Inhibition of sphingolipid de novo synthesis counteracts muscular dystrophy.
Sci Adv
; 8(4): eabh4423, 2022 01 28.
Article
in En
| MEDLINE
| ID: mdl-35089797
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 Ca2+ 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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Muscular Dystrophy, Duchenne
Limits:
Animals
/
Humans
Language:
En
Journal:
Sci Adv
Year:
2022
Document type:
Article
Affiliation country:
Switzerland