Administrative Section of Radiation Protection, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.
Medical Molecular Informatics, Meiji Pharmaceutical University, Noshio, Kiyose, Tokyo, Japan.
BMC Med. 2020 Nov 19;18(1):343. doi: 10.1186/s12916-020-01805-5.
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-dependent manner. However, its roles in dystrophic pathology have not yet been clarified.
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).
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.
nSMase2/Smpd3-modulated lipid raft integrity is a potential therapeutic target for DMD.
杜氏肌营养不良症（DMD）是一种渐进性、退行性肌肉疾病和认知功能障碍，由 dystrophin 基因突变引起。其特征是肌肉中过度的炎症反应，以及反复的退化和再生循环。中性鞘磷脂酶 2/鞘磷脂磷酸二酯酶 3（nSMase2/Smpd3）在脂筏中水解鞘磷脂。这种蛋白质因此以 Ca 依赖性方式调节炎症反应、细胞存活或凋亡途径以及细胞外囊泡的分泌。然而，其在进行性肌营养不良症病理中的作用尚未阐明。
为了研究 nSMase2/Smpd3 缺失对进行性肌营养不良症肌肉的影响及其在 DMD 患者观察到的异常行为中的作用，我们生成了缺乏 nSMase2/Smpd3 基因的 mdx 小鼠（mdx：Smpd3 双敲除 [DKO] 小鼠）。
年轻的 mdx：Smpd3 DKO 小鼠表现出减少的肌肉退化和减少的炎症反应，但后来它们表现出加剧的肌肉坏死。此外，mdx 小鼠表现出的异常应激反应在 mdx：Smpd3 DKO 小鼠中得到改善，伴随着海马体中脑源性神经营养因子（Bdnf）表达的恢复。
nSMase2/Smpd3 调节的脂筏完整性是 DMD 的潜在治疗靶点。
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