title: Neuraminidase-1 mediates skeletal muscle regeneration.
abstract: Neuraminidase-1 (NEU1) is the sialidase responsible for the catabolism of sialoglycoconjugates in lysosomes. Congenital NEU1 deficiency causes sialidosis, a severe lysosomal storage disease associated with a broad spectrum of clinical manifestations, which also include skeletal deformities, skeletal muscle hypotonia and weakness. Neu1(-/-) mice, a model of sialidosis, develop an atypical form of muscle degeneration caused by progressive expansion of the connective tissue that infiltrates the muscle bed, leading to fiber degeneration and atrophy. Here we investigated the role of Neu1 in the myogenic process that ensues during muscle regeneration after cardiotoxin-induced injury of limb muscles. A comparative analysis of cardiotoxin-treated muscles from Neu1(-/-) mice and Neu1(+/+) mice showed increased inflammatory and proliferative responses in the absence of Neu1 during the early stages of muscle regeneration. This was accompanied by significant and sequential upregulation of Pax7, MyoD, and myogenin mRNAs. The levels of both MyoD and myogenin proteins decreased during the late stages of regeneration, which most likely reflected an increased rate of degradation of the myogenic factors in the Neu1(-/-) muscle. We also observed a delay in muscle cell differentiation, which was characterized by prolonged expression of embryonic myosin heavy chain, as well as reduced myofiber cross-sectional area. At the end of the regenerative process, collagen type III deposition was increased compared to wild-type muscles and internal controls, indicating the initiation of fibrosis. Overall, these results point to a role of Neu1 throughout muscle regeneration.
authors.affiliation: Department of Neurology, University of São Paulo, São Paulo, SP 01246-903, Brazil.
authors.forename: Juliana de Carvalho
authors.initials: Jde C
authors.lastname: Neves
authors.affiliation: Department of Neurology, University of São Paulo, São Paulo, SP 01246-903, Brazil.
authors.forename: Vanessa Rodrigues
authors.initials: VR
authors.lastname: Rizzato
authors.affiliation: Department of Neurology, University of São Paulo, São Paulo, SP 01246-903, Brazil.
authors.forename: Alan
authors.initials: A
authors.lastname: Fappi
authors.affiliation: Department of Neurology, University of São Paulo, São Paulo, SP 01246-903, Brazil.
authors.forename: Mariana Miranda
authors.initials: MM
authors.lastname: Garcia
authors.affiliation: Department of Neurology, University of São Paulo, São Paulo, SP 01246-903, Brazil.
authors.forename: Gerson
authors.initials: G
authors.lastname: Chadi
authors.affiliation: Department of Genetics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Diantha
authors.initials: D
authors.lastname: van de Vlekkert
authors.affiliation: Department of Genetics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Alessandra
authors.initials: A
authors.lastname: d'Azzo
authors.affiliation: Department of Neurology, University of São Paulo, São Paulo, SP 01246-903, Brazil. Electronic address: zanoteli@terra.com.br.
authors.forename: Edmar
authors.initials: E
authors.lastname: Zanoteli
keywords: Cell proliferation; Fibrosis; Muscle maturation; NEU1; Sialidosis; Skeletal muscle regeneration