Lipin1 deficiency causes sarcoplasmic reticulum stress and chaperone-responsive myopathy.
Animals
Endoplasmic Reticulum Stress
/ drug effects
Lipid Metabolism
/ drug effects
Male
Mice
Mice, Transgenic
Mitochondria, Muscle
/ drug effects
Molecular Chaperones
/ pharmacology
Muscle, Skeletal
/ drug effects
Muscular Diseases
/ drug therapy
Phosphatidate Phosphatase
/ genetics
Sarcoplasmic Reticulum
/ drug effects
Taurochenodeoxycholic Acid
/ pharmacology
endoplasmic reticulum stress
genetic disease
metabolism
myopathy
Journal
The EMBO journal
ISSN: 1460-2075
Titre abrégé: EMBO J
Pays: England
ID NLM: 8208664
Informations de publication
Date de publication:
03 01 2019
03 01 2019
Historique:
received:
06
04
2018
revised:
21
09
2018
accepted:
02
10
2018
pubmed:
14
11
2018
medline:
1
1
2020
entrez:
14
11
2018
Statut:
ppublish
Résumé
As a consequence of impaired glucose or fatty acid metabolism, bioenergetic stress in skeletal muscles may trigger myopathy and rhabdomyolysis. Genetic mutations causing loss of function of the LPIN1 gene frequently lead to severe rhabdomyolysis bouts in children, though the metabolic alterations and possible therapeutic interventions remain elusive. Here, we show that lipin1 deficiency in mouse skeletal muscles is sufficient to trigger myopathy. Strikingly, muscle fibers display strong accumulation of both neutral and phospholipids. The metabolic lipid imbalance can be traced to an altered fatty acid synthesis and fatty acid oxidation, accompanied by a defect in acyl chain elongation and desaturation. As an underlying cause, we reveal a severe sarcoplasmic reticulum (SR) stress, leading to the activation of the lipogenic SREBP1c/SREBP2 factors, the accumulation of the Fgf21 cytokine, and alterations of SR-mitochondria morphology. Importantly, pharmacological treatments with the chaperone TUDCA and the fatty acid oxidation activator bezafibrate improve muscle histology and strength of lipin1 mutants. Our data reveal that SR stress and alterations in SR-mitochondria contacts are contributing factors and potential intervention targets of the myopathy associated with lipin1 deficiency.
Identifiants
pubmed: 30420558
pii: embj.201899576
doi: 10.15252/embj.201899576
pmc: PMC6315296
pii:
doi:
Substances chimiques
Molecular Chaperones
0
Taurochenodeoxycholic Acid
516-35-8
ursodoxicoltaurine
60EUX8MN5X
Lpin1 protein, mouse
EC 3.1.3.4
Phosphatidate Phosphatase
EC 3.1.3.4
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2018 The Authors. Published under the terms of the CC BY NC ND 4.0 license.
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