The nSMase2/Smpd3 gene modulates the severity of muscular dystrophy and the emotional stress response in mdx mice
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RESEARCH ARTICLE
Open Access
The nSMase2/Smpd3 gene modulates the severity of muscular dystrophy and the emotional stress response in mdx mice Yasunari Matsuzaka1,2, Jun Tanihata3,4, Yoshiko Ooshima1, Daisuke Yamada5,6, Masayuki Sekiguchi5, Shouta Miyatake3, Yoshitsugu Aoki3, Mika Terumitsu1, Ryu Yashiro1, Hirofumi Komaki7, Akihiko Ishiyama7, Yasushi Oya8, Yukiko U. Inoue9, Takayoshi Inoue9, Shin’ichi Takeda3 and Kazuo Hashido1*
Abstract Background: 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 Ca2+-dependent manner. However, its roles in dystrophic pathology have not yet been clarified. Methods: 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 mdx mice lacking the nSMase2/Smpd3 gene (mdx:Smpd3 double knockout [DKO] mice). Results: Young 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. Conclusions: nSMase2/Smpd3-modulated lipid raft integrity is a potential therapeutic target for DMD. Keywords: Duchenne muscular dystrophy, Neutral sphingomyelinase 2/sphingomyelin phosphodiesterase 3, CRISPR-Cas9, Inflammatory cytokine, Monocytes/macrophages, Membrane permeability, Muscle performance, microRNA, Brain-derived neurotrophic factor, Anxiety behavior
Background 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 * Correspondence: [email protected] 1 Administrative Section of Radiation Protection, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan Full list of author information is available at the end of the article
the dystrophin–glycoprotein complex (DGC) on the cell membrane causes cytosolic Ca2+ influx, resulting in protease activation, mitochondrial dysfunction, progressive myofiber degeneration, chronic inflammation, muscle wasting, and fragility. The latter phenomena are caused by the replacement of functional myofibers with fibrotic connective tissue and adipose tissue [2–5]. However, the myofiber-specific loss of dystroglycan (DG), a DGC component, in mice does not result in dystrophia-like muscle de
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