Pathophysiology of Duchenne Muscular Dystrophy: Current Hypotheses

Abstract

Duchenne muscular dystrophy is a devastating inherited neuromuscular disorder that affects one in 3300 live male births. Although the responsible gene and its product, dystrophin, have been characterized for more than 15 years, and a mouse model (mdx) has been developed, comprehensive understanding of the mechanism leading from the absence of dystrophin to the muscular degeneration is still debated. First, dystrophin is considered a key structural element in the muscle fiber, and the primary function of the dystrophin-associated protein complex is to stabilize plasma membrane, although a role of signaling is still possible. Mechanically induced damage through eccentric contractions puts a high stress on fragile membranes and provokes micro-lesions that could eventually lead to loss of calcium homeostasis, and cell death. Altered regeneration, inflammation, impaired vascular adaptation, and fibrosis are probably downstream events that take part in the muscular dystrophy and that probably vary a lot along species (i.e., mdx mice), probands within families, stressing the importance of epigenic factors. Because no etiologic therapy is available for Duchenne muscular dystrophy, a better understanding of the primary and downstream mechanisms could prove useful for producing new adjuvant treatments. All pathophysiologic mechanisms are reviewed together with perspectives on management.

Genetic elevation of Sphingosine 1-phosphate suppresses dystrophic muscle phenotypes in Drosophila

“…This severe X-linked recessive disease affects 1 in 3500 male births (Deconinck and Dan, 2007). In human dystrophic muscles, rounds of contractions result in degeneration/regeneration cycles.…”

In vivo analyzes of dystroglycan function during somitogenesis in Xenopus laevis

“…Originally, Dg was isolated from skeletal muscle membranes and was found to be an essential component of the dystrophin-glycoprotein complex, which links the ECM surrounding myofibers to the actin cytoskeleton. Disruption of Dg-dystrophin interaction has been described in Duchenne-type or limb-girdle-type muscular dystrophy (Deconinck and Dan, 2007). It has been proposed that Dg forms a continuous link from the ECM to the actin cytoskeleton, providing structural integrity and perhaps transduction signals (Winder, 2001).…”

Bex1 knock out mice show altered skeletal muscle regeneration

“…The absence of dystrophin, a membrane-associated protein, is clearly the underlying cause [5]. Nonetheless, the molecular mechanisms of this disease and other myopathies are still under investigation [6]. It is, therefore, essential to identify molecules that contribute to mechanisms underlying muscular dystrophies in order to develop rational treatment strategies to target specific physiological processes [7].…”

“…Experiments performed using cDNA-based microarrays have identified highly coordinated molecular changes involved in skeletal muscle regeneration following cardiotoxin (CTX)-induced injury, a reproducible method to induce muscle regeneration [9,10]. Mdx mice [6] possess a mutation in the gene coding dystrophin, the protein that is absent in humans with DMD [4]. Histological findings, such as centrally nucleated fibers, inflammation, and heterogeneity of fiber size, are similar in the skeletal muscle of mdx mice and of patients with DMD [11].…”