Blocking sphingolipids counteracts muscular dystrophy


Staining of skeletal muscle cross sections showing different types of muscle fibers in young mice. Green: Slow shrink fiber type I; Red: Medium speed muscle fiber type IIA. Purple: Very fast shrinking fiber type IIB. Yellow: Laminin. Credit: Martin Wohlwend (EPFL)

EPFL scientists have made the first link between muscular dystrophy and sphingolipids, a group of bioactive fats involved in many cellular functions and other diseases.

In a new study, Johan Auwerx’s group at EPFL’s Department of Life Sciences Muscular dystrophy A group of sphingolipids, bioactive lipids.The study is published at Science Advances..

Muscular dystrophy

Muscular dystrophy is a general term for diseases in which gene mutations lead to progressive weakness and destruction of skeletal muscle. About half of all muscular dystrophy cases are associated with Duchenne muscular dystrophy (DMD). DMD results from mutations in the gene that encodes dystrophin. Proteins support muscle structure by fixing the cytoskeleton of the muscle. cell In their cytoplasm, sarcolemma.

Mutations in dystrophin affect various biological pathways that cause the characteristic symptoms of Duchenne muscular dystrophy: decreased cell membrane integrity, abnormal calcium homeostasis, Chronic inflammationFibrosis, and impaired tissue remodeling.

Sphingolipid connections

Discovered in 1870 and named after the famous Sphinx, sphingolipids are a group of bioactive lipids thought to be involved in cell signaling and, surprisingly, are many of the symptoms present in DMD. .. Therefore, the researchers asked if the synthesis of sphingolipids could be altered by DMD, and if so, whether the etiology of DMD could be causal. To answer this, researchers have studied a mouse model of muscular dystrophy.

Blocking sphingolipids neutralizes DMD

First, they found that mice with DMD exhibited an accumulation of intermediates in sphingolipid biosynthesis. This was a clue that sphingolipid metabolism was abnormally increased in the context of muscular dystrophy.

Next, researchers used the compound myriocin to block one of the key enzymes in sphingolipids. de novo Synthetic pathway. Blocking sphingolipid synthesis counteracted the loss of DMD-related muscle function in mice.

Digging deeper, researchers found that myriocin stabilizes the turnover of calcium in muscles and reverses diaphragmatic and myocardial fibrosis. At the same time, blocking sphingolipid synthesis also reduced DMD-related inflammation in muscles by disengaging immune macrophage cells from pro-inflammatory states and pushing them into anti-inflammatory states.

“Our study identifies inhibition of sphingolipid synthesis, which simultaneously targets multiple pathogenic pathways, as a potential candidate for the treatment of muscular dystrophy,” the author writes.

Muscle aging and RNA

Research continues Another paper A study of muscle aging by the Auwerx group. It shows the effect of exercise on non-coding RNA genes in skeletal muscle. Deteriorated muscle aging leads to a disease called sarcopenia. It significantly reduces muscle mass and logic Elderly function. EPFL researchers discovered the long non-coding RNA “CYTOR” and investigated its role in rodent, worm, and human cell sarcopenic muscles.The study was published in Scientific translation medicine..

Stem cells promote recovery and regeneration in mice with rare muscle disease

For more information:
Pirkka-Pekka Laurila et al, Inhibition of sphingolipid de novo synthesis counteracts muscular dystrophy, Science Advances (2022). DOI: 10.1126 / sciadv.abh4423..

Martin Wohlwend et al, an exercise-induced long non-coding RNA CYTOR, promotes fast muscle formation during aging. Scientific translation medicine (2021). DOI: 10.1126 /scitranslmed.abc7367

Quote: When blocking sphingolipids, muscular dystrophy (January 28, 2022) was obtained from

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