--- _id: '12747' abstract: - lang: eng text: 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. 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.' article_processing_charge: No article_type: original author: - first_name: Domagoj full_name: Cikes, Domagoj last_name: Cikes - first_name: Kareem full_name: Elsayad, Kareem last_name: Elsayad - first_name: Erdinc full_name: Sezgin, Erdinc last_name: Sezgin - first_name: Erika full_name: Koitai, Erika last_name: Koitai - first_name: Torma full_name: Ferenc, Torma last_name: Ferenc - first_name: Michael full_name: Orthofer, Michael last_name: Orthofer - first_name: Rebecca full_name: Yarwood, Rebecca last_name: Yarwood - first_name: Leonhard X. full_name: Heinz, Leonhard X. last_name: Heinz - first_name: Vitaly full_name: Sedlyarov, Vitaly last_name: Sedlyarov - first_name: Nasser full_name: Darwish-Miranda, Nasser id: 39CD9926-F248-11E8-B48F-1D18A9856A87 last_name: Darwish-Miranda orcid: 0000-0002-8821-8236 - first_name: Adrian full_name: Taylor, Adrian last_name: Taylor - first_name: Sophie full_name: Grapentine, Sophie last_name: Grapentine - first_name: Fathiya full_name: al-Murshedi, Fathiya last_name: al-Murshedi - first_name: Anne full_name: Abot, Anne last_name: Abot - first_name: Adelheid full_name: Weidinger, Adelheid last_name: Weidinger - first_name: Candice full_name: Kutchukian, Candice last_name: Kutchukian - first_name: Colline full_name: Sanchez, Colline last_name: Sanchez - first_name: Shane J. F. full_name: Cronin, Shane J. F. last_name: Cronin - first_name: Maria full_name: Novatchkova, Maria last_name: Novatchkova - first_name: Anoop full_name: Kavirayani, Anoop last_name: Kavirayani - first_name: Thomas full_name: Schuetz, Thomas last_name: Schuetz - first_name: Bernhard full_name: Haubner, Bernhard last_name: Haubner - first_name: Lisa full_name: Haas, Lisa last_name: Haas - first_name: Astrid full_name: Hagelkruys, Astrid last_name: Hagelkruys - first_name: Suzanne full_name: Jackowski, Suzanne last_name: Jackowski - first_name: Andrey full_name: Kozlov, Andrey last_name: Kozlov - first_name: Vincent full_name: Jacquemond, Vincent last_name: Jacquemond - first_name: Claude full_name: Knauf, Claude last_name: Knauf - first_name: Giulio full_name: Superti-Furga, Giulio last_name: Superti-Furga - first_name: Eric full_name: Rullman, Eric last_name: Rullman - first_name: Thomas full_name: Gustafsson, Thomas last_name: Gustafsson - first_name: John full_name: McDermot, John last_name: McDermot - first_name: Martin full_name: Lowe, Martin last_name: Lowe - first_name: Zsolt full_name: Radak, Zsolt last_name: Radak - first_name: Jeffrey S. full_name: Chamberlain, Jeffrey S. last_name: Chamberlain - first_name: Marica full_name: Bakovic, Marica last_name: Bakovic - first_name: Siddharth full_name: Banka, Siddharth last_name: Banka - first_name: Josef M. full_name: Penninger, Josef M. last_name: Penninger citation: ama: 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 apa: 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 chicago: 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. ieee: 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. ista: 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. mla: 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. short: D. Cikes, K. Elsayad, E. Sezgin, E. Koitai, T. Ferenc, M. Orthofer, R. Yarwood, L.X. Heinz, V. Sedlyarov, N. Darwish-Miranda, A. Taylor, S. Grapentine, F. al-Murshedi, A. Abot, A. Weidinger, C. Kutchukian, C. Sanchez, S.J.F. Cronin, M. Novatchkova, A. Kavirayani, T. Schuetz, B. Haubner, L. Haas, A. Hagelkruys, S. Jackowski, A. Kozlov, V. Jacquemond, C. Knauf, G. Superti-Furga, E. Rullman, T. Gustafsson, J. McDermot, M. Lowe, Z. Radak, J.S. Chamberlain, M. Bakovic, S. Banka, J.M. Penninger, Nature Metabolism 5 (2023) 495–515. date_created: 2023-03-23T12:58:43Z date_published: 2023-03-20T00:00:00Z date_updated: 2023-11-28T07:31:33Z day: '20' department: - _id: Bio doi: 10.1038/s42255-023-00766-2 external_id: isi: - '000992064000002' pmid: - '36941451' intvolume: ' 5' isi: 1 keyword: - Cell Biology - Physiology (medical) - Endocrinology - Diabetes and Metabolism - Internal Medicine language: - iso: eng main_file_link: - open_access: '1' url: https://doi.org/10.1101/2022.03.02.482658 month: '03' oa: 1 oa_version: Preprint page: 495-515 pmid: 1 publication: Nature Metabolism