Abstract
BackgroundDuchenne muscular dystrophy (DMD) is a progressive, degenerative muscular disorder and cognitive dysfunction caused by mutations in the dystrophin gene. It is characterized by excess inflammatory responses in the muscle and repeated degeneration and regeneration cycles. Neutral sphingomyelinase 2/sphingomyelin phosphodiesterase 3 (nSMase2/Smpd3) hydrolyzes sphingomyelin in lipid rafts. This protein thus modulates inflammatory responses, cell survival or apoptosis pathways, and the secretion of extracellular vesicles in a Ca2+-dependent manner. However, its roles in dystrophic pathology have not yet been clarified.MethodsTo investigate the effects of the loss of nSMase2/Smpd3 on dystrophic muscles and its role in the abnormal behavior observed in DMD patients, we generated mdx mice lacking the nSMase2/Smpd3 gene (mdx:Smpd3 double knockout [DKO] mice).ResultsYoung mdx:Smpd3 DKO mice exhibited reduced muscular degeneration and decreased inflammation responses, but later on they showed exacerbated muscular necrosis. In addition, the abnormal stress response displayed by mdx mice was improved in the mdx:Smpd3 DKO mice, with the recovery of brain-derived neurotrophic factor (Bdnf) expression in the hippocampus.ConclusionsnSMase2/Smpd3-modulated lipid raft integrity is a potential therapeutic target for DMD.
Highlights
Duchenne muscular dystrophy (DMD) is a progressive, degenerative muscular disorder and cognitive dysfunction caused by mutations in the dystrophin gene
All three genes were upregulated as early as 4 days after induction with differentiation medium, when the cells became phase-bright fused myotubes, and the upregulated levels were sustained for 6 days (Additional file 7: Fig. S1A)
The expression level of the adult myosin heavy chain (Myh1) gene was used as a differentiation marker for C2C12 myoblasts, similar to the expression pattern of nSMase2/Smpd3 (Additional file 7: Fig. S1A)
Summary
Duchenne muscular dystrophy (DMD) is a progressive, degenerative muscular disorder and cognitive dysfunction caused by mutations in the dystrophin gene. It is characterized by excess inflammatory responses in the muscle and repeated degeneration and regeneration cycles. Duchenne muscular dystrophy (DMD) is an X-linked, recessive, inherited, and debilitating disorder affecting one in 3500 males in Japan It is caused by loss-of-function mutations in the dystrophin gene on chromosome Xp21 [1]. Disruption of Matsuzaka et al BMC Medicine (2020) 18:343 muscle regeneration [6, 7] This suggests that myofiber instability is not the only cause of dystrophic degeneration, but rather that the phenotype might be caused by multiple factors, including stem cell and myofiber functions. An effective treatment for these abnormalities has not yet been established
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