Duchenne muscular dystrophy is a heart-breaking genetic disorder that usually kills patients in their teens and twenties. Although the most prominent symptom is a gradual, progressive muscle weakness, most patients die from respiratory or cardiac failure. It's been difficult to determine exactly how the heart is damaged, though, since mice with the same genetic mutation display only mild symptoms.
This lack of an adequate animal model has hampered research on the disorder for decades. But now researchers from the laboratory of Helen Blau, PhD, the Donald E. and Delia B. Baxter Professor, have developed a new strain of mice that more-closely mimics the course of the disease in humans. The study (subscription required) was published yesterday in Nature Cell Biology. According to our release:
The investigators found that the reason humans suffer more serious symptoms than mice has to do with the length of the protective caps, called telomeres, on the ends of chromosomes: Mice have telomeres about 40 kilobases 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.
Humans with Duchenne muscular dystrophy (and mice serving as models for the condition) bear a mutation in the gene that encodes for the dystrophin protein, which supports and protects muscle fibers during contraction. When the researchers closely examined the heart muscle cells of the animals in the study, they found that their heart muscle cells accumulate damage due to oxidative stress as they maintained their rhythmic contractions in the absence of the dystrophin protein. The researchers found that treating affected mice with antioxidants early in the course of their disease delayed the onset of heart failure and increased the animals' life span.
The study reveals an intriguing link between telomere length and cardiac function. It also suggests that a similar approach may aid researchers interested in developing mouse models for other inherited cardiac disorders. But it's real strength lies in the ability to advance our understanding of Duchenne muscular dystrophy and speed the development of new treatments:
"The important thing is that we finally have a mouse model with which we can begin testing a number of potential therapies,” Blau said. “Until now, no one really understood the cardiac basis of the disease, and clinicians have been prescribing nonspecific treatments. Now we can develop more specific drugs for patients that target the cause of their cardiac dysfunction."
Previously: Mouse model of muscular dystrophy points finger at stem cells, Visible symptoms: Muscular-dystrophy mouse model's muscles glow like fireflies as they break down and Doctors develop first standard-of-care guidelines for congenital muscular dystrophy