Guérir la myopathie de Duchenne par l’utrophine ? Utrophin, a way to cure Duchenne muscle dystrophy

Résumé

La myopathie de Duchenne est due à l’absence d’une protéine du cytosquelette des fibres musculaires, la dystrophine. Celle-ci joue un rôle essentiel dans l’intégrité des complexes protéiques membranaires qui assurent la liaison avec la matrice extracellulaire. L’utrophine, codée au niveau du chromosome 6, présente 80 % d’homologie avec la dystrophine et est exprimée à la jonction neuromusculaire. L’utrophine peut-elle remplacer la dystrophine et corriger les anomalies structurelles et fonctionnelles de la myopathie ? Chez des souris transgéniques déficientes en dystrophine et surexprimant de grandes quantités d’utrophine, celle-ci occupe les structures fixant la dystrophine et la récupération des atteintes fonctionnelles, surtout mécaniques, peut être complète. Pour transformer cette approche expérimentale en traitement de la myopathie, les nombreuses recherches en cours visent à obtenir une surexpression d’utrophine dès l’apparition des symptômes myopathiques.

Summary

Duchenne muscle dystrophy results from the absence of dystrophin, a cytoskeletal protein of the muscle fibre. Dystrophin plays an essential role in the integrity of the membrane-associated protein complexes connected to the extracellular matrix. On chromosome 6 is located the gene of a protein presenting 80 % homology with dystrophin : utrophin, which is expressed at the neuromuscular junction. The review examines if utrophin can replace dystrophin and correct the structural and functional characteristics of the myopathy, and how the improvements can be quantitatively expressed. In transgenic mice, deficient in dystrophin, but overexpressing large quantities of utrophin, the latter is found on structures where dystrophin is normally located, histological signs of necrosis disappear and the recovery of functional disorders, specially affecting the mechanical properties of the muscle fibres, can be complete. The review examines also several ways of obtaining overexpression of utrophin in adult mdx mice, such as conditioned expression of the utrophin transgene (using a tetracycline-sensitive transactivator), transfection with viral vectors containing the utrophin cDNA (complete or truncated), actions on factor(s) controlling utrophin expression at the neuromuscular junction (heregulin, 4 N-acetylgalactosamine), and pharmacological ways of inducing expression (NO, arginine). Though partial improvements of the myopathy status have been obtained by these various approaches, they remain limited by their localized action and/or by the moderate level of utrophin expression obtained. Further researchs to overcome these limitations are urgently needed in order to transform the very promising effect of utrophin overexpression into a real treatment of Duchenne myopathy.