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Gene Research Provides Hope for People with Muscle Diseases - 2004-06-24

A gene responsible for so-called "mighty mice," rodents with unusually bulky muscles, appears to work the same way in humans. The discovery was made in a German newborn with a genetic abnormality that caused him to be extremely muscular. The finding gives hope to people with muscular dystrophy and other muscle wasting diseases.

Since the mid-1990s, people with wasting diseases have eagerly followed research on a gene that seems to regulate muscle growth. The presence of a protein manufactured by the gene, called myostatin, causes muscles to grow normally. Absence of the myostatin protein results in bulky muscles.

Creating drugs to manipulate the gene has the potential to benefit individuals with devastating muscle-wasting diseases such as muscular dystrophy, and AIDS and cancer patients who also suffer from wasting, according to Se-Jin Lee of Johns Hopkins University in Baltimore, Maryland.

"The basis for this is really not completely understood, but these patients will lose a tremendous amount of muscle mass over time. And for example in patients with cancer, this is often the actual cause of mortality," he says. "So, again, if one could find a way to maintain that muscle mass for a longer period of time, again it might buy them more time."

Researcher Se-Jin Lee and colleagues discovered the effects of myostatin in 1997. Dubbed the "secret formula," the researchers created "mighty mice" - with muscles twice the size of normal mouse pups -- by knocking out the gene that produces myostatin.

The scientists then found ways to block the production of myostatin in living mice, resulting in increases in muscle mass of 20 to 30 percent. While the research was tantalizing, there was always doubt that similar results could be achieved in humans.

Then along came the birth of a German child a few years ago with huge muscles. A German doctor contacted Dr. Lee at Johns Hopkins, who ran tests confirming what the German researchers had found: the baby's extra large muscles were caused by an inherited genetic abnormality. "He essentially makes little if any myostatin protein. And the result of that is his muscles are twice the normal size."

At least one drug company has been testing various compounds in mice to interfere with production of myostatin in the hope of increasing muscle mass. The discovery of the infant in Germany suggests a similar mechanism for switching off the gene is possible in humans.

Myostatin is but one of a number of biological factors that has been shown to affect muscle growth. As a result, Elizabeth McNally of the University of Chicago Department of Medicine and Human Genetics says it's unlikely myostatin-based therapies will be a magic bullet for people with disease.

Dr. McNally points to another gene called IGF-1 which produces a hormone that regenerates muscle mass, and the potential of stem cell therapies to repair muscle damage, both of which technologies are actively being studied. "And I think it's going to end up being some combination of approaches that hopefully is going to make a difference for kids with muscular dystrophy," she says.

Dr. McNally is encouraged about the work with the "mighty mice," which studies have showed are healthy despite having inactive myostatin genes.

"But things may work differently when you get to humans. There may be consequences that we don't know about. And so we're still really at the very beginning of being able to understand that," she says. And it isn't going to be until a number of studies are done where we look at side effects and safety profiles before we can begin to understand whether there are negative consequences associated with this."

The early results of a lack of myostatin production in humans are encouraging. Doctors say the baby in Germany is now a completely healthy, normal four-year-old boy.

The latest work involving myostatin is reported in the New England Journal of Medicine.