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

Animals Disease Models, Animal Dystrophin / genetics Humans Male Mice Mice, Inbred mdx Mice, Knockout Muscular Dystrophy, Duchenne / genetics Sphingomyelin Phosphodiesterase / metabolism
Anxiety behavior Brain-derived neurotrophic factor CRISPR-Cas9 Duchenne muscular dystrophy Inflammatory cytokine Membrane permeability Monocytes/macrophages Muscle performance Neutral sphingomyelinase 2/sphingomyelin phosphodiesterase 3 microRNA

Journal

BMC medicine
ISSN: 1741-7015
Titre abrégé: BMC Med
Pays: England
ID NLM: 101190723

Informations de publication

Date de publication:
19 11 2020
Historique:
received: 28 01 2020
accepted: 01 10 2020
entrez: 19 11 2020
pubmed: 20 11 2020
medline: 23 2 2021
Statut: epublish

Résumé

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 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.

Sections du résumé

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
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.

Identifiants

DOI: 10.1186/s12916-020-01805-5 PMID: 33208172 PMC: PMC7677854
pubmed: 33208172
doi: 10.1186/s12916-020-01805-5
pii: 10.1186/s12916-020-01805-5
pmc: PMC7677854
doi:

Substances chimiques

Dystrophin 0
Smpd3 protein, mouse EC 3.1.4.12
Sphingomyelin Phosphodiesterase EC 3.1.4.12

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

343

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Auteurs

Yasunari Matsuzaka (Y)

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.

Jun Tanihata (J)

Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.
Department of Cell Physiology, The Jikei University School of Medicine, Tokyo, Japan.

Yoshiko Ooshima (Y)

Administrative Section of Radiation Protection, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.

Daisuke Yamada (D)

Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.
Laboratory of Pharmacology, Department of Pharmacy, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, Japan.

Masayuki Sekiguchi (M)

Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.

Shouta Miyatake (S)

Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.

Yoshitsugu Aoki (Y)

Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.

Mika Terumitsu (M)

Administrative Section of Radiation Protection, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.

Ryu Yashiro (R)

Administrative Section of Radiation Protection, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.

Hirofumi Komaki (H)

Department of Child Neurology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.

Akihiko Ishiyama (A)

Department of Child Neurology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.

Yasushi Oya (Y)

Department of Neurology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.

Yukiko U Inoue (YU)

Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.

Takayoshi Inoue (T)

Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.

Shin'ichi Takeda (S)

Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.

Kazuo Hashido (K)

Administrative Section of Radiation Protection, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan. hashido@ncnp.go.jp.
ORCID: 0000-0002-6677-3546

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › The nSMase2/Smpd3 gene modulates the severity...
questionsmedicales.fr › Techniques d'investigation › Modèles théoriques › Modèles biologiques › Modèles animaux de maladie humaine › The nSMase2/Smpd3 gene modulates the severity...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Dystrophine › The nSMase2/Smpd3 gene modulates the severity...
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questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › The nSMase2/Smpd3 gene modulates the severity...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Souches mutantes de souris › Souris de lignée mdx › The nSMase2/Smpd3 gene modulates the severity...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Souris transgéniques › Souris knockout › The nSMase2/Smpd3 gene modulates the severity...
questionsmedicales.fr › Malformations et maladies congénitales, héréditaires et néonatales › Maladies génétiques congénitales › Dystrophies musculaires › Myopathie de Duchenne › The nSMase2/Smpd3 gene modulates the severity...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Hydrolases › Esterases › Phosphodiesterases › Sphingomyeline phosphodiesterase › The nSMase2/Smpd3 gene modulates the severity...