Scientists at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) and other institutions have demonstrated for the first time that a single drug can rebuild damaged muscle in two strains of mice that develop diseases comparable to two human forms of muscular dystrophy. This advance, which is reported online in Nature Medicine, is the latest from a research collaboration that began several years ago by the teams of Vittorio Sartorelli, M.D., at NIAMS and Pier Lorenzo Puri, M.D., Ph.D., now at Dulbecco Telethon Institute (DTI) in Rome, Italy and The Burnham Institute in La Jolla, Calif.

The scientists tested trichostatin A (TSA), an inhibitor of the enzyme deacetylase, in two mouse models of muscular dystrophy (MD): one that naturally develops a disease similar to Duchenne muscular dystrophy in humans, the other genetically altered to develop a form of dystrophy similar to the human limb-girdle muscular dystrophy. At 45 to 90 days of age, the muscles of the MD mice showed much fibrous tissue and infiltration of inflammatory cells. Unlike healthy mice, the mice with MD were unable to either run on a treadmill or swim. MD mice given TSA daily for two to three months, however, were virtually indistinguishable from healthy mice, and biophysical studies showed virtually no difference between the muscle strength of the mice with MD given the deacetylase inhibitor and healthy mice.

“This is the first example of using a drug to counteract muscular dystrophy in mouse models,” says Dr. Sartorelli. Yet he points out that the drug is only promoting muscle regeneration – it is not curing the defect that causes muscle deterioration. Further studies are needed to determine how long the drug works and if it works in larger animals with bigger muscles, such as dogs, before such drugs can be tested in people.

The finding has its roots in several of the group’s earlier advances, the first of which was reported in 2002 in the Proceedings of the National Academy of Sciences ¹. The scientists found that treating muscle cells with deacetylase inhibitors caused the cells to grow larger and differentiate better, says Dr. Sartorelli, the group leader of the Muscle Gene Expression Group in NIAMS’ Laboratory of Muscle Biology. The next advance, published two years later in the journal Developmental Cell ², was the discovery that the inhibitor worked by changing gene expression, causing some genes to be upregulated, or make more protein, and others to be downregulated, or make less protein. Among the genes positively regulated by the inhibitors was a gene for a key protein called follistatin.

“It was known that follistatin had a role in muscle development, so by understanding normal muscle development we knew that follistatin would block the activity of another protein called myostatin,” says Dr. Sartorelli. “If you block myostatin, you get big muscles.”

One way of inactivating myostatin is to upregulate follistatin. Basically, what follistatin does is to prevent myostatin from working, says Dr. Sartorelli. When his group treated the cells with deacetylase inhibitors, they saw that the cells became large and that follistatin was overexpressed. However, when the group treated the cells with the inhibitors and then used other agents to block follistatin, the cells didn’t become bigger, showing that one of the most important pathways the inhibitors use to create bigger muscles involves the activation of follistatin. “If you didn’t have follistatin anymore, these drugs didn’t work,” he says.

Moreover, Drs. Sartorelli’s and Puri’s groups were able to show that in normal animals, follistatin is upregulated when muscle is damaged. When the researchers induced muscle damage and then gave the inhibitors, follistatin was even more expressed, as were two proteins that reflect increased muscle regeneration.

Other Italian groups contributed to the present study, including the Istituto Dermatologico dell’ Immacolata of Rome; the Department of Experimental Medicine, Human Physiology Unit, University of Pavia; and the Laboratory of Vascular Biology and Genetic Therapy, Centro Cardiologico Monzino, Milan.

This study was supported in part by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health. Other support was provided by Telethon (Italy), the Muscular Dystrophy Association and the Parent Project Organization (Italy).

The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the Department of Health and Human Services’ National Institutes of Health, is to support research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases. For more information about NIAMS, call the information Clearinghouse at (301) 495-4484 or (877) 22-NIAMS (free call) or visit the NIAMS Web site at www.niams.nih.gov.

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