Inhibition of sphingolipid de novo synthesis counteracts muscular dystrophy.
Details
Serval ID
serval:BIB_95F002D1A653
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Inhibition of sphingolipid de novo synthesis counteracts muscular dystrophy.
Journal
Science advances
ISSN
2375-2548 (Electronic)
ISSN-L
2375-2548
Publication state
Published
Issued date
28/01/2022
Peer-reviewed
Oui
Volume
8
Number
4
Pages
eabh4423
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
Abstract
Duchenne muscular dystrophy (DMD), the most common muscular dystrophy, is a severe muscle disorder, causing muscle weakness, loss of independence, and premature death. Here, we establish the link between sphingolipids and muscular dystrophy. Transcripts of sphingolipid de novo biosynthesis pathway are up-regulated in skeletal muscle of patients with DMD and other muscular dystrophies, which is accompanied by accumulation of metabolites of the sphingolipid pathway in muscle and plasma. Pharmacological inhibition of sphingolipid synthesis by myriocin in the mdx mouse model of DMD ameliorated the loss in muscle function while reducing inflammation, improving Ca <sup>2+</sup> homeostasis, preventing fibrosis of the skeletal muscle, heart, and diaphragm, and restoring the balance between M1 and M2 macrophages. Myriocin alleviated the DMD phenotype more than glucocorticoids. Our study identifies inhibition of sphingolipid synthesis, targeting multiple pathogenetic pathways simultaneously, as a strong candidate for treatment of muscular dystrophies.
Keywords
Animals, Disease Models, Animal, Fibrosis, Humans, Mice, Mice, Inbred mdx, Muscle, Skeletal/metabolism, Muscular Dystrophy, Duchenne/drug therapy, Muscular Dystrophy, Duchenne/genetics, Muscular Dystrophy, Duchenne/metabolism, Sphingolipids/metabolism, Sphingolipids/therapeutic use
Pubmed
Web of science
Open Access
Yes
Create date
08/02/2022 10:01
Last modification date
23/11/2022 8:13