Myostatin Therapies Hold Hope for Muscle Diseases

Mighty Mouse was not just a cartoon. Ten years ago, scientists demonstrated that they could increase an animal's muscle mass by manipulating a protein in mice called myostatin. Now drugs that affect myostatin are being hailed as the best hope yet for people with muscle-wasting diseases.

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Now, a story about a mighty mouse, a skinny man, some Belgian cattle, and a remarkable scientific discovery. The outcome could change the lives of hundreds of thousands of people with muscle-wasting diseases.

NPR's Jon Hamilton reports.

JON HAMILTON: The mighty mouse lives with some relatively puny neighbors at Johns Hopkins University in Baltimore. They all live in clear plastic cages under the watchful eye of a scientist named Se-Jin Lee.

Dr. SE-JIN LEE: (Johns Hopkins University): Okay, so here's an example of a completely normal mouse.

HAMILTON: Lee holds the mouse up by its tail. Then he pops the lid on the cage holding Mighty Mouse.

Dr. LEE: This is one that I've actually engineered. It has about four times the muscle mass of normal mice.

HAMILTON: Even dangling by its tail, this mouse looks intimidating. And Lee says the view is a lot more impressive beneath all that fur and skin.

Mr. LEE: If you open up the mouse and actually look at the muscles, it is just really unbelievable.

HAMILTON: But even just looking at him here, he's got huge...

Dr. LEE: Yeah.

HAMILTON: I don't know what muscle that is - quadriceps, bicep?

Dr. LEE: Yeah. Down here? Yeah.

HAMILTON: His shoulders are incredibly bulky.

Dr. LEE: Right. These animals are almost getting to the point where they don't really look like mice, you know, they have a different look to them.

HAMILTON: Dr. Lee is the skinny man in this story.

Ms. ALEXANDRA McFARREN(ph) (Researcher, National Institutes of Health): Other scientists refer to him as the skinniest man in the world.

HAMILTON: That's Alexandra McFarren. She's a researcher at the National Institutes of Health these days, but she was working with Lee at Johns Hopkins when they made the discovery that led to the first Mighty Mouse. They were studying factors that affect growth. McFarren was concentrating on a protein found in muscles. She thought it might be crucial to muscle development. So the team used genetic engineering to create a mouse that was unable to make the protein. McFarren expected the mouse to be weak and die, but it lived.

Ms. MCFARREN: I was very disappointed because the mouse was alive. I just thought, my factor will be so important that the mouse will certainly die. But here I had an adult mouse that was alive, and so that was rather depressing.

HAMILTON: The mouse didn't just survive, it bulked up.

Ms. MCFARREN: Every day, I went down to look at it, watching it get older and older. And I swore that it was kind of funny looking compared to the others. And I tried to show other people in the lab, but they really didn't believe me. It was like, it's just an odd-looking mouse

HAMILTON: How odd didn't become clear until McFarren began to dissect the mouse. She was so shocked by what she saw that she called in Lee.

Dr. LEE: It looked like Schwarzenegger.

HAMILTON: Removing the protein had created a mouse with muscles twice the usual size. That meant the protein's job in normal mice was to limit muscle growth. The team named the protein myostatin, and they immediately began wondering whether blocking myostatin might one day help people whose muscles were wasting away - people with muscular dystrophy or cancer or AIDS.

Mighty Mouse first made headlines in 1997. Lee says the lab's phone started ringing almost immediately. A lot of the calls were from bodybuilders. They wanted to take what Mighty Mouse was taking, which clearly wasn't possible. But Lee realized that bodybuilders might be able to help him. Maybe they had big muscles because they lacked myostatin, too.

LEE: I started by going to the grocery store and buying every bodybuilding magazine I could find to try to learn a little more about this. And you would not believe the looks that you get from the cashier when someone with my body build walks up with a stack of body building magazines.

HAMILTON: Lee put an ad in Muscle and Fitness, asking bodybuilders to volunteer for a study of their DNA.

LEE: We probably had over 1,000 phone calls and letters.

HAMILTON: Unfortunately, Lee didn't find any people with mutations in the myostatin gene. So he decided to investigate some other animals, which is where those Belgian cattle come in. They're a breed known as Belgian Blues.

Ms. DEE GARRELS (Cattle Rancher): Instead of putting on fat, no matter how much you feed them, they put on meat.

HAMILTON: Meat, as in muscle, says Dee Garrels. She and her partner raise Belgian Blues in Stockton, Missouri. Garrels says she got a call from the team at Johns Hopkins. She'd never heard of myostatin, but she agreed to help the researchers anyway.

Ms. GARRELS: Well, they got the cattle in, and contacted our local veterinarian. And he pulled forty vials of blood from full-bloods, three-quarter-bloods, half-bloods, and then just regular cattle.

HAMILTON: It turned out that all the full-bloods had a mutation in the gene for myostatin. Centuries of selective breeding had made them a lot like the mighty mice created by genetic engineering. This confirmed that myostatin affected muscles in more than just mice. But the big question was still, what about people? The answer came from a surprising place, a delivery room in Germany. Lee says a doctor named Marcus Schulke(ph) was called in to examine a newborn baby who seemed jittery.

Dr. LEE: He immediately noticed that the baby was quite muscular. And he went on to show that this child carried a mutation in both copies of his myostatin gene.

HAMILTON: That was several years ago. The child remains healthy and very muscular. By the time the German baby arrived, myostatin was already getting a lot of attention from people hoping for a cure for muscle-wasting diseases. People like Pat Furlong, who lost two sons to muscular dystrophy. She says she could only watch as their muscles got weaker.

Ms. PAT FURLONG (Parent Project Muscular Dystrophy): Your sons can't keep up with their healthy peers. So often there's a delay in walking. And certainly, you might even pass that off. But by the time they're two or three years old, they're really not keeping up with their peers. They can't get off the ground, and they're clearly weak.

HAMILTON: Doctors told Furlong there wasn't much they could do for her boys.

Ms. FURLONG: They were off their feet at eight, they couldn't move their arms by 15, and they died at late 15 and 17.

HAMILTON: That was a decade ago. Today, Furlong runs a group called Parent Project Muscular Dystrophy in Middletown, Ohio. The discovery that myostatin affects muscles in people was what everyone had been hoping for. It helped clear the way for human trials of an experimental treatment that blocks myostatin. The treatment is an antibody being developed by the drug company Wyeth. It's being tested on more than 100 patients with a form of muscular dystrophy. The idea is it might help rebuild their muscles. Furlong says there's a lot of anticipation about the Wyeth study among members of her group.

Ms. FURLONG: I have a parent that calls me from Boston weekly and asks me if I can get the Wyeth results. Is there a way?

HAMILTON: There isn't. The results probably won't be out until the middle of next year. Lee says even if they're disappointing, he's pretty sure that his work with mice and myostatin is going to make a difference to people. One reason is that he's identified a new molecule that acts on myostatin in a slightly different way. And he says it's much more powerful than the antibody being used in the Wyeth trial.

LEE: We can administer just two injections of this protein to a normal adult mouse over a span of two weeks and get the muscle to grow by 60 percent.

HAMILTON: And his latest mouse is the mightiest yet. So he's breeding more. They're waiting in plastic cages in his lab. Flexing.

John Hamilton, NPR News.

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