Faulty Muscle Repair May Lead
to Musculear Dystrophies
Researchers have revealed what may be a
totally new cause for muscular dystrophy (MD). A recent study shows that a
protein defective in two types of late-onset MD plays a critical role in the
normal repair of muscles.
The researchers found that the defective
protein dysferlin causes a glitch during normal muscle repair, suggesting that
faulty muscle repair, rather than an inherent weakness in the muscles'
structural integrity, leads to the progressive muscle degeneration seen in these
two forms of MD.
The study, conducted by Kevin Campbell,
Ph.D., of the University of Iowa in Iowa City, and colleagues, appeared in the
May 8, 2003, issue of Nature. It
identifies the first known component of the membrane-repair machinery in muscle
cells.
"Muscles are continuously being
damaged and repaired, and to find a particular protein that's involved in the
process is very exciting," says study co-author Steven Vogel, Ph.D., acting
chief of the section on cellular biophotonics at the National Institute of
Alcohol Abuse and Alcoholism. This work was done while Dr. Vogel was a grantee
of the National Institute of Neurological Disorders and Stroke (NINDS) at The
Medical College of Georgia in Augusta.
The muscular dystrophies are a group of
genetic diseases characterized by progressive weakness and degeneration of the
muscles that control movement. Adults with either of the two types of MD in this
study - Miyoshi myopathy and limb-girdle MD type 2b - have slowly progressing
weakness and wasting of muscles of the hands, forearms, and lower legs.
An earlier study showed that mutations
affecting dysferlin activity are associated with both Miyoshi myopathy and
limb-girdle MD type 2b, but little was known until now about how the absence of
dysferlin caused disease.
Most genetic mutations that cause MD
have been linked to errors in a large protein complex that controls the
structural integrity of muscle cells. Dysferlin does not appear to be associated
with this protein complex. Instead, dysferlin is normally found throughout the
membranes of muscle cells and in vesicles. Some researchers believe vesicles -
bubbles within muscle cells - might play a role in cell membrane repair.
Dr. Vogel's colleagues at the University
of Iowa and the Howard Hughes Medical Institute engineered mice that lacked the
dysferlin gene. As they aged, these mice developed MD similar to humans with
either Miyoshi or limb-girdle MD in humans.
Interestingly, treadmill tests showed
that their muscles were not much more susceptible to damage than the muscles of
normal mice, demonstrating that the absence of dysferlin did not seem to
interfere with the structural integrity of the muscles.
Under a microscope, the researchers saw
that in the mice lacking dysferlin, unusually high numbers of vesicles
accumulated at damaged membrane sites. The abnormal number of vesicles seemed to
indicate that an error in membrane resealing might be responsible for the MD.
To observe the protein's normal
activity, the researchers tagged dysferlin with a dye marker. They saw
"patches" enriched with dysferlin, which formed when dysferlin-containing
vesicles that traveled to the damaged site fused. These dysferlin
"patches" seemed to play a critical role in the sealing of damaged
membranes.
Dr. Vogel says this new information
about dysferlin's role in muscle repair opens a new pathway for understanding
the causes of the muscular dystrophies, as well as other diseases that affect
cardiac and skeletal muscles.
"It's become clear that errors in
membrane trafficking are linked to human disease," says Dr. Vogel. "A
lot of progress has been made, and there's a lot more that needs to be learned
in terms of the molecular mechanisms of membrane repair."
The NINDS is a component of the National
Institutes of Health in Bethesda, Maryland, part of the U.S. Department of
Health and Human Services, and is the nation's primary supporter of biomedical
research on the brain and nervous system
From the
National Health Institute
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© 2003, S.D. Hunter
