Myostatin is a potent regulator of skeletal muscle. Following Dr. Se-Jin Lee’s (the scientific founder of MetaMorphix®) discovery of the myostatin protein and the gene encoding its production in 1997, he conducted controlled studies to characterize myostatin. Dr. Lee deleted the myostatin gene in mice using a technique referred to as gene “knockout,” which generated mice lacking the capability to produce the myostatin protein. Compared with their otherwise identical littermates, the knockout mice exhibited:

• Increased Muscle Mass: Knockout mice exhibited a two - to threefold
· increase in skeletal muscle mass.
• Decreased Fat Tissue: Knockout mice have 33% less body fat.
• Tissue Specificity: The myostatin protein increases skeletal muscle,
· but has no impact on cardiac or smooth muscle.
• No Abnormalities: Lifespan studies in knockout mice showed they
· had no abnormalities other than increased skeletal muscle.
• No Effect on Reproduction: knockout mice reproduced normally and,
· when bred with control mice, produced offspring with an intermediate
· increase in skeletal muscle.
• Dual Mode of Action: Knockout mice had an increase in number of
· muscle fibers (hyperplasia) as well as size of fibers (hypertrophy).
· They also had fewer and smaller fat cells.
• Broad Application Across Species: The biologically active region of the
· Myostatin gene is identical in mice, pigs, chickens, turkeys, and humans.

Reference: (Nature, May 1997)


Potential Livestock Benefits
Producer and Processor
• Increased live weight
• Accelerated weight gain
• Increased carcass weight
• Improved feeding efficiency
• Reduced waste

Consumer
• Increased protein
• Decreased fat
• Increased tenderness


LIVESTOCK PROOF OF CONCEPT
The Belgian Blue and Piedmontese cattle breeds are known to express a “double muscle” phenomenon and are renowned for their extremely lean, tender meat. Double muscling in cattle has long been a trait of interest to processors as consumers increasingly have favored lean meat.

By sequencing the Myostatin gene in the Belgian Blue and Piedmontese, it was discovered that both “double muscle” breeds had natural mutations in the Myostatin coding sequence. Studies determined that:

• the observed mutations were responsible for the loss of biologically
· functional myostatin.
• Double-muscled Belgian Blue and Piedmontese cattle have large
· bundles of small muscle fibers, due to the lack of a functional
· myostatin gene. This results in a premium-priced meat that is tender
· without added intramuscular fat.

The beneficial effects of the loss of biologically functional myostatin include increased carcass weight, improved feed efficiency, reduced fat content, and increased protein content.

References
Alexandra C. McPherron, Ann M. Lawler, Se-Jin Lee. Regulation of skeletal muscle mass in mice by a new TGF-p superfamily member. Nature 387 , 83 - 90 ( 01 May 1997 ) Letters to Editor.

Alexandra C. McPherron and Se-Jin Lee. Double muscling in cattle due to mutations in the myostatin gene. Proc. Natl. Acad. Sci. USA, Vol. 94, pp. 12457-12461, November 1997.

Hanset, R., Michaux, G., Stasse, A., 1987. Relationships between growth rate, carcass composition, feed intake, feed conversion ratio and income in four biological types of cattle. Genet. Sel. Evol. 19, 225-248.


HUMAN THERAPEUTIC PROOF OF CONCEPT
Muscular dystrophy: Studies conducted by Wyeth and University of Pennsylvania School of Medicine as well as those from JHU demonstrate that abolishing myostatin activity in a line of mice that have muscular dystrophy results in increased muscle mass, size, and strength, while limiting breakdown of muscle tissue. Importantly, the diaphragm muscle shows less replacement of muscle tissue with fibroid and fatty tissue. These exciting results suggest that in addition to increased growth of muscle tissue, inhibition of myostatin may provide a slowing of the muscle degradation typically seen in this disease.

Muscle Wasting Diseases: Studies conducted by JHU demonstrated that over-expression of myostatin induces profound muscle loss analogous to that seen in human cachexia. These observations are important because it identifies myostatin as a key pharmacologic target for treating chronic muscle wasting commonly associated with cancer and AIDS as well as age-related muscle wasting called sarcopenia.

Type II diabetes : Studies conducted by Wyeth, JHU, and others have demonstrated that elimination of myostatin provides for an improved glucose regulation in diabetic mice.

Obesity: Studies by JHU, Wyeth and others have also demonstrated that deletion of myostatin results in a significant and dramatic reduction in fat mass in obese mice.

McPherron, A.C., Lee, S-J. 2002. Suppression of body fat accumulation in myostatin-deficient mice. J Clin Invest. 109 (5): 595–601.
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