SCIENTISTS SHOW DRUG CAN COUNTERACT MUSCULAR DYSTROPHY IN MICE
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
<http://www.niams.nih.gov>
The National Institutes of Health (NIH) -- "The Nation's Medical Research
Agency" -- includes 27 Institutes and Centers and is a component of the
U.S. Department of Health and Human Services. It is the primary federal
agency for conducting and supporting basic, clinical and translational
medical research, and it investigates the causes, treatments, and cures
for both common and rare diseases. For more information about NIH and its
programs, visit
<http://www.nih.gov>
