Muscular German boy sheds new light on muscle development and genetics

By studying the genetic make up of a German boy 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.

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 Johns 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.

"The mutation caused the gene's message, the messenger RNA, to be wrong," says Hopkins neurologist Kathryn 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.)