HomeNewsBlood Pressure Drug Restores Muscle Function in Animal Model of Muscular Dystrophy


Blood Pressure Drug Restores Muscle Function in Animal Model of Muscular Dystrophy


A drug that keeps blood pressure under control may offer new hope for patients with muscular dystrophy.

Extensor digitorum longus muscles

A drug that has long been used to keep blood pressure under control may offer new hope for patients whose muscles have deteriorated due to muscular dystrophy. In studies of mice with symptoms that mimic the human disease, the drug restored the structure and function of muscle lost due to muscular dystrophy. Similarly, the drug strengthened the characteristically frail muscles of animals with Marfan syndrome, a genetic disease that weakens connective tissue.

Harry C. Dietz, a Howard Hughes Medical Institute investigator at Johns Hopkins University School of Medicine, led the research, demonstrating that excessive signaling by a protein known as TGF-beta prevents muscle from regenerating after it is damaged by injury or disease. Dietz and colleagues also demonstrated in animal models of both muscular dystrophy and Marfan syndrome that reducing TGF-beta signaling with the blood pressure drug losartan - which is sold by Merck under the brand name Cozaar - can eliminate the muscle weakness associated with both diseases.

The results of the study are published in the February 2007 issue of the journal Nature Medicine. Ronald D. Cohn, a former fellow in Dietz's lab who is now a professor at Johns Hopkins, was the first author of the study. Additional colleagues at Johns Hopkins, as well as researchers at the University of Medicine and Dentistry of New Jersey and the University of Maryland School of Medicine, also contributed to the work.

These encouraging findings come less than a year after animal studies in Dietz's lab suggested that losartan may prevent aortic aneurysm, a potentially fatal complication of Marfan syndrome. In January 2007, the National Heart, Lung, and Blood Institute began recruiting patients for a clinical trial that will test losartan's ability to prevent weakening of the heart's largest artery, which can rupture and cause fatal bleeding in patients with the disease.

Dietz said that weakened skeletal muscle can be a problem for patients with Marfan syndrome. Most patients notice that they are unable to gain muscle mass even with exercise, and experience muscle loss later in life, Dietz noted. Not only is this clinically burdensome, Dietz said, but it was intriguing from a biological perspective, because it did not quite fit with what was once thought to be the molecular basis of Marfan syndrome.

In 1991, Dietz and his colleagues had shown that mutations in the fibrillin-1 gene cause Marfan syndrome. Fibrillin-1 is a protein that is required during development to make elastic fibers in a range of tissues throughout the body. At the same time, however, this mutation did not seem to explain the complicated spectrum of effects associated with Marfan syndrome, which also include overgrowth of bones, thickened mitral valves, craniofacial deformities, and lung abnormalities. “One of the phenotypes that initially set in motion the concept that there had to be something more to the story,” Dietz said, was the muscle phenotype. “Why should weakness of the tissues lead to low muscle mass and muscular weakness?”

After years of work, Dietz and his colleagues discovered another culprit. In mice without fibrillin-1, which Dietz's lab and others use as a model to study Marfan syndrome, they found that defects in a variety of tissues could be attributed to excessive signaling of a protein known as transforming growth factor beta (TGF-beta). Dietz said he was eager to figure out whether this molecule was also contributing to muscle weakness.

At a late age, we had not only improved, but fully rescued the muscle performance in this mouse model of muscular dystrophy.

Harry C. Dietz

According to Dietz, no one had examined muscle that had been affected by Marfan syndrome. When he, Cohn, and their colleagues did so, they found significant structural abnormalities. In particular, many of the individual muscle fibers appeared to have split - a feature that is often observed in diseases that affect the muscle, and is known to be associated with a defect in muscle regeneration.

The scientists confirmed that TGF-beta was overactive in muscle cells, but they needed more evidence to demonstrate that the growth factor was actually responsible for the structural changes they saw. So Cohn injected the fibrillin-1-deficient mice with an antibody that blocks TGF-beta. “We saw that in a relatively short time - within two to three months of treatment—that the muscle architecture returned to normal,” Dietz said. “It wasn't just subtly improved; it was identical to the muscle architecture of a normal mouse. That not only told us that TGF-beta was involved, but also that the pathology was reversible, which was very exciting. We weren't dealing with a fixed pathology.”

This encouraging finding spurred the researchers to investigate further, focusing on the cells in the muscle that are responsible for regeneration. These cells, known as satellite cells, typically maintain a dormant state, but can be provoked into activity when muscle growth is needed. Both injury and exercise can release satellite cells from dormancy and cause them to proliferate. Once active, they fuse with damaged cells to repair muscle fibers, or fuse to themselves to create new muscle fibers, Dietz explained.

