Blocking Myostatin Proves Beneficial in Mice with DMD

New research shows that using a drug or small molecule to inhibit myostatin -- a secreted protein that inhibits muscle growth -- might one day be an effective treatment for Duchenne muscular dystrophy (DMD).

In a new study published online in November in the Annals of Neurology, MDA grantee Kathryn Wagner of Johns Hopkins University in Baltimore shows that loss of the myostatin gene increases muscle mass and strength in mice with DMD.

In another study published in the Nov. 28 issue of Nature, Tejvir S. Khurana of the University of Pennsylvania and Pennsylvania Muscle Institute in Philadelphia reports that treatment with a myostatin-blocking antibody has similar effects on mice with DMD. Antibodies are the Y-shaped missiles that immune cells use to attack bacteria and other foreign substances.

For her study, Wagner teamed up with Hopkins geneticist Se-Jin Lee, who discovered myostatin and created a strain of mutant mice lacking the gene. The researchers bred those mice to mice with DMD, and found that the offspring had significantly larger, stronger muscles than diseased mice with an intact myostatin gene. The double-mutant mice also had less fibrosis (the replacement of muscle by fat and connective tissue).

For his study, Khurana collaborated with Wyeth Pharmaceuticals of Cambridge, Mass., whose scientists developed the antimyostatin antibody. Khurana gave mice with DMD weekly injections of the antibody into the abdominal cavity, before they showed signs of the disease. After three months, they had increased muscle mass and strength in their leg muscles, and less degeneration and fibrosis of their respiratory muscles, when compared to untreated mice. They also had lower blood levels of creatine kinase (CK) — a protein that leaks out of damaged muscle. (For reasons that aren't clear, in Wagner's study, deleting the myostatin gene didn't lower CK levels in the mice.)

“There’s a real possibility for moving forward in clinical trials with [myostatin inhibition],” Wagner said. “There are other ways to inhibit myostatin that might be pursued, but antibodies are the ones furthest down the pipeline.”

But Khurana said the research is years away from clinical trials, noting that the myostatin-blocking antibodies he used were made in mouse cells to target mouse myostatin. Specific human antibodies would have to be made before proceeding to clinical trials, he said.

He also cautioned that long-term inhibition of myostatin might not be safe for youngsters with DMD, since the protein regulates muscle progenitor cells (immature cells that form muscle).

“There’s a very real risk that if you block myostatin in humans in an unregulated and unmonitored fashion, you could deplete the these cells at an accelerated rate and actually worsen the [muscular dystrophy],” he said.

Khurana's group plans to address this issue in further studies of the mice, and to test myostatin blockade in dogs with DMD — a high benchmark for assessing effectiveness and safety since the dogs are larger and have a more severe disease than the mice. He also plans to test the strategy in animal models of limb-girdle muscular dystrophy.

Wagner plans to “switch off” the myostatin gene in mice with DMD at different time points to determine if the treatment is still effective at late stages of the disease.