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.

Bone muscle crosstalk targets muscle regeneration pathway regulated by core circadian transcriptional repressors DEC1 and DEC2

“…However, when myofibers within SOL with central nuclei (B10-15% of total), which we have suggested is a marker for muscle regeneration in our model, were measured it is apparent that the average CSA was significantly smaller than that for total cells ( Table 2). We believe that this finding is consistent with findings of a large number of publications [23][24][25] and supports ongoing regeneration within Dmp1-Cre Mbtps1 cKO muscle. Specifically, during regeneration of muscle following an injury stimulus, the average CSA of myofibers is initially lower.…”

Elevated expression of NEU1 sialidase in idiopathic pulmonary fibrosis provokes pulmonary collagen deposition, lymphocytosis, and fibrosis

“…The effects of NEU1 expression levels on connective tissue homeostasis appear to be organ specific. NEU1-deficient mice, in addition to basal muscular atrophy, demonstrate an impaired growth rate of regenerating muscle fibers following injury; simultaneously, these mice accumulate collagen type III in the endomysium space (62). Differential cellularity, histoarchitecture, and metabolic profile of different tissues are thus likely to contribute to NEU1-driven regulation of connective tissue.…”

Regulação de receptores de IGF e PDGF na musculatura esquelética de camundongos com deficiência de neuraminidase 1

“…Esta informação é interessante no contexto em que, apesar dos possíveis danos à musculatura esquelética em pacientes com sialidose, não há biópsias musculares de pacientes descritas na literatura. Portanto, todas as análises histológicas da musculatura esquelética na deficiência de Neu1 provêm de estudos com o modelo animal (Zanoteli et al, 2010, Neves et al, 2015.…”

“…As formas totais de Akt e ERK não apresentaram diferenças de expressão entre genótipos nos grupos controle ou não tratados, exceto a expressão de ERK de músculos Neu1 -/controle comparados com os tratados com JNJ-10198409 do mesmo genótipo (Figuras 14 a 17) As análises morfométricas e histológicas após tratamentos com inibidores de IGF-1R ou PDGFR in vivo revelaram menor peso muscular e área da secção transversa das fibras musculares em camundongos do grupo controle Neu1 -/-, corroborando os estudos prévios de nosso grupo de pesquisa (Zanoteli et al, 2010, Neves et al, 2015. Por outro lado, embora ocorra aumento na proliferação de fibroblastos em estágios avançados da degeneração muscular na deficiência de Neu1 (Zanoteli et al, 2010) Os processos de degradação e reciclagem do IGF-1R e do PDGFR ocorrem por uma combinação de ubiquitinação e ação lisossomal (Girnita et al, 2003, Sehat et al, 2008, Goh e Sorkin, 2013) e, curiosamente, as catepsinas L e B estão envolvidas com a regulação e proteólise de IGF-1R e PDGFR respectivamente (Okuyama et al, 2001, Navab et al, 2008…”

“…Quadros de atrofia muscular com reduções na expressão de pAkt são , contudo, eles são menores em comparação aos camundongos Neu1 +/+ desde o nascimento. Além disso, apresentam atrasos na miogênese durante o processo de regeneração muscular induzida por injeção de cardiotoxina, com expressão tardia de MyoD, miogenina e isoformas imaturas de miosina e presença de fibras musculares atróficas ao final dos 28 dias de estudo(Neves et al, 2015).Ao estimular os fibroblastos Neu1 -/com PDGF-BB e tratá-los com inibidores de PDGFR, houve queda na expressão de pAkt e pERK, associada com diminuição da proliferação celular em relação aos controles do mesmo genótipo. A estimulação de IGF-1R e sua respectiva inibição causou redução na expressão do pAkt, porém aumentou a proliferação celular.…”