Waste Not: Proteins suggest ways to thwart muscle loss

Old people, starving people, AIDS patients, cancer patients, and even astronauts. All these groups and others experience muscle atrophy, the wasting away of muscle fiber.

Two research teams have now revealed details of the biochemical signals that drive muscle atrophy. They include a class of proteins that may trigger this degenerative process.

The proteins are the “master switch,” says Alfred Goldberg of Harvard Medical School in Boston, who heads one of the teams. “It would be nice if we could use [them] as a target for drug development and block the atrophy process, or at least reduce it.”

Goldberg’s research is funded in part by NASA because the agency needs to find ways to prevent muscles from atrophying while astronauts are weightless. Even healthy people on Earth, once they reach their late 30s, begin to experience a gradual but inexorable loss of muscle mass called sarcopenia (SN: 8/10/96, p. 90: http://www.sciencenews.org/pages/sn_arch/8_10_96/bob1.htm).

In atrophy, muscle cells shrink but don’t typically die. Among other changes in the cells, proteins that make up muscle fibers begin to break down more rapidly than they can be replaced.

Over the past decade, scientists have identified a cascade of signals that drives muscle-cell growth. The hormones insulin and insulinlike growth factor-1 (IGF-1), for example, activate enzymes that prompt protein synthesis in muscles.

More recently, investigators have been finding genes and molecules that participate in the atrophy process. For example, atrophying muscle contains increased concentrations of two enzymes that mark proteins for destruction. In the April 30 Cell, Goldberg’s team identifies a group of proteins, known as transcription factors, that regulates the gene for one of these enzymes. In the May Molecular Cell, a group led by David Glass of Regeneron Pharmaceuticals in Tarrytown, N.Y., documents that these factors, called Foxo proteins, control the activity of both the enzymes.

Goldberg’s team found that injections of the gene for one of the Foxo proteins make mouse muscles wither significantly within a week or two. “We didn’t expect that just one transcription factor could turn on atrophy,” says Goldberg.

Glass says that his group’s data indicate that another of the Foxo proteins is needed for atrophy but can’t by itself induce it.

The new papers and another one by Goldberg’s team in an upcoming American Journal of Physiology offer evidence that the same hormone-driven signal cascade that directs muscle growth also regulates muscle atrophy. In addition to sending growth signals to muscle cells, IGF-1 seems to suppress genes that induce muscle wasting, both groups found.

Finding that muscle growth and atrophy are controlled by the same regulators is important, says Glass. Researchers can now seek drugs that both spur muscle growth and block the atrophy process, he explains.

While calling the discovery of the role of Foxo proteins in muscle atrophy a “provocative and important advance,” Susan C. Kandarian of Boston University cautions that it’s too early to say whether the proteins represent good drug targets. Researchers have struggled to identify drugs that safely interfere with transcription factors regulating other functions.

From the Nature Index

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