making muscle wasting history

Although the mdx mouse has no dystrophin in its muscles, it does not show the severe clinical symptoms of human Duchenne muscular dystrophy. Prof. Brian Tseng, formerly at the University of Colorado in Denver and now at the Harvard Massachusetts General Hospital in Boston and his team continue to investigate ways to slow down muscular dystrophy. The scientists used screening techniques to find “modifier” genes that are upregulated in mdx mice but downregulated in Duchenne boys. They identified two such genes for the enzymes arginine:glycine amidotransferase, AGAT, and guanidinoacetate methyltransferase, GAMT.

Both are important for the synthesis of creatine, which is required for biological energy in skeletal muscle. Unlike Duchenne boys, the mdx mouse can upregulate both enzymes so it can make its own creatine in its muscle cells. It is known that Duchenne boys have only 20% of the normal amount of creatine found in healthy muscle. In contrast, the mdx mouse has 80-90% of creatine in their muscles compared to healthy control mice. An mdx mouse was created whose GAMT gene was genetically inactivated. This mouse cannot walk well, dies early, and its muscles look more severely affected, similar to those of Duchenne boys.

Now, the researchers in Dr. Tseng’s laboratory are working to create an mdx mouse without the other enzyme, AGAT, which may be severely handicapped, too. And they are investigating how the absence of dystrophin protein seems to interfere with the transport of creatine from the bloodstream into the muscle cells, an effect which may speed up muscular dystrophy. This creatine transportter problem cannot be as effectively treated by dietary creatine alone. Dr. Tseng’s team is also studying the two genes GAMT and AGAT in boys and men with an a typical muscular dystrophy, who have no dystrophin but Beckerlike symptoms and near normal muscle strength. With high throughput screening methods, it may be possible to identify compounds, approved drugs, or “nutriceuticals” (effective dietary substances), which could upregulate the two “modifier” genes GAMT and AGAT in Duchenne boys. This could make their severe symptoms more like those of the hardly handicapped mdx mouse and buy time while efforts for a “real cure” continue.