Journal Article

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

Takeda, Shin’ichi, Aoki, Yoshitsugu, Tanihata, Jun, Matsuzaka, Yasunari, Inoue, Takayoshi, Terumitsu, Mika, Yashiro, Ryu, Sekiguchi, Masayuki, Ooshima, Yoshiko, Hashido, Kazuo, Yamada, Daisuke, Komaki, Hirofumi, Ishiyama, Akihiko, Miyatake, Shouta, Oya, Yasushi, Inoue, Yukiko U.

2020

Overview

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 Ca 2+ -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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Animals / Antibodies / Anxiety / Apoptosis / Biomedicine / Brain-derived neurotrophic factor / Calcium (extracellular) / Calcium ions / Care and treatment / Cell culture / Cell division / Cell survival / Cellular stress response / Cognitive ability / CRISPR / CRISPR-Cas9 / Degeneration / Disease Models, Animal / Duchenne muscular dystrophy / Duchenne's muscular dystrophy / Dystrophin / Dystrophin - genetics / Dystrophin - metabolism / Dystrophin - pharmacology / Dystrophy / Enzymes / Extracellular vesicles / Gene expression / Genetic aspects / Genomics / Health aspects / Humans / Hydrolases / Inflammation / Inflammatory cytokine / Laboratory animals / Lipid rafts / Lipids / Male / Medicine / Medicine & Public Health / Membrane permeability / Mice / Mice, Inbred mdx / Mice, Knockout / Monocytes/macrophages / Muscles / Muscular dystrophy / Muscular Dystrophy, Duchenne - genetics / Mutation / Necrosis / Neurodegeneration / Neutral sphingomyelinase 2/sphingomyelin phosphodiesterase 3 / Phosphodiesterase / Proteins / Psychological aspects / Psychological symptoms / Regeneration / Research Article / Signal transduction / Sphingomyelin phosphodiesterase / Sphingomyelin Phosphodiesterase - metabolism / Stem cells / Stress (Psychology)