myostatin update - Mighty mouse gene works the same way in humans

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Mighty mouse gene works the same way in humans News-Medical in

Medical Science News

Saturday, 26-Jun-2004

By studying the genes of a German child born with unusually well

developed muscles, an international research team has discovered the

first evidence that the gene whose loss makes " mighty mice " also

controls muscle growth in people.

Writing in the June 24 issue of the New England Journal of Medicine,

German neurologist Markus Schuelke, M.D., and the team show that the

child's extra-large muscles are due to an inherited mutation that

effectively silences the myostatin gene, proving that its protein

normally keeps muscle development in check in people.

People with muscle-wasting conditions such as muscular dystrophy, and

others just wanting to " bulk up, " have eagerly followed work on

myostatin, hoping for a way to counteract the protein's effects in order

to build or rebuild muscle mass. But while research with mice has

continued to reveal myostatin's role and the effects of interfering with

it, no one knew whether any of the results would be relevant to humans.

" This is the first evidence that myostatin regulates muscle mass in

people as it does in other animals, " says Se-Jin Lee, M.D., Ph.D.,

professor of molecular biology and genetics in the Institute for Basic

Biomedical Sciences at s Hopkins and co-author on the study. " That

gives us a great deal of hope that agents already known to block

myostatin activity in mice may be able to increase muscle mass in

humans, too. "

Lee and his team discovered in 1997 that knocking out the myostatin gene

led to mice that were twice as muscular as their normal siblings,

lending them the moniker " mighty mice. " Later, others showed that

naturally bulky cattle, such as Belgian Blues, got their extra muscles

from lack of myostatin, too.

An unusual opportunity to examine myostatin's role in humans arose when

Schuelke examined a newborn baby boy, almost five years ago, and was

struck by the visible muscles on the infant's upper legs and upper arms.

When ultrasound proved that the muscles were roughly twice as large as

other infants', but otherwise normal, Schuelke realized that a naturally

occurring mutation in the child's myostatin gene might be the cause.

Sequencing the myostatin gene from the boy and his mother, who had been

a professional athlete, revealed a single change in the building blocks

of the gene's DNA. Surprisingly, the change was not in the gene regions

that correspond to the resulting protein, but in the intervening regions

that are used only to create protein-making instructions, thus changing

the gene's protein-building message.

Neurologist Wagner, M.D., Ph.D., who tested the genetic

mutation's effect in laboratory studies. " If the message had been used

to make a protein, it would be much shorter than it should be. But we

think the process doesn't even get that far; instead the cells just

destroy the message. "

Co-authors from Wyeth Research, Cambridge, Mass., analyzed samples of

the child's blood for evidence of the myostatin protein and found none.

" Both copies of the child's myostatin gene have this mutation, so little

if any of the myostatin protein is made, " says Schuelke. " As a result,

he has about twice the muscle mass of other children. "

Completely lacking myostatin, the boy is stronger than other children

his age, and fortunately has no signs of problems with his heart so far,

Schuelke says. But he adds that it's impossible to know whether the lack

of myostatin in that crucial muscle might lead to problems as the boy

gets older.

While other family members -- the boy's mother and her brother, father

and grandfather -- were also reported to have been usually strong, only

the mother's DNA was available for analysis along with her son's.

Schuelke discovered that only one copy of the mother's myostatin gene

had the mutation found in both copies of her son's myostatin gene. (We

have two copies of each gene; one inherited from the mother and one

inherited from the father.)

The s Hopkins researchers were funded by the National Institutes of

Health and the Muscular Dystrophy Association. The German researchers

were funded by the parents' self-help group (Helft dem muskelkranken

Kind).

Authors on the paper are Schuekle, Christoph Hubner, Riebel and

Wolfgang Komen of Charite, University Medical Center Berlin, Germany;

Wagner and Lee of s Hopkins; Stolz and Tobin of Wyeth

Research, Cambridge, Ma.; and Braun of -Luther-University,

Halle-Wittenberg, Germany.

FOR OTHER NEWS RELEASES on Myostatin go to

http://www.hopkinsmedicine.org/Press_releases/2004/06_23_04.html