Lipin1 deficiency causes sarcoplasmic reticulum stress and chaperone-responsive myopathy.
Talha RashidIvan NemazanyyCecilia PaoliniTakashi TatsutaPaul CrespinDelphine de VilleneuveSusanne BrodesserPaule BenitPierre RustinMartin A BaraibarOnnik AgbulutAnne OlivierFeliciano ProtasiThomas LangerRoman ChrastPascale de LonlayHelene de FoucauldBert BlaauwMario PendePublished in: The EMBO journal (2018)
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.
Keyphrases
- fatty acid
- late onset
- genome wide
- acute kidney injury
- early onset
- endoplasmic reticulum
- cell death
- stress induced
- skeletal muscle
- randomized controlled trial
- copy number
- muscular dystrophy
- young adults
- replacement therapy
- dna methylation
- heat shock protein
- hydrogen peroxide
- nitric oxide
- heat stress
- heat shock
- risk assessment
- transcription factor
- type diabetes
- inflammatory response
- oxidative stress
- data analysis
- electron transfer