CONTACT: JENNIFER BROWN
Iowa City IA 52242
(319) 335-9917; fax(319) 384-4638
Release: Oct. 10, 2002
UI Findings May Point The Way To Muscle Regeneration Therapies
Often in research, an experiment designed to answer one question brings
to light another unexpected result. University of Iowa scientists developed
a genetically altered mouse to investigate the role of a particular protein
in the progression of muscular dystrophy. The mouse model proved that removing
the protein called dystroglycan from skeletal muscle did indeed cause muscular
dystrophy in the animals, but the mice appeared to be protected from the devastating,
muscle-wasting consequences of the disease.
Following up on this surprising finding, the UI team discovered that a specific
group of muscle cells, known as satellite cells, were making dystroglycan
protein and were efficiently repairing the muscle damage caused by muscular
dystrophy in these mice. The UI study showed that maintaining the regenerative
capability of the satellite cells can prevent development of severe muscular
dystrophy. This suggests that malfunctioning satellite cells may influence
the severity of muscular dystrophies and could provide a therapeutic target
for muscular dystrophy and other muscle diseases.
The team, led by Kevin Campbell, Ph.D., the Roy J. Carver Chair of Physiology
and Biophysics and interim head of the department, UI professor of neurology,
and a Howard Hughes Medical Institute (HHMI) Investigator, also discovered
that the capacity of satellite cells to regenerate muscle was not diminished
as the animals aged. This result challenges the idea that ongoing muscle destruction
in muscular dystrophy ultimately exhausts the satellite-cell pool.
"We showed that the satellite cell pool does not necessarily becomes
exhausted, but can stay active," said Ronald Cohn, M.D., the lead author
of the study. "In our mice, the satellite cells are sufficient to regenerate
muscle even during ongoing muscle damage. This leads to a mild form of muscular
dystrophy without muscle wasting."
Cohn was a postdoctoral associate in Campbell's lab; he is now a resident
at the Johns Hopkins Childrens Hospital and the McKusick-Nathans Institute
of Genetic Medicine.
Satellite cells act like stem cells in muscle. Once activated, these cells
divide to form daughter cells that incorporate into damaged muscle fiber to
repair the tissue. The UI study, which appeared in the Oct. 6 issue of Cell,
also may lend support to the possibility of using stem cell-type therapies
for muscular dystrophies.
Dystroglycan is key component of the dystrophin-glycoprotein complex, a
group of proteins that connects structures inside and outside of cells and
helps to stabilize muscle membranes. Recent studies have shown that disruption
of dystroglycan is associated with severe forms of muscular dystrophy, and
mice engineered to lack dystroglycan die before birth. To more closely investigate
the role of this protein, UI researchers removed the dystroglycan gene specifically
from skeletal muscle of mice.
"We made the mouse model, and initial findings showed that it had a
muscular dystrophy," Campbell explained. "But, unlike our other
models of muscular dystrophy, and to our surprise, it seemed that the mice
were able to regenerate muscle very well, and that regeneration capacity was
very high. In fact, the mice developed muscle hypertrophy -- their muscles
actually were bigger than in normal mice."
Although dystroglycan had been knocked out of skeletal muscle in the mice,
the UI team discovered that the protein temporarily reappeared in regenerating
muscle. Experiments proved that this dystroglycan came from activated satellite
Muscle injury activates satellite cells and leads to regeneration. This
natural process is how weight lifting and other strenuous exercise builds
muscle. To show that muscle damage results in dystroglycan appearing in skeletal
muscle, the UI team used a substance called cardiotoxin to induce muscle injury
and force it to regenerate.
"After cardiotoxin damage, all the regenerating fibers contained dystroglycan,"
Campbell said. "The satellite cells with the normal gene keep feeding
into the muscle allowing it to regenerate."
The UI researchers also found the important dystrophin-glycoprotein complex
is restored in regenerating muscle fibers of these mice.
However, when the daughter cells fuse with a muscle fiber, the engineered
genetic mutation turns off production of dystroglycan and gradually the amount
of protein decreases. The repaired muscle fiber becomes susceptible to damage
once more. Thus the cycle of damage and repair by satellite cells is repeated
over and over leading to hypertrophy, or enlarged muscles.
By inactivating the satellite cells with gamma radiation, the UI team disabled
the muscle repair mechanism. After irradiation, there were no regenerating
muscle fibers, and the mice developed severe muscular dystrophy symptoms.
To show the importance of dystroglycan in the regenerative ability of the
satellite cells, the UI team made a different genetically modified mouse,
which lacked dystroglycan in skeletal muscle and in satellite cells. Muscle
regeneration was impaired in these mice and they developed severe muscular
"The results suggested that dystroglycan has a role in regeneration
and that the satellite cells are really very important in maintaining muscles'
potential to regenerate," Campbell said.
The UI study also identified human muscular dystrophy patients who, like
the mouse model, have a form of muscular dystrophy. These individuals also
have a dystroglycan mutation, although it is different from the mouse mutation.
Normal dystroglycan was present in a few muscle fibers from these patients,
suggesting that regenerating fibers are normal. Campbell explained that although
the human cases are not fully understood, they do show that humans can have
a muscular dystrophy where the disease progression is slow and efficient muscle
regeneration occurs. The UI study suggests that maintenance of satellite cells
expressing dystroglycan is likely responsible for mild disease progress in
mice and also possibly in humans.
Other members of Campbell's lab on the study team included Michael Henry,
Dan Michele, Ph.D.; Rita Barresi, Ph.D.; Fumiaki Saito, M.D., Ph.D.; and Jason
Flanagan. Also part of the research team were Steven Moore, M.D., Ph.D., UI
professor of pathology and a staff physician with the Veterans Affairs Medical
Center in Iowa City; Mark Skwarchuk, Ph.D., UI assistant professor of radiation
oncology; Roger Williamson, M.D., UI professor of obstetrics and gynecology;
Michael Robbins, Ph.D., section head, experimental radiation oncology at Wake
Forest University; and Jerry Mendell, M.D., professor and head of neurology
and professor of pathology at Ohio State University.
The study was funded in part by the Muscular Dystrophy Association.
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UI Roy J. and Lucille A. Carver College of Medicine and UI Hospitals and Clinics
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