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 on Jan.
21 at Nature Medicine.
In 2006, a team led by Harry "Hal" Dietz 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," explained Dietz, a
professor at the
McKusick-Nathans Institute of Genetic Medicine at the
Johns Hopkins 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," Dietz said, "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,
Dietz said.
Further study pinpointed how too much TGF-beta
activity leads to this weakened muscle architecture.
According to Ronald Cohn, 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," said Cohn, an assistant professor of
pediatrics and neurology at Johns 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, or 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 persons
with DMD age, their muscles slowly lose the ability to
regenerate and repair, leading to loss of muscle function,
Cohn said.
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 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," Dietz said.
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.
Said Cohn, "We may have a real treatment alternative
for a fatal disease — Duchenne muscular dystrophy
— that improves both length and quality of life."
"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," Dietz said. "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," Dietz said.
"Furthermore," Cohn said, "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. We may only be seeing the tip of the
iceberg."
Losartan, first approved in 1995 for use as a blood
pressure medication 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 Johns 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.
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