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in the October issue of the Journal of Clinical Investigation.

The group, which included MDA grantee Melissa Spencer at the University of California at Los Angeles, tested the effects of calpastatin, a calpain-blocking protein, on mice with genetically caused slow-channel myasthenic syndrome by genetically engineering these mice to over-produce calpastatin.

The disease-affected mice with the extra capastatin showed more normal nerve-to-muscle signaling and better strength than did untreated mice, but they weren’t cured of the disease, leading the researchers to suspect that there are additional enzymes, known as caspases, involved in slow-channel syndrome.

“Our findings showing inhibition of calpain with overexpressed CS [cal-pastatin] demonstrate that calpain can be effectively inhibited while caspase 3 appears unaffected,” the investigators write. “These studies demonstrate that the calpain and caspase ... systems play predominant roles in the pathogenesis [cause] of the slow-channel syndrome. Therapies designed to chronically reduce excessive calpain and caspase activities may be useful in the treatment of the SCS and related ... disorders.”

MicroRNA molecules may
provide new therapeutic
targets in several diseases

A new type of molecular profiling may hold clues to muscle degeneration in general and to variations in muscle degeneration among different diseases, says a multinational team of researchers that included MDA grantee Alan Beggs at Children’s Hospital and Harvard Medical School in Boston.

Lou Kunkel, also at Children’s Hospital and Harvard Medical School, and a member of MDA’s Scientific Advisory Committee, coordinated the multinational research team, which published its findings in the Oct. 23 issue of Proceedings of the National Academy of Sciences.

In their paper, the investigators describe how so-called microRNA signatures provide the basis for a new set of potential targets for therapy in several muscle diseases.

class of very small molecules that regulate gene activity by inactivating genetic information (RNA) that would otherwise lead to the production of proteins.

They can change the way basic processes, including cell death, cell proliferation, tissue development and the immune response take place.

The investigators analyzed 88 muscle samples representing 10 different muscle diseases, including Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), facioscapulohumeral muscular dystrophy (FSHD), types 2A and 2B limb-girdle muscular dystrophies (LGMD2A, LGMD2B), Miyoshi myopathy, nemaline myopathy, poly-myositis (PM), dermatomyositis (DM) and inclusion-body myositis (IBM).

Each of the muscle diseases studied proved to have a unique microRNA signature that’s presumably a result of the underlying genetic defect (such as a dystrophin mutation in DMD or BMD) for each disease.

Measuring levels of 18 of the microRNA molecules allowed researchers to accurately tell disease-affected muscle tissue from normal muscle tissue and to distinguish among the various muscle diseases.

Although each disease showed its own profile, several diseases showed levels of microRNAs involved in regulating inflammation and the immune response that were different from those seen in the normal muscle samples.

The investigators say that their findings “raise the opportunity for therapeutic intervention at the miRNA [microRNA] level in preventing specific physiological pathways underlying [a] disease.”

T-cells in IBM suggest
immune response against
muscle is part of disease

Support for the idea that autoimmunity (a mistaken attack by the immune system on the body’s own tissues) is part of the disease process in nonfamilial inclusion-body myositis (IBM) was recently demonstrated in studies from the laboratory of Marinos Dalakas at the U.S. National Institutes of Health in Bethesda, Md.

Some experts have argued that IBM is primarily an inflammatory, autoimmune disease, while others have argued that it is primarily degenerative in nature. There is evidence for both processes, though which

is primary remains debatable.

Dalakas and colleagues, who published their results in the Oct. 23 issue of Neurology, studied muscle and blood cells from 12 people with nonfamilial (“ sporadic”) IBM and compared the two kinds of cells with each other and with blood cells from unaffected people.

They found that certain proteins on the surfaces of the immune system’s T-cells were different in muscle compared to blood in people with IBM, with the muscle T-cells showing a narrower range of specific surface proteins than the blood cells. Both kinds of cells showed less variation in their surface-protein patterns than did blood T-cells from people without the disease.

The surface proteins the researchers analyzed are those that make up the T-cell receptors, the parts of the cells that participate directly in an immune response.

The results, the investigators say, suggest that the T-cells in IBM are specifically reacting against the patients’ muscle fibers, and that after they enter the fibers from the bloodstream, they begin to specialize in this anti-muscle reaction.

The T-cells that are still in the bloodstream don’t have the same degree of anti-muscle specification, even in the IBM patients, and the T-cells from the unaffected samples don’t show any such specification.

When the researchers compared T-cells in muscle biopsy samples taken from people with IBM a year after the initial samples were examined, they found the degree of specificity of the surface proteins was essentially unchanged.

They say their findings support the view that muscle-fiber proteins are a stimulus for an undesired, chronic response by the immune system in this disease.

They say further probing of the response should help clarify the relationship between inflammation and degeneration in IBM and offer means of “better customizing therapeutic strategies.”

Suppressing myoD could
help immature muscle cells
survive transplantation

Genetically altering immature muscle cells so that they lack a protein known as myoD significantly improves their ability to survive after they’re injected into mouse muscles, researchers have found.

They say the findings, published