Lipin1 deficiency causes sarcoplasmic reticulum stress and chaperone‐responsive myopathy

• Talha Rashid ^[5] ; Ivan Nemazanyy ^[1] ; Cecilia Paolini ^[6] ; Takashi Tatsuta ^[7] ; Paul Crespin ^[8] ; Delphine de Villeneuve ^[8] ; Susanne Brodesser ^[2] ; Paule Benit ^[3] ; Pierre Rustin ^[3] ; Martin A Baraibar ^[9] ; Onnik Agbulut ^[10] ; Anne Olivier ^[11] ; Feliciano Protasi ^[6] ; Thomas Langer ^[7] ; Roman Chrast ^[12] ; Pascale de Lonlay ^[8] ; Helene de Foucauld ^[11] ; Bert Blaauw ^[4] ; Mario Pende ^[8]
  1. [1] Institut Necker Enfants Malades

     Institut Necker Enfants Malades

     París, Francia

     
  2. [2] University of Cologne

     University of Cologne

     Kreisfreie Stadt Köln, Alemania

     
  3. [3] Hôpital Robert Debré

     Hôpital Robert Debré

     París, Francia

     
  4. [4] Venetian Institute of Molecular Medicine

     Venetian Institute of Molecular Medicine

     Padova, Italia

     
  5. [5] 1 Institut Necker‐Enfants Malades Paris France; 2 Inserm, U1151 Paris France; 3 Université Paris Descartes Sorbonne Paris Cité Paris France; 4 Sanofi R&D, Translational Sciences Unit In Silico Biology Chilly‐Mazarin France
  6. [6] 6 Center for Research on Ageing and Translational Medicine (CeSI‐MeT) Department of Neuroscience, Imaging, and Clinical Sciences (DNICS) University G. d’ Annunzio of Chieti Chieti Italy
  7. [7] 7 Max‐Planck‐Institute for Biology of Ageing Cologne Germany
  8. [8] 1 Institut Necker‐Enfants Malades Paris France; 2 Inserm, U1151 Paris France; 3 Université Paris Descartes Sorbonne Paris Cité Paris France
  9. [9] 10 OxiProteomics SAS Paris France
  10. [10] 11 CNRS, Institut de Biologie Paris‐Seine (IBPS) Biological Adaptation and Ageing Sorbonne Université Paris France
  11. [11] 4 Sanofi R&D, Translational Sciences Unit In Silico Biology Chilly‐Mazarin France
  12. [12] 12 Department of Neuroscience and Department of Clinical Neuroscience Karolinska Institutet Stockholm Sweden

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 38, Nº. 1, 2019, pág. 4
• Idioma: inglés
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  • 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.