Lipin1 deficiency causes sarcoplasmic reticulum stress and chaperone-responsive myopathy

Area of Science:

• Muscle physiology
• Metabolic disorders
• Lipid metabolism

Background:

• Impaired glucose or fatty acid metabolism can cause skeletal muscle bioenergetic stress, leading to myopathy and rhabdomyolysis.
• Loss-of-function mutations in the LPIN1 gene are a frequent cause of severe rhabdomyolysis in children, but underlying mechanisms and treatments are unclear.

Purpose of the Study:

• To investigate the consequences of lipin1 deficiency in skeletal muscle.
• To identify the metabolic alterations and underlying causes of lipin1-deficiency-induced myopathy.
• To explore potential therapeutic interventions for lipin1-related myopathy.

Main Methods:

• Studied lipin1 deficiency in mouse skeletal muscle models.
• Analyzed lipid accumulation (neutral and phospholipids).
• Assessed fatty acid synthesis, oxidation, elongation, and desaturation.
• Investigated sarcoplasmic reticulum (SR) stress, lipogenic factor activation (SREBP1c/SREBP2), Fgf21 accumulation, and SR-mitochondria morphology.
• Evaluated therapeutic effects of TUDCA and bezafibrate.

Main Results:

• Lipin1 deficiency in mouse skeletal muscle caused myopathy with significant accumulation of neutral and phospholipids.
• Metabolic imbalances included altered fatty acid synthesis and oxidation, with defects in acyl chain elongation and desaturation.
• Underlying causes involved severe sarcoplasmic reticulum (SR) stress, activating lipogenic factors, accumulating Fgf21, and altering SR-mitochondria morphology.
• Pharmacological treatment with TUDCA and bezafibrate improved muscle histology and strength in lipin1 mutants.

Conclusions:

• Sarcoplasmic reticulum (SR) stress and altered SR-mitochondria contacts are key factors in lipin1-deficiency-induced myopathy.
• These findings identify potential therapeutic targets for treating myopathy associated with lipin1 deficiency.