The Johns Hopkins scientists who first created "mighty mice" have developed, with pharmaceutical company Wyeth and the biotechnology firm MetaMorphix, an agent that's more effective at increasing muscle mass in mice than a related potential treatment for muscular dystrophy now in clinical trials.
The new agent is a version of a cellular docking point for the muscle-limiting protein myostatin. In mice, just two weekly injections of the new agent triggered a 60 percent increase in muscle size, the researchers report in the Proceedings of the National Academy of Sciences, published online Dec. 5 and available publicly through the journal's website.
The researchers' original mighty mice, created by knocking out the gene that codes for myostatin, grew muscles twice as big as normal mice. An antibody against myostatin now in clinical trials caused mice to develop muscles 25 percent larger than those of untreated mice after five weeks or more of treatment.
The researchers' expectation is that blocking myostatin might help maintain critical muscle strength in people whose muscles are wasting due to diseases like muscular dystrophy or side effects from cancer treatment or AIDS.
"This new inhibitor of myostatin, known as ACVR2B, is very potent and gives very dramatic effects in the mice," says Se-Jin Lee, M.D., Ph.D., a professor of molecular biology and genetics in Johns Hopkins' Institute for Basic Biomedical Sciences. "Its effects were larger and faster than we've seen with any other agent, and they were even larger than we expected."
ACVR2B is the business end of a cellular docking point for the myostatin protein, and it probably works in part by mopping up myostatin so it can't exert its muscle-inhibiting influence. But the researchers' experiments also show that the new agent's extra potency stems from its ability to block more than just myostatin, says Lee.
"We don't know how many other muscle-limiting proteins there may be or which ones they are," says Lee, "but these experiments clearly show that myostatin is not the whole story."
The evidence for other players came from experiments with mighty mice themselves. Because these mice don't have any myostatin, any effects of injecting the new agent would come from its effects on other proteins, explains Lee. After five injections over four weeks, mighty mice injected with the new agent had muscles 24 percent larger than their counterparts that didn't get the new agent.
"In some ways this was supposed to be a control experiment," says Lee. "We weren't really expecting to see an effect, let alone an effect that sizeable."
In other experiments with normal female mice, weekly injections of the new agent provided the biggest effect on muscle growth after just two weeks at the highest dose given (50 milligrams per kilogram mouse weight). Depending on the muscle group analyzed, the treated mice's muscles were bigger than untreated mice by 39 percent (the gastrocnemius [calf] muscle) to 61 percent (the triceps).
After just one week, mice given a fifth of that highest dose had muscles 16 percent to 25 percent bigger than untreated mice, depending on the muscle group analyzed, and mice treated with one injection a week for two, three or four weeks continued to gain muscle mass.
But although the new agent seems quite promising, its advantage in potency also requires extra caution. "We don't know what else the new agent is affecting or whether those effects will turn out to be entirely beneficial," says Lee.
Lee says they also are conducting experiments with the mice now to see whether the effect lasts after injections cease and whether it helps a mouse model of muscular dystrophy retain enough muscle strength to prolong life.
The research was funded by grants from the National Institute of Child Health and Human Development and the National Cancer Institute and by funds from Wyeth Research and MetaMorphix Inc. The new agent was produced and first tested at Wyeth, and the inhibitor used in the current mouse studies was produced at MetaMorphix. All of the mouse studies described in this article and in the PNAS paper were conducted in Lee's laboratory at Johns Hopkins.
Authors on the report are Se-Jin Lee and Suzanne Sebald of Johns Hopkins; Lori Reed of Wyeth Exploratory Drug Safety, and Monique Davies, Stefan Girgenrath, Mary Goad, Kathy Tomkinson, Jill Wright and Neil Wolfman of Wyeth Discovery Research; Christopher Barker, Gregory Ehrmantraut, James Holmstrom and Betty Trowell of MetaMorphix Canada; Barry Gertz, Man-Shiow Jiang, Li-fang Liang, Edwin Quattlebaum and Ronald Stotish of MetaMorphix, Beltsville, Md.; Martin Matzuk of Baylor College of Medicine; and En Li of Harvard Medical School.
Myostatin was licensed by The Johns Hopkins University to MetaMorphix and sublicensed to Wyeth. Lee is entitled to a share of sales royalty received by The Johns Hopkins University from sales of this factor. The Johns Hopkins University and Lee also own MetaMorphix stock, which is subject to certain restrictions under university policy. Lee is a paid consultant to MetaMorphix. The terms of these arrangements are being managed by the university in accordance with its conflict of interest policies.
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