Experimental Cancer Drug Improves
Muscle Size, Strength in MD-Affected Mice

Compounds known as histone deacetylase (HDAC) inhibitors, which are being studied for use against certain cancers, may have a future in treating muscular dystrophies, say researchers at several Italian research institutions as well as the Burnham Institute in La Jolla, Calif., and the National Institutes of Health in Bethesda, Md.

MDA grantee Pier Lorenzo Puri of the Dulbecco Telethon Institute in Rome coordinated the research team, which published its findings online Sept. 17 in Nature Medicine.

HDAC inhibitors encourage the acetylation — the adding of acetyl molecules — to histone proteins, which stick to DNA and play a role in controlling gene activity.

After trying three HDAC inhibitors, the researchers selected one called trichostatin A (TSA) to test in dystrophin-deficient and alpha-sarcoglycan-deficient mice. These are animal models of Duchenne muscular dystrophy and one type of limb-girdle muscular dystrophy, respectively.

In both types of mice, daily TSA injections increased muscle fiber size and reduced fibrosis (scarring) and signs of inflammation.

In the dystrophin-deficient mice, which were the more extensively studied, daily injections of TSA for three months starting at 12 weeks of age restored to normal the force generation of a foot muscle; reduced muscle fiber uptake of a dye, which indicates better integrity of muscle fiber membranes; markedly improved exercise performance on a treadmill and on a swimming test; and reduced signs of muscle degeneration and regeneration typical of muscular dystrophy.

The investigators say they think the beneficial effects of TSA are due to its ability to increase production of the follistatin protein. Follistatin is known to interfere with myostatin, a protein that limits muscle growth.

“These data are so far restricted to mice,” Puri said, “and will not necessarily extend to humans. However, we have already planned preclinical studies that will define the
suitability of these treatments in humans.”

Sharon Hesterlee, MDA’s vice president for translational research, said: “The fact that some members of this class of drug are already being used in the clinic makes this finding particularly exciting.”