Rashid, Talha, Nemazanyy, Ivan, Paolini, Cecilia, Tatsuta, Takashi, Crespin, Paul, de Villeneuve, Delphine, Brodesser, Susanne, Benit, Paule, Rustin, Pierre, Baraibar, Martin A., Agbulut, Onnik ORCID: 0000-0003-1923-8871, Olivier, Anne, Protasi, Feliciano, Langer, Thomas, Chrast, Roman ORCID: 0000-0003-4189-3514, de Lonlay, Pascale, de Foucauld, Helene, Blaauw, Bert and Pende, Mario ORCID: 0000-0002-7864-8937 (2019). Lipin1 deficiency causes sarcoplasmic reticulum stress and chaperone-responsive myopathy. Embo J., 38 (1). HOBOKEN: WILEY. ISSN 1460-2075

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Rashid, TalhaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nemazanyy, IvanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Paolini, CeciliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tatsuta, TakashiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Crespin, PaulUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de Villeneuve, DelphineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brodesser, SusanneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Benit, PauleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rustin, PierreUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baraibar, Martin A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Agbulut, OnnikUNSPECIFIEDorcid.org/0000-0003-1923-8871UNSPECIFIED
Olivier, AnneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Protasi, FelicianoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Langer, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chrast, RomanUNSPECIFIEDorcid.org/0000-0003-4189-3514UNSPECIFIED
de Lonlay, PascaleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de Foucauld, HeleneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Blaauw, BertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pende, MarioUNSPECIFIEDorcid.org/0000-0002-7864-8937UNSPECIFIED
URN: urn:nbn:de:hbz:38-159543
DOI: 10.15252/embj.201899576
Journal or Publication Title: Embo J.
Volume: 38
Number: 1
Date: 2019
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 1460-2075
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
UNFOLDED PROTEIN RESPONSE; ENDOPLASMIC-RETICULUM; QUANTITATIVE-ANALYSIS; SKELETAL-MUSCLE; MITOCHONDRIAL; HOMEOSTASIS; METABOLISM; OPA1; MASS; RHABDOMYOLYSISMultiple languages
Biochemistry & Molecular Biology; Cell BiologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/15954

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