Of Mighty Mice and Men
Can maximizing muscle help slow ALS?

The phrase “tiny baby” didn’t apply to a bright-eyed infant born into an unusually athletic European family a few years ago. Doctors wrote “extraordinarily muscular” on the medical notes—but, really, you could call the little one musclebound. Now Center scientist Kathryn Wagner believes studies of the little boy, plus related mouse model research, may offer ways to reduce or delay the muscle weakness and wasting that comes with ALS.

Size does matter: The ALS model mouse at left is in trouble. The "mighty" mouse at right, with double-sized muscles (not an ALS model), is proving its worth in slowing muscular dystrophy. It may do the same with ALS.

Overall, Wagner’s work, as well as that of Center colleague Nicholas Maragakis, follows a new path for ALS research that aims to ease patients’ symptoms. As a side benefit, such studies may also move us closer to a cure.

Wagner, a neurologist, specializes in muscular dystrophy (MD). Her recent work centers on a natural protein found chiefly in skeletal muscle—myostatin—that reins in muscle growth. Myostatin acts as a calming hand on skeletal muscle’s resident stem cells to keep them dormant. It’s the reason people’s muscle cells don’t grow in number, getting replaced only when necessary.

Deprive lab mice of myostatin, however, and they become the “mighty mice” of national headlines, healthy but with muscles twice the usual size and strength. On seeing the mice, Wagner thought of a possible application to muscular dystrophy, where, as in ALS, muscle-wasting is a hallmark. As a start, she bred mice that model MD with those lacking myostatin. The resulting animals had such strength and muscle mass—even though still ill—that they led to current national clinical trials of a myostatin-blocking agent for muscular dystrophy patients.

“As for ALS,” says Wagner, “I believe this could help in the same way. Stimulating muscle growth won’t change the underlying disease, but may slow loss of strength. It could provide extra months or years before significant disability or death.” She’s recently crossed ALS model mice (SOD1 mice) and myostatin-free animals, something she hopes will end in patient trials. “What makes us think what works in mice will help humans?” she asks. For one thing, animal and human myostatin operate in extraordinarily similar ways. For another, she says, the little boy who has a myostatin-blocking mutation, as she and colleagues discovered, seems fine without the protein.

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Previous ties to Johns Hopkins led the Weidemeyer family to the Packard Center.