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  Lipin1 deficiency causes sarcoplasmic reticulum stress and chaperone-responsive myopathy

Rashid, T., Nemazanyy, I., Paolini, C., Tatsuta, T., Crespin, P., de Villeneuve, D., et al. (2018). Lipin1 deficiency causes sarcoplasmic reticulum stress and chaperone-responsive myopathy. EMBO J. doi:10.15252/embj.201899576.

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Item Permalink: https://hdl.handle.net/21.11116/0000-0004-7222-5 Version Permalink: https://hdl.handle.net/21.11116/0000-0004-73A0-5
Genre: Journal Article

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https://www.ncbi.nlm.nih.gov/pubmed/30420558 (Any fulltext)
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 Creators:
Rashid, T.1, Author
Nemazanyy, I.1, Author
Paolini, C.1, Author
Tatsuta, T.1, Author
Crespin, P.1, Author
de Villeneuve, D.1, Author
Brodesser, S.1, Author
Benit, P.1, Author
Rustin, P.1, Author
Baraibar, M. A.1, Author
Agbulut, O.1, Author
Olivier, A.1, Author
Protasi, F.1, Author
Langer, T.1, Author
Chrast, R.1, Author
de Lonlay, P.1, Author
de Foucauld, H.1, Author
Blaauw, B.1, Author
Pende, M.1, Author
Affiliations:
1Max Planck Institute for Biology of Ageing, Max Planck Society, Joseph-Stelzmann-Str. 9b, D-50931 Cologne, DE, ou_1942284              

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Free keywords: endoplasmic reticulum stress genetic disease metabolism myopathy
 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.

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 Dates: 2018-11-122018
 Publication Status: Issued
 Pages: -
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 Rev. Type: -
 Identifiers: Other: 30420558
DOI: 10.15252/embj.201899576
ISSN: 1460-2075 (Electronic)0261-4189 (Linking)
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Title: EMBO J
Source Genre: Journal
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