University of Minnesota
Normal (above) mouse muscle cells show an orderly network of microtubules (green lines) that is disordered in mice with muscular dystrophy (below).
Photo: Evelyn Ralston, NIH
How the key protein in Duchenne muscular dystrophy stabilizes muscle cells during contraction
By Deane Morrison
The tragedy of a broken bridge doesn’t confine itself to the transportation realm. It also stalks the boys born with Duchenne muscular dystrophy, in whose every muscle cell a major bridge lies broken.
Work by James Ervasti, a University of Minnesota professor of biochemistry, molecular biology and biophysics, and his colleagues reveals a new reason why that bridge—a protein called dystrophin—is crucial to normal muscle function.
Published in the Journal of Cell Biology, the research may help efforts to cure the deadly disease, which strikes one in 3,500 boys. (Females may be carriers, but they don't get the disease.)
Pillar of strength
Duchenne patients carry a genetic defect that cripples dystrophin, and with it a muscle cell’s internal structure and ability to absorb the shock from repeated cycles of contraction and relaxation.
Central to the structure of muscle cells are long, thin bundles of protein filaments that shorten to produce contraction and lengthen to produce relaxation. At regular intervals the bundles are encircled by ringlike protein structures; each connects to dystrophin, which in turn is anchored to the “cell membrane,” which encloses the cell.
These multiple connections even out the mechanical stress on cell membranes as the cell contracts and relaxes.
“Dystrophin is a mechanical shock absorber protecting membranes from stresses in contraction and relaxation,” says Ervasti.
He likens dystrophin molecules to shock absorbers in cars, where the bundles of contractile filaments are the wheels and the cell membrane is the shell of the car. With nonfunctional shocks, a car would suffer progressive damage to its body, including doors and windows, and could no longer control who and what gets in or out of the vehicle.
“Dystrophin is a mechanical shock absorber protecting membranes from stresses in contraction and relaxation.”
Similarly, muscle cells have structures on their outer membranes that control what gets in or out of the cells. If dystrophin can’t do its job, those structures deteriorate.
Dystrophin also has long been known to connect to two types of protein filaments that act like 2 x 4’s in a house, giving the cell internal structure and strength. In his most recent work, Ervasti, along with University M.D./Ph.D. student Kurt Prins and Evelyn Ralston’s group at the National Institutes of Health, found that dystrophin also connects to a third supporting element: an orderly, 3-D lattice of filaments called microtubules. These form an internal railroad for transporting nutrients, chemical signals, and other materials.
The researchers showed that this lattice was disordered in mice lacking functional dystrophin. The finding cemented dystrophin’s role as a central pillar of muscle cell organization.
“There are about 40 neuromuscular disorders, and many are caused by defects in either dystrophin or its associated proteins,” Ervasti observes.
Doing the impossible
Can defective dystrophin be replaced? That was long considered impossible, because cells aren’t designed to take delivery of proteins they normally make themselves.
Earlier this year, however, Ervasti, led a team that showed it was possible to replace dystrophin in mice with muscular dystrophy. If successfully adapted to humans, it could mean a therapy to extend the lives of boys born with Duchenne.
“It would be like giving insulin to a patient with type I diabetes,” Ervasti explains.
The researchers still must demonstrate, however, that the technique can be modified to safely replace dystrophin in humans. But things are looking up.
“Several companies are interested in developing dystrophin replacement therapy,” says Ervasti.