The nSMase2/Smpd3 gene modulates the severity of muscular dystrophy and the emotional stress response in mdx mice

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<jats:title>Abstract</jats:title><jats:sec> <jats:title>Background</jats:title> <jats:p>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. 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 Ca<jats:sup>2+</jats:sup>-dependent manner. However, its roles in dystrophic pathology have not yet been clarified.</jats:p> </jats:sec><jats:sec> <jats:title>Methods</jats:title> <jats:p>To 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 <jats:italic>mdx</jats:italic> mice lacking the <jats:italic>nSMase2/Smpd3</jats:italic> gene (<jats:italic>mdx:Smpd3</jats:italic> double knockout [DKO] mice).</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>Young <jats:italic>mdx:Smpd3</jats:italic> 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 <jats:italic>mdx</jats:italic> mice was improved in the <jats:italic>mdx:Smpd3</jats:italic> DKO mice, with the recovery of brain-derived neurotrophic factor (Bdnf) expression in the hippocampus.</jats:p> </jats:sec><jats:sec> <jats:title>Conclusions</jats:title> <jats:p>nSMase2/Smpd3-modulated lipid raft integrity is a potential therapeutic target for DMD.</jats:p> </jats:sec>

Journal

  • BMC Medicine

    BMC Medicine 18 (1), 343-, 2020-11-19

    Springer Science and Business Media LLC

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