Myostatin

Myostatin (also known as growth differentiation factor 8) 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.

Animals lacking myostatin have significantly larger muscles.

Discovery and sequencing

"Mighty mouse"

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.^[1] These mice were subsequently named "mighty mice".

Naturally occurring myostatin "nulls" have been identified in cows, whippets, and humans; in each case the result is a dramatic increase in muscle mass. Further, the gene has been shown to be conserved in invertebrates, including many fish species.

Effects of inactivated myostatin in cattle

"Belgian Blue"

After that opening in the same 1997 in several laboratories cloned and have established sequence of a gene myostatin at a horned cattle of breeds «Belgian blue» and Piedmontese. It was revealed that these animals have mutations in a gene myostatin (various in each of breeds) which in one way or another lead to absence functionally active myostatin (McPherron A., Lee S-J., 1997; Grobet L. et al., 1997; Kambadur R. et al., 1997). Unlike mice to the damaged gene myostatin at these breeds occurs only hyperplasia a muscular fabric without a hypertrophy. Though with reference to this meat cattle use the term "a phenotype of the doubled muscular weight", the total increase in all muscles makes no more than 40 % in comparison with other meat breeds, but also it, is unconditional, invaluable to meat animal industries. The photo of "Belgian Blue" shows, how absence functionally active myostatin (the gene myostatin works, but the synthesized fiber is inactive) leads to increase in muscular weight.^[2][3][4]

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.^{[5][6][7][8][9][10]}

An American boy born in 2005 was diagnosed with a clinically similar condition but with a somewhat different cause.^[11] In contrast to the first case, this boy produces a functional myostatin, however he has a defect in his myostatin receptor so that his muscles do not respond to the myostatin signal.

Performance enhancement in dogs

A "bully whippet" with a homozygous mutation in myostatin.^[12]

A 2007 NIH study in PLOS Genetics^[12] found a significant relationship in whippets between a myostatin mutation and racing performance. Whippets that were heterozygous for a 2 base pair deletion in myostatin were significantly over-represented in the top racing classes. The mutation resulted in a truncated myostatin mRNA, 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. In order for it to be activated, a protease cleaves the NH3-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 co-receptor called Alk-3 or Alk-4. This co-receptor then initiates a cell signaling cascade in the muscle, which includes the activation of transcription factors in the SMAD family - SMAD3 and SMAD4. 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 which 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.^[13] 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, presumably by blocking myostatin's action. Similar results in monkeys were published in 2009.^[14]

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%).^[15] It is thought that binding of myostatin to the soluble activin receptor prevents it from interacting with the cell-bound receptors.

It remains unclear 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.^[16] The inhibitor is called MYO-029, but after an initial clinical trial, Wyeth says they won't be developing the drug.^[17] Some athletes, eager to get their hands on such drugs, turn to the internet, where fake "myostatin blockers" are being sold.^[13]

Johns Hopkins University has developed a technique for detecting mutations in myostatin variants.^[18]

In fiction

• A plot feature in The Incredible Hulk (TV series) episode "A Death in the Family" (Season 1, ep 2) is a fictional drug called myostatin. This episode came out about 20 years before real myostatin was discovered.

See also

• Muscular dystrophy
• Muscle hypertrophy
• Superhuman strength

References

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