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PCYT2-regulated lipid biosynthesis is critical to muscle health and ageing.

Domagoj CikesKareem ElsayadErdinc SezginErika KoitaiFerenc TormaMichael OrthoferRebecca YarwoodLeonhard X HeinzVitaly SedlyarovNasser Darwish MirandaAdrian TaylorSophie GrapentineFathiya Al-MurshediAnne AbotAdelheid WeidingerCandice KutchukianColline SanchezShane J F CroninMaria NovatchkovaAnoop M KavirayaniThomas SchuetzBernhard HaubnerLisa HaasAstrid HagelkruysSuzanne JackowskiAndrey V KozlovVincent JacquemondClaude KnaufGiulio Superti-FurgaTommy R LundbergThomas GustafssonJohn McDermotMartin LoweZsolt RadakJeffrey S ChamberlainMarica BakovicSiddharth BankaJosef M Penninger
Published in: Nature metabolism (2023)
Muscle degeneration is the most prevalent cause for frailty and dependency in inherited diseases and ageing. Elucidation of pathophysiological mechanisms, as well as effective treatments for muscle diseases, represents an important goal in improving human health. Here, we show that the lipid synthesis enzyme phosphatidylethanolamine cytidyltransferase (PCYT2/ECT) is critical to muscle health. Human deficiency in PCYT2 causes a severe disease with failure to thrive and progressive weakness. pcyt2-mutant zebrafish and muscle-specific Pcyt2-knockout mice recapitulate the participant phenotypes, with failure to thrive, progressive muscle weakness and accelerated ageing. Mechanistically, muscle Pcyt2 deficiency affects cellular bioenergetics and membrane lipid bilayer structure and stability. PCYT2 activity declines in ageing muscles of mice and humans, and adeno-associated virus-based delivery of PCYT2 ameliorates muscle weakness in Pcyt2-knockout and old mice, offering a therapy for individuals with a rare disease and muscle ageing. Thus, PCYT2 plays a fundamental and conserved role in vertebrate muscle health, linking PCYT2 and PCYT2-synthesized lipids to severe muscle dystrophy and ageing.
Keyphrases
  • skeletal muscle
  • human health
  • public health
  • healthcare
  • mental health
  • risk assessment
  • early onset
  • fatty acid
  • transcription factor
  • climate change
  • mouse model
  • metabolic syndrome
  • wild type
  • drug induced