• Yasunari Matsuzaka, Jun Tanihata, Yoshiko Ooshima, Daisuke Yamada, Masayuki Sekiguchi, Shouta Miyatake, Yoshitsugu Aoki, Mika Terumitsu, Ryu Yashiro, Hirofumi Komaki, Akihiko Ishiyama, Yasushi Oya, Yukiko U Inoue, Takayoshi Inoue, Shin'ichi Takeda, and Kazuo Hashido.
• Administrative Section of Radiation Protection, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.
• Bmc Med. 2020 Nov 19; 18 (1): 343.

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.

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