November 27,
2002
Myostatin-Blockers Improve Muscle
Function in Dystrophic Mice
(Philadelphia,
PA) - An antibody that blocks the myostatin gene may
aid in treating muscular dystrophy by pushing muscle
precursor cells into making more muscle. According to
researchers at the University of Pennsylvania School
of Medicine, the Ja16 mouse antibody blocks myostatin
protein, which increases body weight and muscle mass
along with a significant decrease in muscle degeneration
in mouse models for Duchenne muscular dystrophy (DMD).
The findings, reported in the November 28th issue of
Nature, offer support for a novel approach to
treating muscular dystrophy while circumventing many
of the problems associated with conventional gene therapy.
"This strategy differs from gene therapy in that
it actually doesn't try to replace a faulty gene, instead
it works around the problem by producing more functional
muscle as a compensatory mechanism," said Tejvir
S. Khurana, MD, PhD, of Penn's Department of Physiology.
"Potentially, this approach may be useful in combination
with other types of therapies to slow the progression
of muscular dystrophy and other muscle wasting diseases."
Naturally occurring mutations in the myostatin gene
were first noted about 200 years ago in the Schwarzenegger-like
musculature of the Belgian Blue breed of cattle. The
sequence or exact identity of the gene itself was only
identified about five years ago in mice. The current
report focuses on blocking mouse myostatin in a mouse
model of muscular dystrophy.
Many species including humans also have myostatin, and
the researchers believe that blocking myostatin is one
way to get Duchenne muscular dystrophy sufferers to
grow more muscle. "In principle, the approach is
doable in humans, if the right reagents are generated,
since humans do have this protein," said Khurana,
who also has an appointment in the Pennsylvania Muscle
Institute, a university-wide multidisciplinary group
that investigates muscle and cell motility.
The approach, however, also has its limitations. It
did not improve the susceptibility of muscles to damage
related to muscular dystrophy pathology. Additionally,
the researchers do not know if blockading myostatin
will deplete pre-existing stem/muscle progenitor cell
pools faster.
"It could be like putting a turbocharger on your
old compact car - you'll get performance, but it may
eat all of your gas and deteriorate your engine in the
process," said Khurana. "If the Ja16 antibody
depletes stem or precursor cells, then perhaps we may
need to use it as judiciously pulsed doses or, perhaps,
not at all."
Khurana and his colleagues believe that the longer-term
studies that they plan to undertake will help address
these issues. For the time being, however, the Ja16
antibody, which was developed in mice, will likely not
work in humans or other DMD animal-models.
Duchenne's muscular dystrophy is one of the most frequent
inherited diseases of men, affecting one in 3,500 boys.
DMD occurs when the dystrophin gene, located on the
short arm of the X-chromosome, is broken. Since males
only carry one copy of the X-chromosome, they only have
one copy of the dystrophin gene. Without the dystrophin
protein, muscle is easily damaged during cycles of contraction
and relaxation. While early in the disease muscle compensates
by regeneration, later on their progenitor cells of
muscle cannot keep up with the ongoing damage and healthy
muscle is replaced by non-functional fibro-fatty tissue.
Sasha Bogdanovich and Thomas Krag were the lead authors
of the study; other Penn researchers include Elisabeth
R. Barton and Linda D. Morris of the Department of Physiology,
and Rexford S. Ahima of the Department of Endocrinology.
Co-author Lisa-Anne Whittemore is from the Musculoskeletal
Sciences Department of Wyeth Research in Cambridge,
Massachusetts.
The research conducted in this study was supported in
part by a grant from the Wyeth Research/Genetics Institute.
# # #
Editor's Note: Dr. Khurana is a paid
consultant for Wyeth Research/Genetics Institute, however,
he does not own stock in Wyeth.
.
|
