A complex of proteins protects muscles from collapsing during contraction.

The surface of a muscle cell, with ankyrin proteins (red) and neuromuscular junctions (yellow).

A protein important for maintaining the heart's rhythm also helps muscle cells retain their structure during stress. The discovery has broad implications for other cell types and for human diseases, including muscular dystrophy, says Vann Bennett, an HHMI investigator at Duke University Medical Center.

Bennett's group is studying a family of three proteins called ankyrins, which Bennett discovered in red blood cells in 1979. In many cell types, ankyrins anchor membrane-spanning proteins. The current study—published in the December 26, 2008, issue of Cell—focuses on two ankyrins: ankyrin-B, which the Bennett group established as important to heart rhythm, and ankyrin-G.

Mice that lack ankyrin-B die soon after birth. But Gai Ayalon, a postdoctoral fellow in Bennett's lab, found a way to study its effects by suppressing it in the leg muscles of adult mice. In the ankyrin-B-deficient cells, two other proteins known to support cell structure were missing from the cell membrane. One, dystrophin, is key to cellular structure and support (mutations in the human dystrophin gene cause some types of muscular dystrophy). Another, beta-dystroglycan, forms a complex with dystrophin to protect the cell membrane during muscle contraction. Both proteins were still made but were not where they needed to be.

Without the protective proteins, the ankyrin-deficient muscle cells broke apart during exercise, a phenomenon similar to what occurs in muscular dystrophy.

When the group suppressed ankyrin-G in leg muscle cells, dystrophin and beta-dystroglycan were transported to the membrane but were not organized properly.

“These two ankyrins are a tag team,” Bennett says. “Ankyrin-B mediates transport of newly synthesized proteins, and ankyrin-G retains them in the right place.”

Researchers knew that, without dystrophin, the entire muscle-protecting complex was lost, but nobody knew why. The group found that dystrophin binds directly to ankyrins, and that gave them the beginning of an answer. “We have found the outlines of a pathway through which dystrophin assembles this [protective] complex,” Bennett says. The missing piece of the puzzle was the ankyrin proteins.

Photo: Bennett lab