PUBLICATION
PCYT2-regulated lipid biosynthesis is critical to muscle health and ageing
- Authors
- Cikes, D., Elsayad, K., Sezgin, E., Koitai, E., Ferenc, T., Orthofer, M., Yarwood, R., Heinz, L.X., Sedlyarov, V., Miranda, N.D., Taylor, A., Grapentine, S., Al-Murshedi, F., Abot, A., Weidinger, A., Kutchukian, C., Sanchez, C., Cronin, S.J.F., Novatchkova, M., Kavirayani, A., Schuetz, T., Haubner, B., Haas, L., Hagelkruys, A., Jackowski, S., Kozlov, A., Jacquemond, V., Knauf, C., Superti-Furga, G., Rullman, E., Gustafsson, T., McDermot, J., Lowe, M., Radak, Z., Chamberlain, J.S., Bakovic, M., Banka, S., Penninger, J.M.
- ID
- ZDB-PUB-230322-34
- Date
- 2023
- Source
- Nature metabolism 5(3): 495-515 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Animals
- Failure to Thrive*
- Humans
- Mice
- Mice, Knockout
- Muscle Weakness/genetics
- Muscles
- RNA Nucleotidyltransferases*/chemistry
- RNA Nucleotidyltransferases*/genetics
- Zebrafish
- PubMed
- 36941451 Full text @ Nat Metab
Citation
Cikes, D., Elsayad, K., Sezgin, E., Koitai, E., Ferenc, T., Orthofer, M., Yarwood, R., Heinz, L.X., Sedlyarov, V., Miranda, N.D., Taylor, A., Grapentine, S., Al-Murshedi, F., Abot, A., Weidinger, A., Kutchukian, C., Sanchez, C., Cronin, S.J.F., Novatchkova, M., Kavirayani, A., Schuetz, T., Haubner, B., Haas, L., Hagelkruys, A., Jackowski, S., Kozlov, A., Jacquemond, V., Knauf, C., Superti-Furga, G., Rullman, E., Gustafsson, T., McDermot, J., Lowe, M., Radak, Z., Chamberlain, J.S., Bakovic, M., Banka, S., Penninger, J.M. (2023) PCYT2-regulated lipid biosynthesis is critical to muscle health and ageing. Nature metabolism. 5(3):495-515.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping