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

Domagoj Cikes, Kareem Elsayad, Erdinc Sezgin, Erika Koitai, Torma Ferenc, Michael Orthofer, Rebecca Yarwood, Leonhard X Heinz, Vitaly Sedlyarov, Nasser Darwish Miranda, Adrian Taylor, Sophie Grapentine, Fathiya Al-Murshedi, Anne Abot, Adelheid Weidinger, Candice Kutchukian, Colline Sanchez, Shane J F Cronin, Maria Novatchkova, Anoop KavirayaniThomas Schuetz, Bernhard Haubner, Lisa Haas, Astrid Hagelkruys, Suzanne Jackowski, Andrey Kozlov, Vincent Jacquemond, Claude Knauf, Giulio Superti-Furga, Eric Rullman, Thomas Gustafsson, John McDermot, Martin Lowe, Zsolt Radak, Jeffrey S Chamberlain, Marica Bakovic, Siddharth Banka, Josef M Penninger

Research output: Contribution to journalArticlepeer-review

34 Downloads (Pure)

Abstract

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.

Original languageEnglish
JournalNature Metabolism
DOIs
Publication statusPublished - 20 Mar 2023

Fingerprint

Dive into the research topics of 'PCYT2-regulated lipid biosynthesis is critical to muscle health and ageing'. Together they form a unique fingerprint.

Cite this