June 27, 2008

Myotilin Overproduction Worsens LGMD1A in Mice

Overproduction of the protein myotilin worsens the symptoms of type 1A limb-girdle muscular dystrophy (LGMD1A) in mice, say researchers at Duke University in Durham, N.C., who published their findings in the May issue of Muscle & Nerve. MDA supported Michael Hauser at the Center for Human Genetics at Duke for this work.

The myotilin gene is located on chromosome 5; it carries instructions for the large myotilin protein found in the Z-disc – the structure that anchors the thick and thin filaments that slide together to cause the muscle cell to contract. Defects (mutations) in the myotilin gene lead to the production of abnormal (mutated) myotilin protein, which causes disorganization in the muscle fibers. This is the underlying cause of LGMD1A, a slowly progressive, genetic disease characterized by onset of muscle degeneration and weakness in young adulthood.

The investigators examined the severity of muscle degeneration and conducted microscopic analysis of muscle fibers in mice bred to produce mutated myotilin alone or mutated myotilin and higher-than-average levels of normal myotilin. They found that the mice making mutant myotilin had signs of LGMD1A, but the same mice making increased levels of normal myotilin had even more severe symptoms, including earlier onset and a greater involvement of muscles less affected in mice that produced only mutant myotilin.

These findings, the researchers suggest, indicate a "knockdown" approach, in which the amounts of both abnormal and normal myotilin are reduced, might be an effective therapeutic strategy for LGMD1A.

"Our mouse experiment is a big step forward in understanding the mechanism in LGMD1A," Hauser said, noting the questions the data raises in terms of therapeutic strategies.

"This improved understanding of mechanism is an important part of designing effective therapies for any muscular dystrophy, as is a highly efficient delivery system," he said. "Recent advances in gene delivery using AAV vectors have provided hope of more effective therapies for many muscular dystrophies."

Hauser suggested more work may be needed in developing highly efficient knockdown methods, and "it may turn out that effective therapy will require a combination of several different methods at once." Anti-aggregate drugs, he noted, may be another possibility.