PCYT2-regulated lipid biosynthesis is critical to muscle health and ageing
Cikes D, Elsayad K, Sezgin E, Koitai E, Ferenc T, Orthofer M, Yarwood R, Heinz LX, Sedlyarov V, Darwish-Miranda N, Taylor A, Grapentine S, al-Murshedi F, Abot A, Weidinger A, Kutchukian C, Sanchez C, Cronin SJF, 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 JS, Bakovic M, Banka S, Penninger JM. 2023. PCYT2-regulated lipid biosynthesis is critical to muscle health and ageing. Nature Metabolism. 5, 495–515.
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Author
Cikes, Domagoj;
Elsayad, Kareem;
Sezgin, Erdinc;
Koitai, Erika;
Ferenc, Torma;
Orthofer, Michael;
Yarwood, Rebecca;
Heinz, Leonhard X.;
Sedlyarov, Vitaly;
Darwish-Miranda, NasserISTA 
;
Taylor, Adrian;
Grapentine, Sophie
All
;
Taylor, Adrian;
Grapentine, Sophie
All
Department
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.
Keywords
Publishing Year
Date Published
2023-03-20
Journal Title
Nature Metabolism
Publisher
Springer Nature
Acknowledgement
The authors thank the participants and their families for participating in the study. We thank all members of our laboratories for helpful discussions. We are grateful to Vienna BioCenter Core Facilities: Mouse Phenotyping Unit, Histopathology Unit, Bioinformatics Unit, BioOptics Unit, Electron Microscopy Unit and Comparative Medicine Unit. We are grateful to the Lipidomics Facility, and K. Klavins and T. Hannich at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences for assistance with lipidomics analysis. We also thank T. Huan and A. Hui (UBC Vancouver) for mouse tissue and mitochondria lipidomics analysis. We thank A. Klymchenko (Laboratoire de Bioimagerie et Pathologies Université de Strasbourg, Strasbourg, France) for providing the NR12S probe. We are thankful to the Sen. Paul D. Wellstone Muscular Dystrophy Cooperative Specialized Research Center Viral Vector Core Facility for AAV6 production. We also thank K. P. Campbell and M. E. Anderson (University of Iowa, Carver College of Medicine) for advice on muscle tissue handling. We thank A. Al-Qassabi from the Sultan Qaboos University for the clinical assessment of the participants. D.C. and J.M.P. are supported by the Austrian Federal Ministry of Education, Science and Research, the Austrian Academy of Sciences, and the City of Vienna, and grants from the Austrian Science Fund (FWF) Wittgenstein award (Z 271-B19), the T. von Zastrow Foundation, and a Canada 150 Research Chairs Program (F18-01336). J.S.C. is supported by grants RO1AR44533 and P50AR065139 from the US National Institutes of Health. C.K. is supported by a grant from the Agence Nationale de la Recherche (ANR-18-CE14-0007-01). A.V.K. is supported by European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement no. 67544, and an Austrian Science Fund (FWF; no P-33799). A.W. is supported by Austrian Research Promotion Agency (FFG) project no 867674. E.S. is supported by a SciLifeLab fellowship and Karolinska Institutet Foundation Grants. Work in the laboratory of G.S.-F. is supported by the Austrian Academy of Sciences, the European Research Council (ERC AdG 695214 GameofGates) and the Innovative Medicines Initiative 2 Joint Undertaking (grant agreement no. 777372, ReSOLUTE). S.B., M.L. and R.Y. acknowledge the support of the Spastic Paraplegia Foundation.
Volume
5
Page
495-515
ISSN
IST-REx-ID
Cite this
Cikes D, Elsayad K, Sezgin E, et al. PCYT2-regulated lipid biosynthesis is critical to muscle health and ageing. Nature Metabolism. 2023;5:495-515. doi:10.1038/s42255-023-00766-2
Cikes, D., Elsayad, K., Sezgin, E., Koitai, E., Ferenc, T., Orthofer, M., … Penninger, J. M. (2023). PCYT2-regulated lipid biosynthesis is critical to muscle health and ageing. Nature Metabolism. Springer Nature. https://doi.org/10.1038/s42255-023-00766-2
Cikes, Domagoj, Kareem Elsayad, Erdinc Sezgin, Erika Koitai, Torma Ferenc, Michael Orthofer, Rebecca Yarwood, et al. “PCYT2-Regulated Lipid Biosynthesis Is Critical to Muscle Health and Ageing.” Nature Metabolism. Springer Nature, 2023. https://doi.org/10.1038/s42255-023-00766-2.
D. Cikes et al., “PCYT2-regulated lipid biosynthesis is critical to muscle health and ageing,” Nature Metabolism, vol. 5. Springer Nature, pp. 495–515, 2023.
Cikes D, Elsayad K, Sezgin E, Koitai E, Ferenc T, Orthofer M, Yarwood R, Heinz LX, Sedlyarov V, Darwish-Miranda N, Taylor A, Grapentine S, al-Murshedi F, Abot A, Weidinger A, Kutchukian C, Sanchez C, Cronin SJF, 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 JS, Bakovic M, Banka S, Penninger JM. 2023. PCYT2-regulated lipid biosynthesis is critical to muscle health and ageing. Nature Metabolism. 5, 495–515.
Cikes, Domagoj, et al. “PCYT2-Regulated Lipid Biosynthesis Is Critical to Muscle Health and Ageing.” Nature Metabolism, vol. 5, Springer Nature, 2023, pp. 495–515, doi:10.1038/s42255-023-00766-2.
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