February 11, 1999
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Gene Boosts Muscle Strength

Mighty Mice Raise Hopes For A Stronger Life

By William J. Cromie

Gazette Staff

The mouse in front received an engineered gene that makes it bigger and stronger than its companion. Such engineered mice show none of the muscle degeneration typical of aging, despite the fact that they don't do extra exercise. Photo by Jon Chase.

Nadia Rosenthal is raising mighty mice whose muscles don't deteriorate with age. The Harvard Medical School researcher inserts a particular gene into mouse embryos, and the pups grow bigger and stronger than normal mice.

At the age of four weeks, the rodents begin to show progressive strengthening of almost every muscle in their bodies. Laboratory technicians call them "Arnold Schwarzenegger mice." At the age of 20 months -- equivalent to senior-citizen age in humans -- the animals show none of the muscle degeneration typical of old age.

Does this research herald a time when humans will be born and die strong without bothering with difficult, boring, and time-consuming exercises?

Nadia Rosenthal expects her work on building stronger mice to someday lead to new treatments for human problems like muscular dystrophies, heart enlargement, diabetes, and age-related muscle weakness. Photo by Jon Chase.

"No," Rosenthal says flatly. "We certainly have no plans to add the gene to human embryos so that they can become muscular children and adults. We are doing basic research to determine how this gene operates during the life span."

But Rosenthal does not deny that what she is learning will bear on gene therapy for treating muscle diseases, heart failure, diabetes, and age-related muscle degeneration.

Recently, she and H. Lee Sweeney of the University of Pennsylvania announced results of experiments with adult mice who received injections of the gene into their muscles. The inoculations prevented muscle deterioration in mice as old as 2 years -- 80 years in human terms. The shots even regenerated muscle, restoring some of the lost strength and size.

Old mice regained 27 percent of muscle lost to age; younger mice experienced a 15 percent increase, Sweeney reported. "You build muscle mass and strength even without exercise," he says.

Many safety questions must be answered before experiments begin on humans. "We hope to start such safety trials this year or next," says Rosenthal, an associate professor of medicine. "The muscle-building protein would be given first to young people suffering from a mild form of muscular dystrophy called Becker. A logical next step would be to test the protein against Duchenne muscular dystrophy, a more severe disorder that often kills people before they reach their 20s. Becker progresses more slowly and patients can survive well into middle age."

Increasing the health span of older, healthy people looms as another possibility, albeit more years away. And Rosenthal is interested in seeing if cardiac muscle can be strengthened in people who suffer from damaged hearts. She also wants to probe the association between the muscle-building protein and insulin.

"I want to understand what happens when the same mechanisms that cause a beneficial enlargement of an athlete's heart result in a disabling, life-threatening disease," Rosenthal explains. "And evidence exists that skeletal muscle is involved in insulin resistance, so there may be a way to use [the protein] to treat adult-onset diabetes. I want to determine if my genetically engineered mice are resistant to this type of diabetes."

Replacement Therapy

The mighty mouse protein is known as "insulin-like growth factor type 1," or IGF-1. The researchers package the gene needed to make this factor in the shell of a virus. The virus cannot cause a disease but retains its ability to infect muscle cells. Researchers inject the gene-virus package into the muscles of adult mice or into a fertilized egg as it begins to grow into an embryo.

Rosenthal notes that the Food and Drug Administration is close to approving the virus system for use with humans.

The gene and its product, IGF-1, occur naturally in muscle, but less is made as a person ages. "It is not a foreign substance that we introduce into the body," Rosenthal points out.

Normally, the IGF gene churns out the protein when an injury occurs, or during hard exercise -- a form of mild injury. Working at Massachusetts General Hospital in Boston, Rosenthal and her laboratory team engineered the injected gene so it remains on at times when the natural gene is off.

"It's like hormone replacement therapy," Rosenthal comments. "You're giving people something they already have but don't have enough of when they get older."

All mice run around a lot, particularly at night, but those given extra IGF-1 gene are much larger and stronger. They look like they've been exercising like Schwarzenegger, but they don't move any more than their skinny, Woody Allen-like litter mates. Even when these mighty mice get old, their muscles stay well- formed and lack invasions of strength-robbing fibrous tissue.

Schemes to get the same effect with IGF-1 pills don't work, Rosenthal notes. You can't get enough of it in the right places; plus there's a danger of causing the overgrowth of nonmuscle cells. That might lead to cancers.

"The genes are engineered so they will turn off if they get into tissues and organs where cells proliferate rapidly," Rosenthal remarks. "Also, you don't have to keep injecting the IGF-1 gene. Once it's put in, it stays there for the life of the muscle cell."

Nor does it have to be injected into all muscles. "In muscular and motor diseases, such as the various muscular dystrophies, only certain cells are affected," Rosenthal notes. "Even in aging, not every muscle degenerates to the same extent. Those most important are muscles that keep people breathing --like the diaphragm -- and prevent them from falling."

One looming side issue concerns the fact that, because IGF-1 stays in muscle, it cannot be detected in blood. If the protein proves safe and effective in humans, therefore, Olympic and other athletes might take it illegally to improve their performance without fear of detection.

"That's something we don't want to happen," admits Rosenthal, "but not something we could necessarily control."


Copyright 1999 President and Fellows of Harvard College