Scientists at the University of Pennsylvania Medical Center have developed a novel gene therapy treatment that permanently blocks the age-related loss of muscle size and strength in mice. Mice, like humans and all mammals, lose up to a third of their muscle mass and power with age. In humans, the result is an advancing weakness in the elderly that can lead to unsteadiness and impaired mobility, increased susceptibility to falls and injury, and joint stress and degeneration.
Even in young adult mice, the new treatment increased muscle strength by a dramatic 15 percent over untreated muscle. But in older mice, the improvement was even more remarkable: The researchers documented a 27 percent increase in strength over untreated muscle in these mice -- fully restoring their strength to what it was in young adulthood.
The technique suggests human therapies that could reverse the feebleness associated with old age or counter the muscle-wasting effects of muscular dystrophies and related diseases. It also raises the possibility, however, that the technique could be used -- or abused -- for athletic or cosmetic enhancements.
Results from the experimental study will be presented at the 38th annual meeting of the American Society for Cell Biology in San Francisco on December 14 and will be published in the December 22 issue of the Proceedings of the National Academy of Sciences. (Copies of the paper are available to reporters through the journal's news office, reachable by telephone at 202-334-2138 or by e-mail at firstname.lastname@example.org.)
"Our results show that it may be possible to preserve muscle size and strength in old age using this approach," says H. Lee Sweeney, PhD, professor of physiology and senior investigator on the study. "We're now looking to see whether the technique might also be used to increase muscle strength in diseases such as muscular dystrophy."
To develop the new treatment, the researchers took advantage of the ability of some viruses to integrate their genetic material into the cells they infect. For these experiments, they selected an adeno-associated virus, or AAV, known to be highly efficient at introducing its genes into target cells. They then stripped the AAV of its own disease-causing -- and immune-system provoking -- genes and reloaded it with a normally occurring gene called insulin-like growth factor I, or IGF-I, as well as a muscle-specific promoter to drive high production levels of the growth factor. The investigators then injected the engineered virus into the muscles of the mice.
IGF-I is a growth factor critical in the process of muscle repair. Under normal circumstances, damaged muscles release quantities of IGF-I as an activation signal to neighboring cells known as satellite cells. Satellite cells are muscle stem cells -- progenitor cells -- that become functional muscle cells after activation and then migrate into the muscle to repair it.
The researchers theorized that age-related muscle loss might be the result of a declining efficiency in the satellite-cell activation process due to a decreased IGF-I signaling capability with age on the part of muscles in need of repair. They hypothesized that using gene therapy to command high levels of IGF-I production in aging muscle might stimulate more effective repair and regeneration by the satellite cells, which proved to be the case.
If this work is to be extended into humans, a number of ethical considerations will need to be addressed, according to senior author Sweeney.
"The beneficial effects of this gene therapy could easily be used in humans for athletic or even cosmetic enhancements and not only for limiting age-related muscle loss or for treating diseases of the muscle," Sweeney notes.
Elisabeth R. Barton-Davis, PhD, is the lead author on the study, and Daria I. Shoturma is a coauthor. The remaining coauthors are Antonio Musaro, PhD, and Nadia Rosenthal, PhD, both based at Massachusetts General Hospital. This work was supported by grants from the National Institutes of Health and the Muscular Dystrophy Association.
The University of Pennsylvania Medical Center's sponsored research and
training ranks third in the United States based on grant support from the
National Institutes of Health, the primary funder of biomedical research and
training in the nation -- $175 million in federal fiscal year 1997. In addition,
for the third consecutive year, the institution posted the highest annual growth
in these areas -- 17.6 percent -- of the top ten U.S. academic medical centers.
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