Journal
SCIENCE ADVANCES
Volume 8, Issue 4, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abh4423
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Funding
- EPFL
- European Research Council [ERC-AdG-787702]
- Swiss National Science Foundation [SNSF 31003A_179435]
- Fondation Suisse de Recherche sur les Maladies Musculaires (FSRMM)
- National Research Foundation of Korea [GRL 2017K1A1A2013124]
- Fondation Marcel Levaillant [190917]
- Academy of Finland
- Finnish Diabetes Research Society
- Folkhalsan Research Foundation
- Novo Nordisk Foundation
- Finska Lakaresallskapet
- Finnish Foundation for Cardiovascular Research
- Juho Vainio Foundation
- Signe and Ane Gyllenberg Foundation
- University of Helsinki
- Sigrid Juselius Foundation
- Ministry of Education
- Ahokas Foundation
- Emil Aaltonen Foundation
- Paavo Nurmi Foundation
- Orion Foundation
- Scottish Senior Clinical Fellowship [SCD/09]
- European Union Horizon 2020 Marie Sklodowska-Curie Individual Fellowship AmyloAge [896042]
- Sigrid Juselius Fellowship
- FAPESP [2019/22512-0]
- Marie Curie Actions (MSCA) [896042] Funding Source: Marie Curie Actions (MSCA)
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Inhibition of sphingolipid synthesis, targeting multiple pathogenic pathways, shows promise as a potential treatment for muscular dystrophies.
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.
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