Dataset Information

Lipin1 deficiency causes sarcoplasmic reticulum stress and chaperone-responsive 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.

INSTRUMENT(S): Liquid Chromatography MS - Alternating (LC-MS (Alternating))

SUBMITTER: Ivan Nemazanyy

PROVIDER: MTBLS750 | MetaboLights | 2019-01-07

REPOSITORIES: MetaboLights

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Lipin1 deficiency causes sarcoplasmic reticulum stress and chaperone-responsive myopathy.

Rashid Talha T Nemazanyy Ivan I Paolini Cecilia C Tatsuta Takashi T Crespin Paul P de Villeneuve Delphine D Brodesser Susanne S Benit Paule P Rustin Pierre P Baraibar Martin A MA Agbulut Onnik O Olivier Anne A Protasi Feliciano F Langer Thomas T Chrast Roman R de Lonlay Pascale P de Foucauld Helene H Blaauw Bert B Pende Mario M

The EMBO journal 20181112 1

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 accumula ...[more]

PMID: 30420558

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Project description:Skeletal muscle is the largest tissue in the body and mainly relies on mitochondrial oxidative metabolism for sustainable ATP production. Reduced oxygen availability, also known as hypoxia, can be caused by high altitude or pathology and impacts mitochondria. Whereas long-term hypoxia results in increased reliance on glycolysis, reduced fatty acid oxidation and a decreased skeletal muscle mass, the in vivo mechanisms of adaptation of skeletal muscle to acute hypoxia remain elusive. Therefore, we aimed to provide an integrated description of the response of the M. gastrocnemius to acute hypoxia. Fasted male C57BL/6JOlaHsd mice were exposed to 12% oxygen representing normobaric hypoxia versus 21% oxygen (normoxia) for six hours (n=12 mice per group). Whole-body energy metabolism and the transcriptome response of the M. gastrocnemius mice was analyzed and confirmed by acylcarnitine determination and RT-qPCR. On whole-body level, six hours of hypoxia reduced energy expenditure, increased blood glucose and tended to further decrease the respiratory exchange ratio (RER). Whole genome transcriptome analysis revealed upregulation of the FOXO signalling pathway including an increased expression of Trib3, which was positively correlated with blood glucose. Apart from upregulation of Cpt1a, which negatively correlated with the RER, and SLC25a25 (Cact), fatty acid β-oxidation was not regulated. Together with significantly increased muscle C14 and C16-acylcarnitines this supports no increased fatty acid catabolism in muscle. In addition, the hypoxia-induced FOXO activation could also be connected to altered gene profiles related to fiber type switching, extracellular matrix remodelling, muscle differentiation and the denervation of neuromuscular junctions (NMJ). Conclusively, our results suggest that an acute, six hours exposure of mice to hypoxia impacts M. gastrocnemius via FOXO1, initiating alterations in skeletal muscle that may ultimately contribute to tissue remodelling. This supports an early role of hypoxia in tissue alterations in hypoxia-associated conditions such as aging and obesity. The observed impact of hypoxia on denervated NMJ is novel and warrants further investigation.

Dataset Information

Lipin1 deficiency causes sarcoplasmic reticulum stress and chaperone-responsive myopathy

Publications

Lipin1 deficiency causes sarcoplasmic reticulum stress and chaperone-responsive myopathy.

Similar Datasets

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