Common Blood Pressure Drug Treats Muscular Dystrophy In Mice
Main Category: Genetics News
Article Date: 22 Jan 2007 - 0:00 PST

Researchers at Johns Hopkins have shown that a drug commonly used to
lower blood pressure reverses muscle wasting in genetically
engineered mice with Marfan syndrome and also prevents muscle
degeneration in mice with Duchenne muscular dystrophy. The results
are reported online this week at Nature Medicine.

In 2006, a team led by Harry "Hal" Dietz, M.D., discovered that
treating Marfan mice with losartan (Cozaar) dramatically strengthens
the aorta, the major artery carrying blood away from the heart, and
prevents enlargement and risk of bursting, a condition known as
aortic aneurysm. A clinical trial to assess how effective losartan is
for treating people with Marfan will launch within weeks.

"In addition to the aortic defect, children with severe Marfan
syndrome often have very small, weak muscles, and adults with Marfan
often can't gain muscle mass despite adequate nutrition and
exercise," explains Dietz, a professor at the McKusick-Nathans
Institute of Genetic Medicine at The Johns Hopkins University School
of Medicine.

Dietz and his colleagues had previously discovered that many features
of Marfan syndrome, including aortic aneurysm, arise from excess
activity of TGF-beta, a protein that instructs cell behavior. Marfan
mice have muscles containing much scar tissue between unusually small
muscle fibers, which also show evidence of too much TGF-beta
activity. Dietz's team reasoned that blocking the activity of TGF-
beta might restore normal muscle structure and function.

First, the research team injected Marfan mice with a protein that
binds TGF-beta and renders it inactive. This TGF-beta-blocking
protein caused muscle fibers in these mice to grow bigger than those
in untreated Marfan mice. "Not only did the muscles look bigger and
better under the microscope," says Dietz, "the mice were also
stronger and showed reduced fatigue."

The team then treated Marfan mice with losartan, a medication known
to be safe in treating hypertension in all age groups and more
importantly, known to block TGF-beta activity. Losartan treatment
over six months "completely restored muscle architecture" and vastly
improved strength, according to Dietz.

Further study pinpointed how too much TGF-beta activity leads to this
weakened muscle architecture. According to Ronald Cohn, M.D., lead
author on this study, normal muscle, by mobilizing muscle stem cells,
can repair itself after injury. The team discovered that excessive
TGF-beta blocks muscle regeneration and repair. "The simplest things
can injure muscle," explains Cohn, an assistant professor of
pediatrics and neurology at Hopkins. "Running a mile down the street
causes microscopic tears in leg muscles, which normally go unnoticed
because muscles are so efficient at repairing themselves."

Dietz's team then wondered whether the muscle improvement from
blocking TGF-beta was specific to Marfan syndrome or possibly
represented a strategy that could be applied to other muscle diseases
such as Duchenne muscular dystrophy (DMD). Duchenne muscular
dystrophy, the most common form of incurable muscular dystrophy in
children, generally leads to death in early adulthood or before. DMD
causes muscle fibers to be incredibly fragile. As a person with DMD
ages, their muscles slowly lose the ability to regenerate and repair,
which leads to loss of muscle function, explains Cohn.

TGF-beta never had been implicated as a cause of the inability to
repair muscle in DMD. So the researchers examined muscles from mice
genetically engineered to have DMD and found evidence of increased
TGF-beta activity.

The team treated one group of DMD mice with TGF-beta-blocking protein
and another group with losartan. Both groups of treated mice showed
completely restored ability to regenerate muscle after injury,
whereas untreated mice had large patches of scar tissue in place of
muscle. Losartan treatment over many months preserved muscle
architecture "over the long haul," says Dietz.

The team then measured muscle strength of untreated DMD mice as well
as mice treated for nine months with losartan by connecting the
muscles to tiny "force-meters" that measured contraction after an
electrical stimulus. While the untreated DMD muscles were "very
weak," according to Dietz, losartan-treated DMD muscles
were "indistinguishable" from normal muscles in how strongly they
contracted.

"We may have a real treatment alternative for a fatal disease-
Duchenne muscular dystrophy-that improves both length and quality of
life," says Cohn.

"For so many reasons, we're excited about these studies and their
potential to transform the care of patients with both Marfan syndrome
and Duchenne muscular dystrophy," says Dietz. "First, this treatment
strategy comes from understanding the basic science, the molecular
underpinnings of the disease. Second, the treatment has worked
exceptionally well in animal models. Third, we are not dealing with a
mysterious compound that was simply pulled off the shelf - losartan
has already been proven safe," says Dietz.

"Furthermore, losing the ability to regenerate muscle over time is
seen in many inherited and acquired muscle diseases and is even part
of the normal aging process," adds Cohn. "We may only be seeing the
tip of the iceberg."

Losartan, first approved for use as a blood pressure medication in
1995 by the U.S. Food and Drug Administration, often is used as an
alternative to other antihypertensive drugs in people who cannot
tolerate other blood pressure medicines.

The research was funded by the Howard Hughes Medical Institute, the
National Institutes of Health, the Smilow Center for Marfan Syndrome
Research, the Dana and Albert "Cubby" Broccoli Center for Aortic
Diseases and the National Marfan Foundation.

Authors on the paper are Cohn, Christel van Erp, Jennifer Habashi,
Arshia Soleimani, Erin Klein, Matthew Lisi, Matthew Gamradt, Colette
ap Rhys, Tammy Holm, Bart Loeys, Daniel Judge, and Dietz, all of
Hopkins; Christopher Ward of the University of Maryland; and
Francesco Ramirez of the University of Medicine and Dentistry of New
Jersey-Robert Wood Johnson Medical School.

Johns Hopkins Medical Institutions
901 S. Bond St., Ste 550 Baltimore, MD 21231 United States
http://www.hopkinsm edicine.org/

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