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Common Blood Pressure Drug Treats Muscular Dystrophy in Mice
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."