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Muscular Dystrophy Research

The term muscular dystrophy (MD) encompasses a variety of degenerative muscle diseases. The most common of these diseases is Duchenne's muscular dystrophy

(DMD) (also called pseudohypertrophic MD), which is an X-linked hereditary disease affecting mostly male children (1 of 3,500 live male births). DMD is manifested by progressive muscular weakness during the growing years, becoming apparent by age 4. A characteristic enlargement of the affected muscles, especially the calf muscles, is due to a gradual degeneration and necrosis of muscle fibers and their replacement by fibrous and fatty tissue. By age 12, most sufferers are no longer ambulatory, and death usually occurs by the late teens or early twenties. The most serious defects are in skeletal muscle, but smooth and cardiac muscle are affected as well, and many patients suffer from cardiomyopathy (see Chapter 10). A related (and rarer) disease, Becker's muscular dystrophy (BMD), has similar symptoms but is less severe; BMD patients often survive into adulthood. Some six other rarer forms of muscular dystrophy have their primary effect on particular muscle groups.

Using the genetic technique of chromosome mapping (using linkage analysis and positional cloning), researchers have localized the gene responsible for both DMD and BMD to the p21 region of the X chromosome, and the gene itself has been cloned. It is a large gene of some 2.5 million base pairs; apparently because of its great size, it has an unusually high mutation rate. About one third of DMD cases are due to new mutations and the other two thirds to sex-linked transmission of the defective gene. The BMD gene is a less severely damaged allele of the DMD gene.

The product of the DMD gene is dystrophin, a large protein that is absent in the muscles of DMD patients. Aberrant forms are present in BMD patients. The function of dystrophin in normal muscle appears to be that of a cytoskeletal component associated with the inside surface of the sarcolemma. Muscle also contains dystrophin-re-lated proteins that may have similar functional roles. The most important of these is laminin 2, a protein associated with the basal lamina of muscle cells and concerned with mechanical connections between the exterior of muscle cells and the extracellular matrix. In several forms of muscular dystrophy, both laminin and dystrophin are lacking or defective.

A disease as common and devastating as DMD has long been the focus of intensive research. The recent identification of three animals—dog, cat, and mouse—in which genetically similar conditions occur promises to offer significant new opportunities for study. The manifestation of the defect is different in each of the three animals (and also differs in some details from the human condition). The mdx mouse, although it lacks dystrophin, does not suffer the severe debilitation of the human form of the disease. Research is underway to identify dystrophin-related proteins that may help compensate for the major defect. Mice, because of their rapid growth, are ideal for studying the normal expression and function of dystrophin. Progress has been made in transplanting normal muscle cells into mdx mice, where they have expressed the dystrophin protein. Such an approach has been less successful in humans and in dogs, and the differences may hold important clues. A gene expressing a truncated form of dystrophin, called utrophin, has been inserted into mice using transgenic methods and has corrected the myopathy.

The mdx dog, which suffers a more severe and humanlike form of the disease, offers an opportunity to test new therapeutic approaches, while the cat dystrophy model shows prominent muscle fiber hypertrophy, a poorly understood phenomenon in the human disease. Taking advantage of the differences among these models promises to shed light on many missing aspects of our understanding of a serious human disease.

References

Burkin DJ, Kaufman SJ. The alpha7beta1 integrin in muscle development and disease. Cell Tissue Res 1999; 296: 183-190.

Tsao CY, Mendell JR. The childhood muscular dystrophies: Making order out of chaos. Semin Neurol 1999;19:9-23.

ternal membranes with several critical functions (see Fig. 8.7). A skeletal muscle fiber is surrounded on its outer surface by an electrically excitable cell membrane supported by an external meshwork of fine fibrous material. Together these layers form the cell's surface coat, the sarcolemma. In addition to the typical functions of any cell membrane, the sarcolemma generates and conducts action potentials much like those of nerve cells.

Contained wholly within a skeletal muscle cell is another set of membranes called the sarcoplasmic reticulum (SR), a specialization of the endoplasmic reticulum. The SR is specially adapted for the uptake, storage, and release of calcium ions, which are critical in controlling the processes of contraction and relaxation. Within each sarcomere, the SR consists of two distinct portions. The longitudinal element forms a system of hollow sheets and tubes that are closely associated with the myofibrils. The ends of the longitudinal elements terminate in a system of terminal cister-nae (or lateral sacs). These contain a protein, calsequestrin, that weakly binds calcium, and most of the stored calcium is located in this region.

Closely associated with both the terminal cisternae and the sarcolemma are the transverse tubules (T tubules), inward extensions of the cell membrane whose interior is continuous with the extracellular space. Although they traverse the muscle fiber, T tubules do not open into its interior. In many types of muscles, T tubules extend into the muscle fiber at the level of the Z line, while in others they penetrate in the region of the junction between the A and I bands. The association of a T tubule and the two terminal cisternae at its sides is called a triad, a structure important in linking membrane action potentials to muscle contraction.

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