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.
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,"
Se Jin Lee, a professor of
molecular biology and
genetics in Johns Hopkins' Institute for Basic
Biomedical Sciences, said. "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,
Lee said.
"We don't know how many other muscle-limiting proteins
there may be or which ones they are," Lee said, "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, Lee said. 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," Lee said. "We weren't really expecting to see
an effect, let alone an effect that sizable."
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 those of 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 those of 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.
Although the new agent seems quite promising, its
advantage in potency also requires extra caution, Lee said.
"We don't know what else the new agent is affecting or
whether those effects will turn out to be entirely
beneficial."
Lee said they 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. The new agent was produced and first
tested at Wyeth, and the inhibitor used in the current
mouse studies was produced at MetaMorphix. All 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 Lee and Suzanne Sebald, both
of Johns Hopkins; Lori Reed, Wyeth Exploratory Drug Safety;
Monique Davies, Stefan Girgenrath, Mary Goad, Kathy
Tomkinson, Jill Wright and Neil Wolfman, Wyeth Discovery
Research; Christopher Barker, Gregory Ehrmantraut, James
Holmstrom and Betty Trowell, MetaMorphix Canada; Barry
Gertz, Man Shiow Jiang, Li fang Liang, Edwin Quattlebaum
and Ronald Stotish, MetaMorphix, Beltsville, Md.; Martin
Matzuk, Baylor College of Medicine; and En Li, 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 JHU from sales of this
factor. JHU 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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