Genetic switch discovered may lead to new treatments for muscle-wasting diseases

At the Dana Farber Cancer Institute, Bruce Spiegelman (right) and Zoltan Arany discovered a genetic switch that may lead to new treatments for muscle-wasting diseases and enhance athletic abilities. Image credit: Stephanie Mitchell from Harvard News O
Date:29 January 2007 Tags:

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 fibres that move our bones from one type to another. Biologists catagorise these movers and shakers into four types. Those labelled 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 fibres 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 fibres are enriched in different locations. Quadriceps in our thighs, for example, contain more fast fibres and help us to run faster. Soleus muscles in our calves hold more slow fibres 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 the Dana-Farber Cancer Institute and the Brigham and Women’s Hospital, as well as from Boston University School of Medicine. Their report in Cell Metabolism details how the beta gene can make mighty mice out of normal rodents.

Spiegelman and his colleagues genetically engineered a group of mice with muscles dramatically enriched in the beta gene and thus with the mysterious IIX fibres 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 metres per minute every two minutes, and the animals raced to exhaustion. Non-betas ran about 0,3 metres in 26 minutes before they gave out. The betas ran about 0,75 metres 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 per cent of IIX fibres into nearly 100 per cent. That transformation increased mouse endurance 25 per cent. 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.

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 fibres naturally or as a result of extensive training, Spiegelman was negative. “We are more interested in treating muscle diseases, ” he said.

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