Function and Genetics of Dystrophin and Dystrophin-Related Proteins in Muscle

Abstract

The X-linked muscle-wasting disease Duchenne muscular dystrophy is caused by mutations in the gene encoding dystrophin. There is currently no effective treatment for the disease; however, the complex molecular pathology of this disorder is now being unravelled. Dystrophin is located at the muscle sarcolemma in a membrane-spanning protein complex that connects the cytoskeleton to the basal lamina. Mutations in many components of the dystrophin protein complex cause other forms of autosomally inherited muscular dystrophy, indicating the importance of this complex in normal muscle function. Although the precise function of dystrophin is unknown, the lack of protein causes membrane destabilization and the activation of multiple pathophysiological processes, many of which converge on alterations in intracellular calcium handling. Dystrophin is also the prototype of a family of dystrophin-related proteins, many of which are found in muscle. This family includes utrophin and alpha-dystrobrevin, which are involved in the maintenance of the neuromuscular junction architecture and in muscle homeostasis. New insights into the pathophysiology of dystrophic muscle, the identification of compensating proteins, and the discovery of new binding partners are paving the way for novel therapeutic strategies to treat this fatal muscle disease. This review discusses the role of the dystrophin complex and protein family in muscle and describes the physiological processes that are affected in Duchenne muscular dystrophy.

Postnatal overexpression of the CT GalNAc transferase inhibits muscular dystrophy in mdx mice without altering muscle growth or neuromuscular development: Evidence for a utrophin-independent mechanism

“…Utrophin upregulation does occur in some mdx myofibers, particularly in regenerating myofibers in younger mdx animals [3,35,36]. Indeed, some of our early experiments with AAV2-Galgt2, which yielded far fewer infected myofibers on a vg basis than our later experiments with AAV1-Galgt2, showed that some utrophin upregulation did occur in some Galgt2 overexpressing myofibers.…”

“…mdx mice are a commonly used model for testing therapeutic approaches to DMD; mdx animals do not express dystrophin protein in most of their skeletal myofibers, and mdx myofibers exhibit several important pathological hallmarks of DMD [3,4]. In addition, loss of dystrophin protein expression, both in DMD and mdx muscles, correlates with loss of membrane expression of proteins in the dystrophin-glycoprotein complex, including dystroglycans and sarcoglycans, along the myofiber membrane [5].…”

Cytoplasmic γ-actin expression in diverse animal models of muscular dystrophy

“…While studies of mdx mice have greatly advanced our understanding of dystrophinopathies in humans, there are a number of important pathological differences between dystrophindeficient humans and mice. Furthermore, mutations in genes encoding other DGC components or associated proteins have been implicated in clinically distinct forms of muscular dystrophy [2,3]. Finally, the complexity of the costameric protein network supports the hypothesis that additional proteins may form distinct mechanical linkages parallel to the DGC γ cyto -actin axis.…”

“…Utrophin is upregulated in both animals [37][38][39][40] suggesting that a similar compensatory remodeling program is activated in dystrophindeficient mice and dogs. However, GRMD dogs suffer a severe and rapidly progressing muscle disease with premature lethality more closely resembling DMD in humans while mdx mice exhibit a milder phenotype with no dramatic reduction in lifespan [3]. Thus, it appears that compensatory cytoskeletal remodeling is not as effective in dystrophin-deficient dogs compared to mice, which may be due to the greater mechanical stresses imposed on the sarcolemma of larger animals with correspondingly larger myofibers [30,41].…”

“…Dystrophin functions as part of a larger oligomeric protein complex named the dystrophin-glycoprotein complex (DGC), which includes the dystroglycan subcomplex, the sarcoglycan/sarcospan subcomplex, dystrobrevins and syntrophins [2,3]. The DGC spans the sarcolemma and links the actin cytoskeleton with the extracellular matrix of myofibers [2,3].…”