The Johns Hopkins researchers who first identified myostatin as a key restrictor of muscle growth in animals now report that excessive amounts of the protein in mice cause rapid and dramatic loss of both muscle and fat, without affecting appetite.
The results, obtained by implanting cells engineered to make extra myostatin into adult mice, support the idea of targeting myostatin to find potential new treatments for muscle-wasting diseases like muscular dystrophy, the team from Johns Hopkins and pharmaceutical company Wyeth report in the May 24 issue of Science.
"We now know that myostatin can affect muscle growth and maintenance in adult animals and that it acts throughout the body," says Se-Jin Lee, M.D., Ph.D., professor of molecular biology and genetics in the School of Medicine's Institute for Basic Biomedical Sciences. "These are key pieces of information, because agents interfering with myostatin could only help if the protein normally acts postnatally."
The situation observed in mice is similar to a common and largely untreatable complication of certain cancers, AIDS and other diseases in humans -- extreme loss of both muscle and fat, even while food consumption is normal. However, the researchers caution that it's still unknown whether myostatin is involved in the human wasting syndrome, called cachexia (ka-KEX-ee-a).
"We don't know whether myostatin is a key mediator in human wasting syndromes, but our findings raise the possibility that blocking myostatin activity may have beneficial effects in patients with cachexia," says Teresa Zimmers, Ph.D., who carried out the studies as a graduate student at Hopkins. "At the very least the finding will help clarify aspects of muscle wasting in general."
Previous studies had proved that myostatin normally limits muscle growth; mice without a working myostatin gene develop more muscle than normal mice, making them so-called "mighty mice." Until now the researchers weren't sure if myostatin would affect adult animals as well.
To find out, the researchers engineered cellular myostatin factories -- hamster cells altered to make and release lots of the protein. The scientists also created a line of these cells that make a naturally occurring myostatin blocker, a protein called follistatin.
After implanting the cells into mice, the scientists saw that those with myostatin-producing cells had dramatic weight loss, even though they ate the same as other mice. Mice with follistatin-producing cells to counteract their myostatin-producing ones lost significantly less weight, the researchers report.
"A few other proteins have been shown to cause muscle wasting in mice, but they also reduced the animals' appetites," says Zimmers. "That myostatin causes wasting without appetite changes makes its wasting syndrome much more similar, at least on the surface, to that in people."
But despite the similarities, the researchers don't know yet whether myostatin is actually important in human muscle wasting diseases or conditions. "Based on what we know about myostatin, we're hopeful that it's involved, but we have no direct evidence of that yet," says Lee.
"Regardless, treating cachexia still would not treat the underlying condition -- cancer, AIDS or what-have-you," notes Lee. "But because cachexia is the direct cause of death in many cases, we hope that relieving it could improve outcomes and treatment options for patients."
When animals don't eat, fat is lost at a predictable rate depending on the body's burning of calories. However, in cachexia, muscle and fat are both lost at an inexplicably fast rate even when food intake is normal. For people, the condition is defined by a loss of 10 percent of body weight in six months or 5 percent in 30 days, says Lee.
Other authors on the paper are Leonidas Koniaris, Aurora Esquela and Alexandra McPherron of the Johns Hopkins School of Medicine; and Monique Davies, Paul Haynes, Kathy Tomkinson and Neil Wolfman of Wyeth Pharmaceuticals, Cambridge, Mass. Zimmers and Koniaris are now at the University of Rochester School of Medicine and Dentistry. Haynes is now at the Torrey Mesa Research Institute, San Diego.
The research was supported by grants from the National Institutes of Health and funds from American Home Products (AHP). Myostatin was licensed by The Johns Hopkins University to MetaMorphix (MMI) and sublicensed to AHP. Lee and McPherron are entitled to a share of sales royalty received by the University from sales of this factor. The University, Lee, McPherron and Esquela also own MMI stock, which is subject to certain restrictions under University policy. Lee is a paid consultant to MMI. The terms of these arrangements are being managed by the University in accordance with its conflict of interest policies.
The above story is based on materials provided by Johns Hopkins Medical Institutions. Note: Materials may be edited for content and length.
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