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New 'mighty mice' research brings muscle growth closer to reality

Johns Hopkins Medicine

The Johns Hopkins scientists who first created "mighty mice" by genetically engineering animals with a missing growth regulator called myostatin have now created a second group of mice whose genetic makeup shows it's possible to get the same effect by blocking the gene for myostatin, rather than entirely knocking it out.

Reporting in the July 16 issue of the Proceedings of the National Academy of Sciences, the researchers say they have identified several proteins (follastatin, mutant activin type II receptors, and myostatin propetide) that can block the activity of myostatin. Moreover, they have engineered mice with normal myostatin, but various levels of these blockers.

"By expressing high levels of these proteins in mice, we have been able to increase muscle mass to levels comparable to those seen in mice completely lacking myostatin," says Se-Jin Lee, M.D., Ph.D., lead author of the Hopkins study. "Although more study is needed to prove that these mice are good models for humans and to find other myostatin signaling components, our work suggests that these kinds of myostatin antagonists may be effective muscle-enhancing agents for both human and agricultural applications."

The 1997 report from Lee and his colleagues focused on the muscle-building capability of knocking out, or deleting the myostatin gene, to allow the buildup of skeletal muscle in the animals.

"Until now, it's been purely theoretical that we could block the gene and obtain the same muscle-building effect as deleting the gene," Lee continues.

The researchers discovered that while mice that were engineered to produce large amounts of follistatin exhibited the most herculean muscles, the other two groups, one with excess mutant activin II receptors and one with myostatin peptide, also showed increased muscle growth.

Scientists are hopeful that the finding will provide new opportunities to treat many muscle-wasting diseases like muscular dystrophy or cachexia, the muscle loss that accompanies some cancers and AIDS. Blocking myostatin in animals could also create livestock with more meat and relatively less fat.

"The agricultural applications are probably more straightforward, since conceivably, one could try to find ways to block myostatin activity early during development," says Lee. "For human applications, this research is just the beginning." Among the important remaining questions is whether blocking myostatin postnatally, as would be required to treat human diseases, is effective. "These proteins all block myostatin outside the cell, so we need to see if administering these proteins, rather than altering the genome, can provide similar results," he explains.


The other author of the study is Alexandra McPherron, Ph.D., from Hopkins. The study was funded by the National Institutes of Health. Myostatin was licensed to MetaMorphix, which was founded by Lee in 1995. The company was established to commercialize on work by Hopkins and Genetics Institute, a private pharmaceutical company, in the field of growth and differentiation factors. Myostatin is sublicensed to American Home Products and Cape Aquaculture Technologies (CAT). The authors are entitled to a share of sales royalty received by the University for sales of this factor. The authors and the University own MetaMorphix stock; the authors also own CAT stock. Both stocks are subject to certain restrictions under University policy. Lee is a consultant to MetaMorphix and CAT, and McPherron is a consultant to CAT. The terms of these arrangements are being managed by the University in accordance with its conflict-of- interest policies.

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