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Definition of Myostatin

E-Newsletter No. 62

Myostatin: A growth factor that regulates the size of muscles beginning in early embryonic development and continuing throughout life. Myostatin acts by inhibiting the growth of muscles. It prevents them from growing too large. Myostatin is also known as growth and differentiation factor 8 (GDF-8). It is a protein made up of two identical subunits. Each subunit contains 110 amino acids. The gene encoding myostatin is termed MSTN (or GDF8) and is on chromosome 2 in band 2q32.1.

Myostatin is a member of the transforming growth factor beta (TGF-beta) family. All of the members of this gene family regulate growth and differentiation from early embryogenesis to mature cell types and tissues.

Myostatin was first found to regulate muscle mass in mice from which the gene encoding myostatin had been knocked out (deleted). In these "mighty mice," there is muscle overgrowth due to an increase both in the number of myocytes (muscle cells) and the size (hypertrophy) of the myofibers (muscle fibers). Breeds of cattle with exceptional muscle development -- referred to as "double-muscled" cattle -- have a mutation in the bovine MSTN gene encoding myostatin.

A child born with very large muscles was discovered to have mutation of the MSTN gene encoding myostatin, providing very strong evidence that myostatin is a lead actor in regulating muscle mass in humans. Aside from the increase in the size of his muscles, the child appeared normal at age 4. The child has a loss-of-function mutation in the MSTN gene that inactivates myostatin It may be possible to increase muscle mass and strength by inactivating myostatin in people with muscle wasting due to disease (Schuelke M et al. New Engl J Med 350:2682,2004)

Higher concentrations of myostatin in the body cause the individual to have less developed muscles. The myostatin protein is produced in skeletal muscle cells, circulates in the blood and acts on muscle tissue, apparently by slowing down the development of muscle stem cells . The precise mechanism remains unknown. Myostatin and the associated gene were discovered in 1997 by geneticists McPherron and Se-Jin Lee, who also produced a strain of mutant mice that lack the gene and are about twice as strong as normal mice. The gene has been sequenced in humans, mice, zebrafish and several other animals, showing few differences among species. Lee found in 1997 that the strong /Belgian Blue / and /Piedmontese/ cattle strains have a defective myostatin gene; these strains have been produced through breeding. In 2001, Lee created mice with intact myostatin gene and large muscle mass by inserting mutations that boosted the production of various myostatin blocking substances. 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. 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. In 2004 , 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%). 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 dystropy with myostatin inhibitors is beneficial: the depletion of muscle stem cells could worsen the disease later on. As of 2006, no myostatin inhibiting drugs for humans are on the market, but an antibody genetically engineered to neutralize myostatin is being developed by New Jersey pharmaceutical company Wyeth . The inhibitor is called MYO-029 and is currently undergoing human testing. Some athletes, eager to get their hands on such drugs, turn to the internet, where fake "myostatin blockers" are being sold. Myostatin is a member of the TGF-beta superfamily of proteins. Human Myostatin consists of two identical subunits, each consisting of 110 amino acid residues. Its total molecular weight is 25.0 kDa . It can be produced in genetically engineered E. coli and is available for sale. Johns Hopkins University owns the patents on myostatin.

Also see:

Big Blue Double-Muscle Syndrome

Sarcopenia -- The Role of Mitochondrial DNA (mt DNA) Deletion Mutation

Myoplex® Effectiveness For Sarcopenia of Aging

Muscle Builder Myoplex®Induces Il-4

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