New Mouse Model For Duchenne Muscular Dystrophy May Improve Screening of New Treatments

BUFFALO, N.Y. -- University at Buffalo biologists have developed a new mouse model of Duchenne muscular dystrophy that may more accurately than current models simulate the progression of this fatal disease.

The research provides scientists with a more precise tool with which to screen new treatments for the disease, whose victims are all males and usually do not live beyond their teens or 20s. It should also provide an enhanced understanding of the disease, particularly the role played by mast cells, which are part of the body's inflammatory-response system.

A research paper describing the model and its implications is published in the July issue of the Journal of Neurological Sciences.

Michael S. Hudecki, Ph.D., research associate professor of biological sciences at UB, who himself is afflicted with limb-girdle muscular dystrophy, is senior author. Co-authors are Joseph A. Granchelli, UB postdoctoral fellow, and Catherine M. Pollina, UB research associate.

The work was funded by the Muscular Dystrophy Association.

"There has not been a good model for Duchenne muscular dystrophy," said Hudecki. "This specially bred mouse gives us a very good handle on studying the Duchenne disease."

Duchenne muscular dystrophy (DMD) is a genetic muscle disease marked by an absence of dystrophin, the critical protein that appears to support muscle-fiber membranes.

"Muscle without dystrophin is analogous to a building without girder supports," Hudecki said.

Without dystrophin, he said, young boys with DMD can still perform physical activities. But beginning in early adolescence, the growth process puts greater stress on muscles and they undergo severe weakening, as well as loss of muscle fibers, which are replaced by connective tissue. Patients grow progressively weaker and usually die from respiratory failure.

Hudecki explained that while the prevailing animal model of the disease is a mouse deficient in dystrophin, it doesn't exhibit the progressive weakness that is a symptom of Duchenne muscular dystrophy.

He said those mice exhibit a degree of muscle weakness and degeneration, but only after they are physically stressed by running on treadmills for periods of time or are injected with chemicals that induce mast-cell activity.

"We wanted a model that would express the full symptoms of the human disease," said Hudecki.

He and his colleagues bred mice with both characteristics: the dystrophin deficiency and the exaggerated activity of mast cells throughout the body.

"We have simulated a Duchenne-like weakness," said Hudecki.

The findings show that not only does dystrophin-deficient muscle contain a greater number of mast cells, but the muscle tissue also appears to be hypersensitive to mast-cell products, he added.

Under normal conditions, mast cells play an integral role in responding to wound signals.

"They act like internal smoke alarms," Hudecki said. "They respond to injury by triggering the release of various chemicals that will help to begin making repairs."

In Duchenne muscular dystrophy, muscles weakened by the lack of dystrophin contain a greater number of mast cells than normal muscles and appear to send out wound signals even from normal usage.

"The mast cells seem to be responding to the wounding signal, in turn triggering the release of certain enzymes that break down tissue," said Hudecki.

When the enzymes go about trying to repair the "damage," they may further weaken the muscle tissue, Hudecki said.

For example, the job of the mast-cell enzyme, tryptase, is to digest injured tissue.

Hudecki said that in the Duchenne patient, the result of this "housecleaning" process is to further break down muscle-fiber membrane, already weakened by the disease.

"In the patient, normal muscle usage may activate the wound-repair cycle, whereby there is chronic insult to the muscle," said Hudecki.

No treatments exist today that significantly reduce the muscle damage and disability that result from dystrophin deficiency.

While Hudecki noted that the best hope for a cure lies in gene therapy, still years away, he said that this research may help scientists design new treatments.

"Our goal is to find a way to modulate or manage the progression of the disease," said Hudecki. "With this mouse, we may be able to better screen new drugs that may help modulate this internal wounding process."