Jan. 22, 2007
 
HEALTH: Blood-Pressure Drug Could Also Treat Muscle Disease
 
By Lee Bowman
Scripps Howard News Service
 
A drug commonly used to lower blood pressure reverses muscle wasting in lab mice genetically engineered to develop either Marfan syndrome or Duchenne muscular dystrophy, according to new findings reported by researchers at the Johns Hopkins University School of Medicine.
 
In Marfan syndrome, the chemical makeup of connective tissue -- the substance and support of tendons, ligaments, blood-vessel walls, cartilage and heart valves -- is abnormal and leaves those structures weakened.
 
Last year, a team led by Dr. Harry Dietz discovered that treating Marfan mice with the drug losartan, or Cozaar, dramatically strengthens the aorta, the major artery carrying blood away from the heart. This helps prevent enlargement and possible fatal rupture of the artery.
 
The researchers expect to begin a trial to assess how effective losartan is at treating people with Marfan in a few 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," Dietz said.
 
He and his colleagues had already learned that many features of Marfan arise from excess activity of a protein called TGF-beta, which guides behavior in muscle cells.
 
So first, the researchers injected Marfan mice with another protein that binds TGF-beta and makes it inactive. This allowed the muscle fibers in the mice to grow bigger and the mice to be stronger and show less fatigue.
 
Then they began treating the animals with losartan, which is also known to block TGF activity. After six months, the mice had "completely restored muscle architecture" and much improved strength, Dietz said.
 
More research established how excess TGF activity weakens muscle. While normal muscle can repair itself by mobilizing muscle stem cells, high levels of TGF activity block this process.
 
"The simplest things can injure muscle," said Dr. Ronald Cohn, an assistant professor of pediatrics and neurology and lead author of the study, published online Sunday, Jan. 21, 2007 by the journal Nature Medicine. "Running a mile down the street causes microscopic tears in leg muscles, which normally go unnoticed because muscles are so efficient at repairing themselves."
 
So Dietz's team then considered whether blocking excess TGF might be a strategy against other muscle diseases, particularly Duchenne MD, the most common form of muscular dystrophy in children, which causes muscle fibers to be extremely fragile. The disease often kills before victims reach early adulthood.
 
In another round of tests on mice genetically engineered to have MD, the researchers tested both the blocking protein and losartan, while leaving another group of mice untreated.
 
Both treated groups had restored ability to regenerate muscle after injury, but losartan treatment over many months appeared to better preserve muscle structure over the long term. And in a strength test, losartan-treated muscles were "indistinguishable" from those of normal mice in how strongly they contracted, the researchers said.
 
Dietz said the findings are particularly promising toward developing treatment since they've lead to basic understanding of the diseases and how the drugs work and shown good results in animals.
 
"We are not dealing with a mysterious compound that was simply pulled off the shelf -- losartan has already been proven safe," Dietz explained.
 
"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," Cohn said. "We may only be seeing the tip of the iceberg."
 
On the Net: http://www.nature.com
 
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