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 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 lead author Se-Jin Lee, an associate professor in the Department of Molecular Biology and Genetics in the School of Medicine. "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," Lee says. "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.
The other author of the study is Alexandra McPherron, a postdoctoral fellow in Molecular Biology and Genetics. The study was funded by the National Institutes of Health.