Dec. 29, 2008

Sarcospan Protein Saves Muscle Fibers in MD

The small protein sarcospan appears to have much more potential as a treatment for Duchenne muscular dystrophy (DMD) and perhaps other types of muscular dystrophy (MD) than previously believed, say researchers at the University of California-Los Angeles.

Rachelle Crosbie, who has received intermittent MDA funding since the late 1990s, and colleagues published the sarcospan findings in the Nov. 3 issue of the Journal of Cell Biology. (Crosbie received support from the National Institutes of Health for this project.)

Sarcospan is part of a cluster of proteins at the muscle-fiber membrane that also includes dystrophin, the protein missing in DMD, and the sarcoglycans, which are missing in some types of limb-girdle muscular dystrophy (LGMD).

Normally, these clusters, closely spaced at intervals around the periphery of muscle fibers, protect the fibers from injury related to mechanical stress. A loss or deficiency of any of the elements of the cluster, such as occurs in DMD and some LGMDs, can destabilize the entire structure, leaving the muscle fiber vulnerable to damage.

Until early in life, utrophin, which is very similar to dystrophin, is in these clusters, but it's replaced by dystrophin as the muscles mature. Utrophin is still produced, however, and it continues to be part of the clusters at the junctions between nerve and muscle fibers throughout life.

Several studies have shown dystrophin-deficient mice with extra utrophin do better than those without it, and various methods to increase utrophin production are being explored as strategies for DMD treatment. Crosbie and colleagues decided instead to explore raising sarcospan levels in muscle fibers.

Unexpectedly, the presence of extra sarcospan (created by giving dystrophin-deficient mice several sarcospan genes) led to the appearance of utrophin-containing protein clusters all around muscle fibers, not just at the specialized neuromuscular junction where they're normally found. Moreover, the sarcospan-enriched muscles looked healthier than those of the untreated dystrophin-deficient mice, with fewer degenerating fibers.

The investigators say they don't believe sarcospan increased utrophin production. Instead, they think it stabilized utrophin and allowed it to expand its role and its territory and to substitute for dystrophin.

They note the small size of the sarcospan gene compared to genes for dystrophin or utrophin would make it relatively easy to administer as a gene therapy, and that its widespread presence in muscle tissue would make an unwanted immune response to it unlikely.