Mystery muscles make mightier mice

Scientists have muscled in on a genetic switch that allows mice to run longer and faster. Humans possess the same switch, so the discovery might open new paths to treating muscle-wasting diseases and building better bodies.

Last year, Bruce Spiegelman and Alfred Goldberg, professors of cell biology at Harvard Medical School, found that a gene called PGC-1 alpha protects skeletal muscles from wasting away. Spiegelman had discovered alpha in 1998 and a sister gene he named PGC-1 beta in 2002. After finding that alpha has such intriguing prospects, he began experiments to see if beta might also be used to treat such diseases as muscular dystrophy, Lou Gerhrig’s disease, and various forms of paralysis.

These master switches turn on a cascade of other genes that can transform the muscle fibers that move our bones from one type to another. Biologists catagorize these movers and shakers into four types. Those labeled I and IIA are “slow twitchers,” and they support the endurance needed for activities like walking or waiting on long lines. Muscles called IIB, are “fast twitch” types that provide more powerful contractions and come into play for rapid bursts of activity like running. Then there are IIX fibers that serve a mixture of both endurance and quickness, and about which not much is known.

Skeletal muscles in animals, including humans, contain a mix of all types, but different fibers are enriched in different locations. Quadriceps in our thighs, for example, contain more fast fibers and help us to run faster. Soleus muscles in our calves hold more slow fibers and aid us in standing for long periods.

To find out what the beta gene could do for these muscles and the problems we have with them, Spiegelman assembled a team of experts from two Harvard research hospitals – Dana-Farber Cancer Institute and Brigham and Women’s Hospital – and Boston University School of Medicine. The team published their findings in the January issue of Cell Metabolism, a scientific journal. This report details how the beta gene can make mighty mice out of normal rodents.

‘Damn good athletes’

Mice were used because, ethically, scientists can’t go around trying to change muscles in humans just to see what will happen. Spiegelman and his colleagues genetically engineered a group of mice with muscles dramatically enriched in the beta gene and thus with the mysterious IIX fibers made with beta’s help. They then paired these mice with normal mice, littermates that had the usual amount of slow, fast, and IIX muscles.

Both groups then “worked out” on a treadmill set at a 10-degree incline. Treadmill speed increased by 6.6 meters per minute every two minutes, and the animals raced to exhaustion. Non-betas ran 1,703 feet, or about a third of a mile, in 26 minutes before they gave out. The betas ran 2,462 feet, or almost a half-mile, and kept going for 32.5 minutes.

“They’re damn good little athletes,” a surprised Spiegelman said of the genetically hyped beta mice.

Zoltan Arany, an instructor in medicine at Brigham and Women’s Hospital who is the lead author of the team’s report, noted that the beta switch transformed mouse muscles that normally contain 15-20 percent of IIX fibers into nearly 100 percent. That transformation increased mouse endurance 25 percent. In normal mice, the genetic path from fast twitch, or spurt muscles, to slow twitch, or endurance muscles, goes through an IIX stage, the researchers believe.

A next step might be to develop drugs that change the expression of beta or alpha genes to produce more IIX muscle. Then get permission to test such drugs on humans.

Will he do such experiments? Spiegelman was asked. “Maybe,” he replied.

Arany speculated that athletes might try to improve their performance if such genetic steroids became available. “Something,” he says, “that I wouldn’t necessarily approve of.”

Asked whether he would test marathon runners, triathlon competitors, or others in high-endurance sports to see if they have more IIX fibers naturally or as a result of extensive training, Spiegelman was negative. “We are more interested in treating muscle diseases, ” he said.