Naturally Protected Muscle Phenotypes: Development of Novel Treatment Strategies for Duchenne Muscular Dystrophy

Primary abnormalities in the dystrophin gene underlie x-linked muscular dystrophy. However, the absence of the dystrophin isoform Dp427 does not necessarily result in a severe dystrophic phenotype in all muscle groups. Distal mdx muscles, namely extraocular and toe fibres, appear to represent a protected phenotype in muscular dystrophy. Thus, a comparative analysis of affected versus naturally protected muscle cells should lead to a greater knowledge of the molecular pathogenesis of inherited neuromuscular disorders. Furthermore, rationalising the protective cellular mechanisms might help in developing new treatment strategies for muscular dystrophy. The rescuing of extraocular and toe muscle fibres has previously been attributed to the special protective properties of fasttwitching small-diameter fibres. More recent biochemical studies have shown that the upregulation of the autosomal dystrophin homologue named utrophin and the concomitant rescue of dystrophin-associated glycoproteins also plays an important role in the mechanical stabilisation of Dp427-deficient fibres. This result is mirrored in the dystrophic mdx brain where the dystrophin isoform Dp71 seems to be responsible for the preservation of the dystroglycan complex. It is envisaged that future proteomics-based comparisons of naturally protective extraocular, toe and brain tissues with severely affected skeletal muscle fibres will greatly add to our general understanding of the pathophysiology of muscular dystrophy.