Plugs and Patches
Improve Muscle Health

Much attention has been paid to gene therapy and stem cell strategies for treating muscle diseases, but several less dramatic strategies also appear to hold potential, especially if used in conjunction with more definitive therapies to enhance their effectiveness.

One such new approach proposes stopping a leak of calcium inside muscle fibers affected by Duchenne muscular dystrophy (DMD). Two others focus on repairing or shoring up the muscle-fiber membrane, a structure that’s affected in many diseases, such as DMD, Becker muscular dystrophy (BMD), some types of limb-girdle muscular dystrophy, and a type of congenital muscular dystrophy (CMD).

Plugging an internal leak

Investigators conducting experiments in mice with a disease resembling DMD have discovered that calcium can leak from internal storage areas in muscle fibers, and may be contributing to muscle degeneration. “Plugging” this leak could complement more definitive strategies, such as gene transfer, they say.

Andrew Marks at Columbia University in New York coordinated a team that included researchers from Montpellier (France) University and other institutions in Montpellier. They published their findings in the March 2009 issue of Nature Medicine.

The mice in these experiments lack the muscle protein dystrophin. In the mice — and in humans with DMD — a lack of dystrophin means 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.

Excess calcium entry into cells (which is not related to dietary intake of calcium) can cause multiple types of damage, and it’s been assumed that it’s responsible for some of the fiber degeneration see

However, until recentl ⁿ in this form of MD. y not much attention was paid to the release of calcium from internal storage areas in muscle fibers.

A burst of calcium from inside the fiber is necessary for it to contract (see In Focus: Periodic Paralysis, page 45), but a continuous leak of calcium can be damaging.

Marks and colleagues discovered internal calcium leakage in the dystrophic muscle that they say could contribute significantly to calcium-related damage in muscles and might be relatively amenable to preventive therapies.

When the researchers treated some of their mice, either orally or under the skin, with a compound called S107, they found it plugged the calcium leak without interfering with normal calcium release.

The treated mice developed better grip strength and tolerated downhill running better than their untreated counterparts, and 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.

Investigators say therapeutic strategies for DMD that inhibit internal calcium leakage into the muscle fiber with a small molecule such as S107 could provide an additional way to help protect against muscle damage and improve function in this disease.

whole muscle

bundle of muscle fibers

muscle-fiber membrane proteins

muscle-fiber membrane

dystrophin

Repairing or reinforcing a fragile muscle-fiber membrane could be helpful in treating several muscular dystrophies.

New membrane repair protein ID’d

Scientists in the United States and Japan say they’ve identified a previously unknown but crucial step in a natural muscle-cell repair process that could have implications for the treatment of muscular dystrophies, particularly those in which membrane defects are implicated.

Jianjie Ma of the Robert Wood Johnson Medical School in Piscataway, N.J. (part of the University of Medicine and Dentistry of New Jersey), with Hiroshi Takeshima of the Kyoto (Japan) University Graduate School of Pharmaceutical Sciences, and colleagues, have found that a muscle protein called mitsugumin 53 (MG53) is an essential component of the membrane repair machinery in muscle cells.

The researchers, who published their findings in the January 2009 issue of Nature Cell Biology, say the finding is relevant to both skeletal muscle fibers and