1. Lipin1 deficiency causes sarcoplasmic reticulum stress and chaperone-responsive myopathy.
- Author
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Rashid T, Nemazanyy I, Paolini C, Tatsuta T, Crespin P, de Villeneuve D, Brodesser S, Benit P, Rustin P, Baraibar MA, Agbulut O, Olivier A, Protasi F, Langer T, Chrast R, de Lonlay P, de Foucauld H, Blaauw B, and Pende M
- Subjects
- Animals, Endoplasmic Reticulum Stress drug effects, Lipid Metabolism drug effects, Lipid Metabolism genetics, Male, Mice, Mice, Transgenic, Mitochondria, Muscle drug effects, Mitochondria, Muscle metabolism, Molecular Chaperones pharmacology, Molecular Chaperones therapeutic use, Muscle, Skeletal drug effects, Muscle, Skeletal metabolism, Muscle, Skeletal pathology, Muscular Diseases drug therapy, Muscular Diseases metabolism, Muscular Diseases pathology, Sarcoplasmic Reticulum drug effects, Sarcoplasmic Reticulum pathology, Taurochenodeoxycholic Acid therapeutic use, Endoplasmic Reticulum Stress genetics, Muscular Diseases genetics, Phosphatidate Phosphatase genetics, Sarcoplasmic Reticulum metabolism, Taurochenodeoxycholic Acid pharmacology
- Abstract
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., (© 2018 The Authors. Published under the terms of the CC BY NC ND 4.0 license.)
- Published
- 2019
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