MDA RESEARCHERS CREATE SUPER-MICE RESISTANT TO AGE-RELATED MUSCLE WASTING

TUCSON, Ariz., Jan. 30, 2001 - Researchers funded by the Muscular Dystrophy Association have created a breed of muscled, superstrong mice that resist much of the muscle wasting that occurs during aging.

The mice were genetically engineered to produce a growth-promoting protein called muscle insulinlike growth factor 1 (mIgf1) in their voluntary muscles (those that control movement). The protein, said lead researcher Nadia Rosenthal, holds the potential to prevent the muscle decay caused by aging and by certain muscle diseases, including some forms of muscular dystrophy.

"Muscle Igf1 naturally helps skeletal [voluntary] muscle to regenerate itself after injury," said Rosenthal, a molecular geneticist at Harvard-affiliated Massachusetts General Hospital-East in Charlestown. But somehow, she said, the muscle's capacity for regeneration "drops off during aging, in ways that may mimic the later stages of muscular dystrophy."

Boosting the production of mIgf1 appears to sustain muscle regeneration in aged mice, and supplying extra mIgf1 - perhaps via gene therapy - might have a similar effect in people, she said.

"In people who are affected by aging or by neuromuscular disease, muscle weakness can significantly interfere with daily living. If muscle Igf1 proves to be an effective treatment, it could dramatically improve the quality of life," said Sharon Hesterlee, MDA director of Research Development.

Muscle Igf1, Rosenthal said, is one of many versions of the Igf1 protein, which has long attracted interest as a potential treatment for chronic wasting diseases. Though other types of Igf1 circulate throughout the body, mIgf1 is made specifically by voluntary (or skeletal) muscle, and is normally stuck there.

This focused action of mIgf1 could make it ideal for safely and effectively combating muscle frailty in both aging and disease, Rosenthal suggested. Genetically engineered mice that overproduce a circulating type of Igf1, she pointed out, develop increased muscle mass and die from abnormal enlargement of the heart.

In contrast, Rosenthal's research shows that mice overproducing mIgf1 develop large, powerful limb and trunk muscles, and normal cardiac muscles. Also, the mice are able to recover from muscle injuries during old age, while aged mice that don't have extra mIgf1 lose that capacity.

Those findings appear in the February issue of the journal Nature Genetics.

Rosenthal co-led the new MDA-funded study with H. Lee Sweeney, a molecular biologist at the University of Pennsylvania in Philadelphia. Other key contributors to the study included Elisabeth Barton, a member of Sweeney's lab, and Antonio Musaro, formerly in Rosenthal's lab, but now a professor at the University of Rome "La Sapienza" in Italy.

The same team previously used a gene therapy technique to administer mIgf1 to single muscles in aged mice, and found that the mIgf1 prevented wasting of the treated muscles.

But, given the effects of circulating Igf1, the researchers were concerned that large-scale treatment with mIgf1 might be harmful. The answer - made clear by the mIgf1-producing mice - is that "more appears to be better," Rosenthal said.

The team also figured out that mIgf1 promotes skeletal muscle regeneration by stimulating satellite cells - cells that can repair damaged muscle by replacing lost muscle cells.

Finding a way to stimulate satellite cells is considered one possibility for treating people with muscular dystrophy, but some researchers have suggested this strategy might quickly exhaust a person's supply of satellite cells.

"Our data suggest that this is not the case in older muscle," Rosenthal said. "Since our animals continue to regenerate [muscle] in later stages of life, it appears that [satellite cells] can maintain the muscle in a healthy state."

"It remains to be seen if this will hold true in a disease state, but using these animals we can begin to test that hypothesis vigorously," she added. To determine if mIgf1 can protect muscles from disease, the team plans to crossbreed the mIgf1-producing mice with mice that have muscular dystrophy.

MDA is a voluntary health agency working to defeat neuromuscular diseases through programs of worldwide research, comprehensive services, and far-reaching professional and public health education. The Association's programs are funded almost entirely by individual private contributors.

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please read the Q&A, More about "Super-Mice".