DMD: Restarting Muscle Development?

Laminin 111 prevents injury and loss of muscle function in DMD mice

by Quest Staff on April 24, 2009 - 11:55am

A protein called laminin 111 had a marked therapeutic effect in mice that lack the dystrophin protein and have a muscle disease resembling human Duchenne muscular dystrophy (DMD), say researchers at the University of Nevada School of Medicine.

Dean Burkin and colleagues, whose results were published online April 28, 2009, in Proceedings of the National Academy of Sciences, found systemic treatment with laminin 111 restored several aspects of muscle health and prevented exercise-related damage in the dystrophin-deficient mice.

The Muscle-Fiber Membrane and Its Proteins
Laminin 111 is normally present in skeletal and cardiac muscles only during embryonic development. It disappears and is replaced by other forms of laminin as tissues mature. When injected as a therapy, however, it may reactivate a muscle development program and also may help stabilize the fiber membrane.

In their paper, Jachinta Rooney, Praveen Gurpur and Burkin say laminin 111 is a "highly potent therapeutic agent" in the mouse model of DMD and could have applications for human muscle disease.

(Note: Some mainstream news reports seem to suggest that laminin 111 is a treatment or cure for human Duchenne muscular dystrophy. Although this protein looks promising as a therapy, the experiments described are in mice. Laminin 111 will have to go through many types of testing, including safety trials in humans, if it is to be developed into a treatment.)

Earlier this year, Burkin and colleagues showed laminin 111 improved the muscle health of mice with an integrin-deficient form of congenital muscular dystrophy (CMD). (See Research Updates, Quest, April 2009.)

Widespread distribution

When the investigators gave DMD mice a systemic injection of the laminin 111 protein and analyzed their tissues a month later, they were surprised to see laminin 111 throughout limb, diaphragm and cardiac muscles. They had suspected the large size of the laminin molecule might prevent it from migrating far from the injection site.

More importantly, the laminin-treated mice showed signs that their muscle-cell membranes, the site of damage in DMD, were intact. An enzyme called creatine kinase (CK) was not leaking from their muscle fibers into the circulation, an indication of membrane integrity. (Dystrophin-deficient muscles leak CK.)

And, when the muscles of laminin-treated DMD mice were examined after the mice ran downhill on a treadmill, they showed very little damage, while their untreated counterparts showed significant injury.

About laminin 111

See a video of Dean Burkin describing the finding.
See a video of Dean Burkin describing the finding.

The protein normally is present in skeletal and cardiac muscles in mice and humans only during embryonic development. As tissues mature, it disappears and is replaced by other forms of laminin.

During development, it's located just outside the membrane that surrounds each muscle cell, in a gel-like substance called the extracellular matrix. While there, it increases production of a membrane protein called alpha 7 integrin, which is known to play a role in skeletal muscle regeneration and repair. (Burkin received MDA funding from 2000 to 2003 to study the role of integrin in alleviation of muscular dystrophy.)

Earlier research by Burkin and colleagues suggests the presence of the embryonic laminin protein may activate a muscle regeneration "program" like the one used to make muscle during early development. They believe it may have played additional roles in the DMD mice, such as directly reinforcing the muscle-fiber membrane.

Protective effect

"In this study, we show that systemic delivery of laminin 111 not only prevents dystrophin-deficient muscle from degeneration but also protects muscle from contraction-induced injury," the researchers say. "These results strongly suggest that laminin protein therapy may prevent the repetitive cycles of injury, fibrosis [scarring], and loss of muscle function in DMD."

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