Résumé :
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Myostatin and homologous molecules restrain growth of skeletal muscle by signalling via the transmembrane Activin-receptor-IIB (ActRIIB). Treatment with soluble ActRIIB-Fc fusion protein sequesters ActRIIB-ligands, which inhibits signal transduction via this receptor, thereby stimulating muscle growth. Currently, a multicentre phase IIa clinical trial is ongoing on ambulant patients suffering from Duchenne Muscular Dystrophy (DMD).We here studied the effect of soluble ActRIIB-Fc on growth and function of dystrophin-deficient muscles of mdx mice and we tested the added value of this approach when combining with AAV-U7-mediated dystrophin exon skipping. We show that 5 weeks systemic treatment of mdx mouse with ActRIIB-Fc enlarged muscle size (19% increase) and muscle fibre diameter (15% increase). Despite muscle being larger following treatment with ActvRIIb-Fc, tetanic force was not modified. However, ActRIIB-Fc ameliorated muscle resistance to eccentric contractions by 52%. Restoration of dystrophin expression following AAV-U7-mediated exon skipping is considered the most potent therapeutic strategy for DMD. We here show that restoration of dystrophin expression not only increased specific tetanic force to 120% but increased resistance to eccentric contractions to 288%, demonstrating the functional improvement 2 months following intramuscular AAV-U7 injection. When AAV-U7 was combined with ActRIIB-Fc, muscle mass increased by 14%. However, combined treatment had no additional effect on muscle resistance to eccentric contractions. Importantly, the positive effect of dystrophin restoration on muscle specific force was lost when combined with ActRIIB-Fc. In summary, combined ActRIIB-Fc and AAV-U7-mediated exon skipping treatment restores dystrophin expression and increases muscle size; however, there is no synergistic effect on muscle function. In fact, only dystrophin restoration but not activin receptor blockade, improved muscle function in mdx mice. Importantly, we here studied limb muscle of mdx mouse which is characterised by little dystrophic changes and no muscle wasting compared to DMD. Therefore, future experiments will focus on the effect of ActRIIB-Fc in combination with dystrophin exon skipping on overt dystrophic muscle.
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