BIOTECH AND PHARMANEWS

Blockading sphingolipids counteracts muscular dystrophy

Staining of a skeletal muscle gruesome-piece showing diversified forms of muscle fiber in younger mice. Inexperienced: unhurried-twitch fibers kind I; Crimson: Intermediate snappy-twitch fibers kind IIA; Crimson: Very snappy-twitch fibers kind IIB; Yellow: Laminin. Credit rating: Martin Wohlwend (EPFL)

EPFL scientists have made the first hyperlink between muscular dystrophy and a bunch of bioactive fat, the sphingolipids, which would maybe presumably well be alive to about lots of cell functions and diversified ailments.

In a brand unique review, the group of Johan Auwerx at EPFL’s College of Lifestyles Sciences has made the first connection between and sphingolipids, a bunch of bioactive lipids. The review is published in Science Advances.

Muscular dystrophy

Muscular dystrophy is an umbrella term for ailments where gene mutations end result in progressive weakness and breakdown of skeletal muscle groups. About half of all muscular dystrophy instances involve Duchenne muscular dystrophy (DMD). DMD arises from a mutation of the gene that codes for dystrophin, a protein supports muscle structure by anchoring the cytoskeleton of muscle with their cytoplasm, the sarcolemma.

Mutations of dystrophin have an ticket on lots of biological pathways inflicting the hallmark signs of Duchenne muscular dystrophy: compromised cells membrane integrity, aberrant calcium homeostasis, , fibrosis, and impaired tissue remodeling.

The sphingolipid connection

Found in 1870 and named after the well-known Sphinx, sphingolipids are a bunch of bioactive lipids belief to be alive to about cell signaling, and, surprisingly, plenty of the signs fresh in DMD. As a result of this fact, the researchers asked whether or no longer the synthesis of sphingolipids may per chance presumably be altered in DMD—and if that’s the case, if they would maybe presumably be causally alive to about the pathogenesis of DMD. To answer this, the researchers studied a mouse model of muscular dystrophy.

Blockading sphingolipids counteracts DMD

First, they found that mice with DMD declare an accumulation of intermediates of sphingolipid biosynthesis. This was as soon as already a clue that sphingolipid metabolism is abnormally elevated within the context of muscular dystrophy.

Subsequent, the researchers old the compound myriocin to block one in all the main enzymes of the sphingolipid de novo synthesis pathway. Blockading synthesis of sphingolipids counteracted the DMD-connected lack of muscle characteristic within the mice.

Digging deeper, the researchers found that myriocin stabilized the turnover of muscular calcium, and reversed fibrosis within the diaphragm and heart muscle. At the identical time, blocking off the synthesis of sphingolipids also reduced DMD-connected inflammation within the muscle groups by piquant the immune macrophage cells off their legit-inflammatory jabber and pushing them in direction of an anti-inflammatory one.

“Our review identifies inhibition of sphingolipid synthesis, focused on a pair of pathogenetic pathways, concurrently, as sturdy candidate for therapy of muscular dystrophies,” write the authors.

Muscle aging and RNA

The review follows one other paper on muscle aging by Auwerx’s group, showing the rating of exercise on non-coding RNA genes in skeletal muscle. Exacerbated muscle aging outcomes in a illness called sarcopenia, which is characterised by markedly reduced muscle groups and characteristic in ragged other folks. The EPFL researchers found the long noncoding RNA “CYTOR” and investigated its characteristic in sarcopenic muscle groups of rodents, worms, and human cells. The review was as soon as published in Science Translational Medication.



Extra data:
Pirkka-Pekka Laurila et al, Inhibition of sphingolipid de novo synthesis counteracts muscular dystrophy, Science Advances (2022). DOI: 10.1126/sciadv.abh4423. www.science.org/doi/10.1126/sciadv.abh4423

Martin Wohlwend et al, The exercise-induced long noncoding RNA CYTOR promotes snappy-twitch myogenesis in aging, Science Translational Medication (2021). DOI: 10.1126/scitranslmed.abc7367

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Blockading sphingolipids counteracts muscular dystrophy (2022, January 28)
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