Lipin1 deficiency causes sarcoplasmic reticulum stress and chaperone‐responsive myopathy

Abstract As a consequence of impaired glucose or fatty acid metabolism, bioenergeticstress in skeletal muscles may trigger myopathyand rhabdomyolysis. Genetic mutations causing loss of function of the LPIN1 gene frequently lead to severe rhabdomyolysisbouts 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 sarcoplasmicreticulum (SR) stress, leading to the activation of the lipogenic SREBP1c/SREBP2 factors, the accumulation of the Fgf21cytokine, and alterations of SR–mitochondria morphology. Importantly, pharmacological treatments with the chaperone TUDCA and the fatty acid oxidation activator bezafibrateimprove 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 myopathyassociated with lipin1 deficiency.