Blocking sphingolipids counteracts muscular dystrophy

Date:
January 28, 2022
Source:
Ecole Polytechnique Fe'de'rale de Lausanne
Summary:
Scientists have made a link between muscular dystrophy and a group
of bioactive fats, the sphingolipids, which are involved in numerous
cell functions and other diseases.



FULL STORY ==========================================================================
In a new study, the group of Johan Auwerx at EPFL's School of Life
Sciences has made the first connection between muscular dystrophy and sphingolipids, a group of bioactive lipids. The study is published in
Science Advances.


========================================================================== Muscular dystrophy Muscular dystrophy is an umbrella term for diseases
where gene mutations result in progressive weakness and breakdown of
skeletal muscles. About half of all muscular dystrophy cases 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 cells with their cytoplasm,
the sarcolemma.

Mutations of dystrophin affect various biological pathways causing the
hallmark symptoms of Duchenne muscular dystrophy: compromised cells
membrane integrity, aberrant calcium homeostasis, chronic inflammation, fibrosis, and impaired tissue remodeling.

The sphingolipid connection 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, many of the symptoms
present in DMD. Therefore, the researchers asked whether the synthesis of sphingolipids can be altered in DMD -- and if so, if they can be causally involved in the pathogenesis of DMD. To answer this, the researchers
studied a mouse model of muscular dystrophy.



========================================================================== Blocking sphingolipids counteracts DMD First, they found that
mice with DMD show an accumulation of intermediates of sphingolipid biosynthesis. This was already a clue that sphingolipid metabolism is abnormally increased in the context of muscular dystrophy.

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

Digging deeper, the researchers found that myriocin stabilized the
turnover of muscular calcium, and reversed fibrosis in the diaphragm and
heart muscle. At the same time, blocking the synthesis of sphingolipids
also reduced DMD-related inflammation in the muscles by moving the
immune macrophage cells off their pro-inflammatory state and pushing
them towards an anti-inflammatory one.

"Our study identifies inhibition of sphingolipid synthesis, targeting
multiple pathogenetic pathways, simultaneously, as strong candidate for treatment of muscular dystrophies," write the authors.

Muscle aging and RNA The study follows another paper on muscle aging by Auwerx's group, showing the effect of exercise on non-coding RNA genes
in skeletal muscle. Exacerbated muscle aging leads to a disease called sarcopenia, which is characterized by markedly reduced muscle mass and
muscle function in aged individuals. The EPFL researchers discovered
the long noncoding RNA "CYTOR" and investigated its role in sarcopenic
muscles of rodents, worms, and human cells. The study was published in
Science Translational Medicine.

List of contributors
* University of Lausanne * Chungnam National University School of
Medicine * Novo Nordisk Foundation Copenhagen * Norwegian University
of Science and Technology * University of Helsinki ========================================================================== Story Source: Materials provided by
Ecole_Polytechnique_Fe'de'rale_de_Lausanne. Original written by Nik Papageorgiou. Note: Content may be edited for style and length.


========================================================================== Journal References:
1. Pirkka-Pekka Laurila, Peiling Luan, Martin Wohlwend, Nade`ge Zanou,
Barbara Crisol, Tanes Imamura de Lima, Ludger J. E. Goeminne,
Hector Gallart-Ayala, Minho Shong, Julijana Ivanisevic, Nicolas
Place, Johan Auwerx. Inhibition of sphingolipid de novo synthesis
counteracts muscular dystrophy. Science Advances, 2022; 8 (4)
DOI: 10.1126/sciadv.abh4423
2. Martin Wohlwend, Pirkka-Pekka Laurila, Kristine Williams, Mario
Romani,
Tanes Lima, Pattamaprapanont Pattawaran, Giorgia Benegiamo, Minna
Salonen, Bernard L. Schneider, Jari Lahti, Johan G. Eriksson, Romain
Barre`s, Ulrik Wislo/ff, Jose' B. N. Moreira, Johan Auwerx. The
exercise- induced long noncoding RNA CYTOR promotes fast-twitch
myogenesis in aging. Science Translational Medicine, 2021; 13
(623) DOI: 10.1126/ scitranslmed.abc7367 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/01/220128141257.htm

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