Investigators conducting experiments in mice with a disease resembling Duchenne muscular dystrophy (DMD) believe they’ve uncovered a new strategy to protect against muscle damage and improve strength in this disease.
Andrew Marks at Columbia University in New York coordinated the team, which included researchers from Montpellier (France) University and other institutions in Montpellier. They published their findings in the March issue of Nature Medicine.
The mice in these experiments lacked the muscle protein dystrophin, the same protein missing in boys with DMD. Without dystrophin, a cluster of proteins nestled in a membrane surrounding each muscle fiber can't preserve the integrity of the membrane. Leaks and tears in the membrane occur and are accompanied by entry of excess calcium into muscle fibers.
Calcium that leaks into cells (which is unrelated to dietary intake of calcium) can cause multiple types of damage. It's long been assumed that it’s responsible for some of the fiber degeneration seen in DMD.
However, until recently, not much attention has been paid to the normal burst of calcium released by internal storage areas in muscle fibers, which is necessary for them to contract. Marks and colleagues discovered that in dystrophic muscle, calcium is leaking from these internal storage areas. Although a burst of calcium is necessary for muscle function, a chronic calcium leak may contribute significantly to muscle damage.
The good news is: This internal calcium leakage may be relatively amenable to treatment. Researchers found that when they treated some of their mice with a compound called S107, it plugged the calcium leak without interfering with normal calcium release.
The mice, which were treated either orally or by injection under the skin, developed better grip strength and tolerated downhill running better than their untreated counterparts. Biochemical and microscopic signs of muscle degeneration were much less severe than in the untreated group.
Improved exercise tolerance was seen after only one week of treatment, and improvement in the appearance of the muscle tissue after four weeks.
Researchers say that inhibiting internal calcium leakage into the muscle fiber with a small molecule such as S107 may become a new strategy for therapy development in DMD, and might complement more definitive strategies such as gene transfer.