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).
|Repairing or reinforcing a fragile muscle-fiber membrane could be helpful in treating several muscular dystrophies.|
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 seen in this form of MD.
However, until recently 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), 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.
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 cardiac muscle cells.
Muscle-membrane repair, the researchers note, is required in response to exercise, injury, aging and a variety of muscle conditions. They describe a three-part repair process in which MG53 first senses damage to the membrane; MG53 steers vesicles (bubbles) carrying repair molecules to the damage site and holds them in place; and the vesicles fuse with the membrane, forming a repair patch.
Several years ago, MDA-supported researchers identified another protein, now called dysferlin, which participates in the membrane repair process. The researchers say future studies are needed to see whether MG53 and dysferlin are part of the same or different repair pathways.
A protein called laminin 111 had a marked therapeutic effect in dystrophin-deficient mice that have a DMD-like disease, say researchers at the University of Nevada School of Medicine.
Dean Burkin and colleagues, whose results were published online in Proceedings of the National Academy of Sciences on April 28, 2009, found systemic treatment with laminin 111 restored several aspects of muscle health and prevented exercise-related damage in these mice.
In their paper, Jachinta Rooney, Praveen Burpur 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.
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, April-June 2009.)
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 were intact. An enzyme called creatine kinase (CK) was not leaking from their muscle fibers into the circulation, a positive 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.
The laminin 111 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.