title: Muscle degeneration in neuraminidase 1-deficient mice results from infiltration of the muscle fibers by expanded connective tissue.
abstract: Neuraminidase 1 (NEU1) regulates the catabolism of sialoglycoconjugates in lysosomes. Congenital NEU1 deficiency in children is the basis of sialidosis, a severe neurosomatic disorder in which patients experience a broad spectrum of clinical manifestations varying in the age of onset and severity. Osteoskeletal deformities and muscle hypotonia have been described in patients with sialidosis. Here we present the first comprehensive analysis of the skeletal muscle pathology associated with loss of Neu1 function in mice. In this animal model, skeletal muscles showed 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. These combined features could lead to abnormal remodeling of the extracellular matrix that could be responsible for sarcolemmal invagination and progressive muscle fiber degeneration, ultimately resulting in an overt atrophic phenotype. This unique pattern of muscle damage, which has never been described in any myopathy, might explain the neuromuscular manifestations reported in patients with the type II severe form of sialidosis. More broadly, these findings point to a potential role of NEU1 in cell proliferation and extracellular matrix remodeling.
authors.affiliation: Department of Genetics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. zanoteli@terra.com.br
authors.forename: Edmar
authors.initials: E
authors.lastname: Zanoteli
authors.forename: Diantha
authors.initials: D
authors.lastname: van de Vlekkert
authors.forename: Erik J
authors.initials: EJ
authors.lastname: Bonten
authors.forename: Huimin
authors.initials: H
authors.lastname: Hu
authors.forename: Linda
authors.initials: L
authors.lastname: Mann
authors.forename: Elida M
authors.initials: EM
authors.lastname: Gomero
authors.forename: A John
authors.initials: AJ
authors.lastname: Harris
authors.forename: Giulio
authors.initials: G
authors.lastname: Ghersi
authors.forename: Alessandra
authors.initials: A
authors.lastname: d'Azzo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D003238:Connective Tissue / Q000473:pathology / Q000503:physiopathology*; D005109:Extracellular Matrix / Q000473:pathology / Q000502:physiology; D005347:Fibroblasts / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D018485:Muscle Fibers, Skeletal / Q000473:pathology*; D009133:Muscular Atrophy / Q000209:etiology* / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D009137:Muscular Dystrophy, Animal / Q000235:genetics / Q000473:pathology; D009336:Necrosis / Q000235:genetics / Q000473:pathology; D009439:Neuraminidase / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D012508:Sarcolemma / Q000473:pathology
chemical_list: C110128:Neu1 protein, mouse; D009439:Neuraminidase
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