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

Nat Metab. 2023 Mar;5(3):495-515. doi: 10.1038/s42255-023-00766-2. Epub 2023 Mar 20.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Failure to Thrive*
  • Humans
  • Mice
  • Mice, Knockout
  • Muscle Weakness / genetics
  • Muscles
  • RNA Nucleotidyltransferases* / chemistry
  • RNA Nucleotidyltransferases* / genetics
  • Zebrafish


  • RNA Nucleotidyltransferases
  • Ethanolamine-phosphate cytidylyltransferase