Résumé :
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Lysosomal neuraminidase (NEU1) is the glycosidase responsible for the catabolism of sialic acid-containing glycoconjugates. A deficiency of this enzyme is associated with the lysosomal storage disease sialidosis. Children affected by this disease have severe systemic and neurological abnormalities, which include muscle hypotonia, atrophy and osteoskeletal deformities. Neu1-/- mice are a close phenocopy of the severe human condition. Histological examination of Neu1-/- muscle reveals an expansion of the epimysial and perimysial spaces, associated with proliferation of fibroblast-like cells and abnormal deposition of collagens. Muscle fibers located adjacent to the expanded connective tissue underwent extensive invagination of their sarcolemma, which resulted in the infiltration of the fibers by fibroblast-like cells and extracellular matrix, and in their progressive cytosolic fragmentation. Both the expanded connective tissue and the juxtaposed infiltrated muscle fibers were strongly positive for lysosomal markers and displayed increased proteolytic activity of lysosomal cathepsins and metalloproteinases. In addition, an overt atrophic phenotype has been observed. In this study we demonstrated an up-regulation of Neu1 RNAm in the atrophied muscle after sciatic denervation in mice indicating an involvement of this enzyme in the proteolytic processes that follow the induction of atrophy. After denervation, muscle fibers from Neu1-/- mice had bigger size variability compared to wild type fibers, with great enlargement of the endomysium. Accumulation of sialylated glycoconjugates in the extracellular matrix of NEU1 deficient muscle tissue may lead to a time-dependent infiltration of fibrous connective tissue, with a secondary involvement of the skeletal muscle tissue itself. Overall these studies highlight a novel role of NEU1 in the processes that follow initiation of an atrophic phenotype in skeletal muscle.(Sponsored by FAPESP 2009/02937-4)
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