Mighty Mice Are Less Susceptible To Muscular Dystrophy Gene’s Effects

The Johns Hopkins scientists who first discovered that knocking out a particular muscle gene results in “mighty mice” now report that it also softens the effects of a genetic mutation that causes muscular dystrophy.

The findings, scheduled for the December issue of the Annals of Neurology and currently online, build support for the idea that blocking the activity of that gene, known as myostatin, may one day help treat humans with degenerative muscle diseases.

Working with mice carrying the genetic mutation that causes Duchenne muscular dystrophy in humans, the scientists discovered that mice without the gene for myostatin had less physical damage to their muscles and were stronger than other mice with the Duchenne mutation.

“‘Knocking out’ the myostatin gene isn’t possible for treating patients, but blocking the myostatin protein might be,” says senior investigator Se-Jin Lee, M.D., Ph.D., professor of molecular biology and genetics at Johns Hopkins School of Medicine. “However, myostatin still needs to be studied in people to see if it has the same role in our muscles as it has in mice.”

The researchers caution that, even if myostatin does limit muscle growth in people, blocking it would not cure muscular dystrophy or any other degenerative muscle condition because the underlying cause of disease would be unchanged.

“However, increasing muscle mass and strength by blocking myostatin could conceivably delay progression or improve quality of life,” notes first author Kathryn Wagner, M.D., Ph.D., assistant professor of neurology at Hopkins.

The Hopkins team bred mice without the myostatin gene with mice carrying the genetic mutation that causes Duchenne muscular dystrophy in humans. Muscular dystrophy mice completely lacking myostatin were more muscular and stronger than those with myostatin at 3, 6 and 9 months of age, the researchers report. Perhaps most importantly, their muscle tissue appeared to be healthier.

Duchenne muscular dystrophy is the most common muscular dystrophy and the most common inherited lethal disease of childhood, affecting 1 in 3,500 live male births. (The genetic mutation that causes it is found on the X chromosome, and so is “covered up” in girls, who have two X chromosomes.) There’s no good treatment at this time, and few patients survive into adulthood.

Early in the disease in humans, the regenerative capacity of stem cells in muscle, known as satellite cells, keep up with the damage, but eventually the damaging factors win. The result is not just loss of muscle, but also its replacement with non-muscle tissues, essentially scar tissue and fat.

This scarring process, called fibrosis, is also seen in mice with the muscular dystrophy-causing mutation. The Hopkins team reports that loss of myostatin function significantly reduced the amount of fibrosis, suggesting that the muscle regenerative process was improved.

The Hopkins scientists hope to unravel the mechanism of muscle regeneration in mice with and without myostatin, possibly revealing even better targets for improving the process. They also plan to use special genetic manipulations to turn off the myostatin gene in adult mice, rather than at conception, to see if losing myostatin later in the course of muscular dystrophy is also beneficial.

Authors on the study are Wagner, Lee, Alexandra McPherron and Nicole Winik, all of The Johns Hopkins University School of Medicine. Funding was provided by the National Institutes of Health, the Duchenne Parent Project, and the Muscular Dystrophy Association.

Myostatin was licensed by The Johns Hopkins University to MetaMorphix, Inc., and sublicensed to Wyeth Pharmaceuticals, Inc. Lee and McPherron are entitled to a share of sales royalty received by the University from sales of this factor. Lee, McPherron and the University own MetaMorphix stock, which is subject to certain restrictions under University policy. Lee is a paid consultant to MetaMorphix. The terms of these arrangements are being managed by the University in accordance with its conflict of interest policies.