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New mouse model reveals a mystery of Duchenne muscular dystrophy, Stanford scientists say
Date:7/7/2013

bases in length, while human telomeres range from around 5 to 15 kilobases (a kilobase is 1,000 nucleotides). When the investigators introduced a second mutation in the animals that reduced telomere length to more closely match that of humans, the animals began to display the typical symptoms of the disease, including progressive muscle weakness, enlarged hearts and significantly shortened life spans.

Duchenne muscular dystrophy is the most prevalent form of the heritable muscular dystrophies. It is caused by mutations in the dystrophin gene that inhibit the production of the dystrophin protein, which connects the inside of the muscle cell to the outside matrix. The new mouse model showed that, in the absence of the dystrophin protein, the animals' heart muscle cells accumulate stress and damage due to repetitive contraction. Early treatment of a small group of animals with antioxidants protected their heart function and prolonged their lives.

Interestingly, cells in the animals from tissues that normally express dystrophin had telomeres much shorter than those in other tissues in the body that don't rely on the protein. This discovery indicates that the lack of the protein further exacerbates telomere shrinking a fact borne out when the researchers compared affected mice and humans.

"Telomeres in heart muscle cells from four young men who had died of Duchenne muscular dystrophy were about half the length of control samples," Mourkioti said. "They are greatly shortened."

In the context of shortened telomeres, the dystrophin mutation in the mice leads to significant impairment of cardiac function. "Essentially, the heart cannot contract well," said Mourkioti, who performed a variety of functional and imaging tests, including electrocardiograms, echocardiography and MRIs, on mice in the study. When she looked at the heart muscle cells, or cardiomyocytes, of animals with the two mutations, she found damage to the cells' energy gener
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Contact: Krista Conger
kristac@stanford.edu
650-725-5371
Stanford University Medical Center
Source:Eurekalert

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