively, mice that produced decreased levels of myostatin had more muscle mass, less adipose tissue, and were double the size of wild type mice.

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. 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.

Pigs

A South Korean-Chinese team has engineered "double muscle" pigs, as with cattle, aiming for cheaper breeds for the meat market. Similar health problems have resulted as with other mammals, such as birthing difficulties due to excessive size.

Fish

Myostatin-disabled red sea breams grow to 1.2 the natural average size with the same amount of food and are sold as food in Japan by a startup.

Clinical significance

Mutations

A technique for detecting mutations in myostatin variants has been developed. Mutations that reduce the production of functional myostatin lead to an overgrowth of muscle tissue. Myostatin-related muscle hypertrophy has an incomplete autosomal dominance pattern of inheritance. 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) have increased muscle bulk, but to a lesser degree.

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.

An American boy born in 2005 was diagnosed with a clinically similar condition, but with a somewhat different cause: 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 myostatin receptors is thought to prevent his muscle cells from responding normally to myostatin. He appeared on the television show ''World's Strongest Toddler''.

Therapeutic potential

Further research into myostatin and the myostatin gene may lead to therapies for muscular dystrophy.
* The idea is to introduce substances that block myostatin. A monoclonal antibody specific to myostatin increases muscle mass in mice and monkeys.
*

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%). 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 activin type 2 receptors-signalling proteins myostatin and activin A via activin A/ myostatin inhibitor ACVR2B – tested preliminarily in humans in the form of ACE-031 in the early 2010s – can protect against both muscle and bone loss 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 genetic engineering for targeted deletion of the myostatin gene – under microgravity.
Treating progeric 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.

It remains unclear as to whether long-term treatment of muscular dystrophy with myostatin inhibitors is beneficial, as the depletion of muscle stem cells could worsen the disease later on. , no myostatin-inhibiting drugs for humans are on the market. An antibody genetically engineered to neutralize myostatin, stamulumab

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