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 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.