MDA FINDS KEY PROTEIN FOR REBUILDING MUSCLE

TUCSON, Ariz., June 26, 2003 — Researchers supported by the Muscular Dystrophy Association have found that secreted proteins involved in building muscles during embryonic life also play a role in rebuilding adult muscle after an injury.

These proteins, or drugs that stimulate them, might one day be used to treat a variety of muscle-wasting conditions, including muscular dystrophy, a group of genetic diseases that affect hundreds of thousands of Americans.

Michael Rudnicki and colleagues at the Ottawa Health Research Institute in Ontario, Canada, discovered the proteins’ role in muscle regeneration by studying a type of stem cell in adult muscle.

These cells appear capable of replacing cells lost to injury or disease. But the signals that encourage muscle stem cells to repair damaged muscles have been elusive.

In an attempt to identify these signals, Rudnicki first injected the hind limb muscles of mice with a muscle-damaging toxin. Four days afterward, one type of muscle stem cell (identified by the cell surface “marker” CD45) had gone into high gear, increasing its numbers by tenfold.

Next, the researchers took a cue from studies of embryonic development, which have shown that Wnts — a family of secreted proteins — are required for sculpting embryonic muscle.

To test the involvement of Wnts in adult muscle regeneration, they isolated the mouse CD45-positive cells and exposed them to lithium chloride, a chemical that simulates aspects of Wnt signaling. In a laboratory dish by themselves, the cells normally become blood or skin cells, but lithium chloride turned many of them into muscle cells. Putting the stem cells together with other cells made to manufacture and release Wnts had a similar effect.

Finally, when toxin-damaged muscles were injected daily with proteins that naturally inhibit Wnt signaling, the stem cells lost much of their ability to regenerate muscle.

The findings, which appear in the June 27 issue of Cell, offer rare insights into the biology of muscle stem cells and hint at the possibility of using Wnts to treat muscular dystrophy.

Previously, Rudnicki showed that a gene called Pax7 was essential for converting muscle stem cells into satellite cells, a group of cells that build adult muscle during growth or after an injury. It now appears that Wnt might be the signal for turning on Pax7.

In people with muscular dystrophy, “Wnts wouldn’t correct the underlying genetic defect, but they could keep repair going at a pace that could compensate for the muscle fiber loss,” Rudnicki said.

“Right now, we’re delivering Wnts to mice with [Duchenne] muscular dystrophy to see if we can ameliorate the disease,” he said. Rudnicki is using viruses or cells to deliver Wnt genes into the mice, but plans to start injecting the mice with Wnt proteins, which were recently purified in active form.

MDA is a voluntary health agency working to defeat more than 40 neuromuscular diseases through programs of worldwide research, comprehensive services, and far-reaching professional and public health education.