The scientists injected mice with a toxin that kills muscle cells, then watched to see how the satellite cells responded. As expected, the satellite cells quickly repaired the damage in the normal mice, restoring muscle architecture within 18 days. In the mice that lacked fibrillin-1, however, there seemed to be little attempt to regenerate the muscle at all, and eighteen days after the damage, the muscle structure had become increasingly chaotic. This, they found, was due to an inability of the satellite cells to respond to the signal to proliferate and initiate repair.

Blocking TGF-beta with an antibody could correct for this inability to repair muscle, Cohn and the other scientists found. And when they tested the grip strength of the mice, they found treatment with the antibody had made the fibrillin-1-deficient mice stronger and less likely to fatigue.

In previous studies on Marfan syndrome's effects on the aorta, Dietz and his colleagues had discovered that treating mice with the blood pressure drug losartan mimicked the effects of TGF-blocking antibodies. “So we tested losartan,” he said, “and showed that it also rescued steady-state muscle architecture, muscle regeneration, and muscle performance in the mouse model of Marfan syndrome.”

“That, in and of itself, was a pretty complete story,” Dietz said. “Once again, TGF-beta is driving this aspect of Marfan syndrome, and once again, blocking TGF-beta with losartan is sufficient to rescue the phenotype.” But the team wanted to know more. The next step, Dietz said, was to determine whether their findings applied only to muscle affected by Marfan syndrome, or whether they had learned something fundamental about muscle biology that could be relevant to other disease states. To find out, they next turned to a mouse model of muscular dystrophy.

“It's known that in many inherited and acquired muscle disorders, there is also a failure of muscle regeneration,” Dietz said. “In muscular dystrophy in particular, there is a desperate need for efficient muscle regeneration, because there is such rapid muscle turnover.” He explained that in patients with Duchenne muscular dystrophy, the most common type of the disease, a structural abnormality makes the muscle fibers particularly fragile. “Early in life, children with Duchenne muscular dystrophy have an intact regeneration process. Their muscle regeneration keeps pace with destruction and they retain muscle function. But over time, kids with Duchenne muscular dystrophy show a gradual loss in regenerative capacity. That correlates with a rapid decline in muscle function, muscle failure, and death due to cardiac and pulmonary complications.”

This loss of regenerative capacity, they reasoned, might be due to the same type of signaling defect they had found in Marfan syndrome. They soon found that TGF-beta was indeed overactive in the muscle of mdx mice, which, like patients with Duchenne muscular dystrophy, lack a protein called dystrophin that helps give muscle its stability. As with the mouse model of Marfan syndrome, blocking TGF-beta signaling with an antibody restored normal muscle architecture, enabled muscle regeneration, and greatly improved muscle strength.

So, Dietz said, “we made the logical leap to losartan, because it is an FDA approved drug and if it was efficacious it could rapidly move to a patient population. And we saw that losartan was every bit as good as TGF-beta-blocking antibody in rescuing muscle architecture and muscle regeneration in the mdx mouse.”

It was important to know whether these benefits were long lasting, so they started animals on drug treatment when they were just three months old. When the mice reached a year old - quite a long life for an mdx mouse, Dietz noted - the researchers performed detailed testing of muscle structure and function. Using a muscle that helps move the animal's paw, they stimulated the muscle with an electric current and measured how much force the muscle generated in response. They collected and compared this data from three groups of mice.

“When that analysis was done,” Dietz said, “we found that one group of mice had very poor performance, and two groups of mice had a dramatically better performance, and that their performance was indistinguishable. To our delight, the poor performance was in the placebo-treated mdx mice, and the two groups that showed identical performance were loarsartan-treated mdx mice and wild type mice. So at a late age, we had not only improved, but fully rescued the muscle performance in this mouse model of muscular dystrophy.”

Currently, the only treatment available for Duchenne muscular dystrophy is steroids, which do significantly improve muscle function. “But that improvement declines, so at most it's buying someone a couple of years of better muscle function,” Dietz said. “The fact that we've shown that losartan has a very enduring effect in the mouse and that it can achieve full rescue of muscle performance strongly suggests that it will perform better in people - but we have to test that. So we're very actively working with a number of organizations to plan a clinical trial of losartan for children with Duchenne muscular dystrophy.”

While losartan's effects on muscle have been remarkable in animal studies, Dietz cautions that that does not ensure similar success in patients. With that in mind, his lab is already exploring alternative methods of improving muscle regeneration. “If losartan doesn't achieve the effects that we saw in the mouse, we want to address every issue now, so we'll be prepared to address that possibility,” he said. One question they are pursuing is whether inhibiting thrombospondin I - a potent activator of TGF-beta that seems to be abated by losartan - might also restore muscle.

Meanwhile, the researchers are also beginning to investigate mouse models of other forms of muscular dystrophy to see if they, too, might be aided by losartan treatment. Similarly, they are curious whether TGF-beta contributes to the weakening and loss of regenerative capacity of muscle that occurs during normal aging, and whether blocking its signaling might improve muscle function in later life.

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The Johns Hopkins University
Genetics, Medicine and Translational Research

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