publication_identifier: issn: - 2522-5812 publication_status: published publisher: Springer Nature quality_controlled: '1' related_material: link: - relation: erratum url: https://doi.org/10.1038/s42255-023-00791-1 scopus_import: '1' status: public title: PCYT2-regulated lipid biosynthesis is critical to muscle health and ageing type: journal_article user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87 volume: 5 year: '2023' ... --- _id: '12203' abstract: - lang: eng text: 'Geranylgeranyl diphosphate synthase (GGPPS, EC: 2.5.1.29) catalyzes the biosynthesis of geranylgeranyl diphosphate (GGPP), which is a key precursor for ginkgolide biosynthesis. Here we reported for the first time the cloning of a new full-length cDNA encoding GGPPS from the living fossil plant Ginkgo biloba. The full-length cDNA encoding G. biloba GGPPS (designated as GbGGPPS) was 1657bp long and contained a 1176bp open reading frame encoding a 391 amino acid protein. Comparative analysis showed that GbGGPPS possessed a 79 amino acid transit peptide at its N-terminal, which directed GbGGPPS to target to the plastids. Bioinformatic analysis revealed that GbGGPPS was a member of polyprenyltransferases with two highly conserved aspartate-rich motifs like other plant GGPPSs. Phylogenetic tree analysis indicated that plant GGPPSs could be classified into two groups, angiosperm and gymnosperm GGPPSs, while GbGGPPS had closer relationship with gymnosperm plant GGPPSs.' acknowledgement: This study was financially supported by China National High-Tech “863” Program. The authors are very thankful to Dr Li Wang (School of Life Sciences, Fudan University, Shanghai, China) for her kind help with constructing the phylogenetic tree. article_processing_charge: No article_type: original author: - first_name: Zhihua full_name: Liao, Zhihua last_name: Liao - first_name: Min full_name: Chen, Min last_name: Chen - first_name: Yifu full_name: Gong, Yifu last_name: Gong - first_name: Liang full_name: Guo, Liang last_name: Guo - first_name: Qiumin full_name: Tan, Qiumin last_name: Tan - first_name: Xiaoqi full_name: Feng, Xiaoqi id: e0164712-22ee-11ed-b12a-d80fcdf35958 last_name: Feng orcid: 0000-0002-4008-1234 - first_name: Xiaofen full_name: Sun, Xiaofen last_name: Sun - first_name: Feng full_name: Tan, Feng last_name: Tan - first_name: Kexuan full_name: Tang, Kexuan last_name: Tang citation: ama: Liao Z, Chen M, Gong Y, et al. A new geranylgeranyl Diphosphate synthase gene from Ginkgo biloba, which intermediates the biosynthesis of the key precursor for ginkgolides. DNA Sequence. 2004;15(2):153-158. doi:10.1080/10425170410001667348 apa: Liao, Z., Chen, M., Gong, Y., Guo, L., Tan, Q., Feng, X., … Tang, K. (2004). A new geranylgeranyl Diphosphate synthase gene from Ginkgo biloba, which intermediates the biosynthesis of the key precursor for ginkgolides. DNA Sequence. Informa UK Limited. https://doi.org/10.1080/10425170410001667348 chicago: Liao, Zhihua, Min Chen, Yifu Gong, Liang Guo, Qiumin Tan, Xiaoqi Feng, Xiaofen Sun, Feng Tan, and Kexuan Tang. “A New Geranylgeranyl Diphosphate Synthase Gene from Ginkgo Biloba, Which Intermediates the Biosynthesis of the Key Precursor for Ginkgolides.” DNA Sequence. Informa UK Limited, 2004. https://doi.org/10.1080/10425170410001667348. ieee: Z. Liao et al., “A new geranylgeranyl Diphosphate synthase gene from Ginkgo biloba, which intermediates the biosynthesis of the key precursor for ginkgolides,” DNA Sequence, vol. 15, no. 2. Informa UK Limited, pp. 153–158, 2004. ista: Liao Z, Chen M, Gong Y, Guo L, Tan Q, Feng X, Sun X, Tan F, Tang K. 2004. A new geranylgeranyl Diphosphate synthase gene from Ginkgo biloba, which intermediates the biosynthesis of the key precursor for ginkgolides. DNA Sequence. 15(2), 153–158. mla: Liao, Zhihua, et al. “A New Geranylgeranyl Diphosphate Synthase Gene from Ginkgo Biloba, Which Intermediates the Biosynthesis of the Key Precursor for Ginkgolides.” DNA Sequence, vol. 15, no. 2, Informa UK Limited, 2004, pp. 153–58, doi:10.1080/10425170410001667348. short: Z. Liao, M. Chen, Y. Gong, L. Guo, Q. Tan, X. Feng, X. Sun, F. Tan, K. Tang, DNA Sequence 15 (2004) 153–158. date_created: 2023-01-16T09:24:50Z date_published: 2004-01-01T00:00:00Z date_updated: 2023-05-08T10:58:29Z department: - _id: XiFe doi: 10.1080/10425170410001667348 extern: '1' external_id: pmid: - '15352294' intvolume: ' 15' issue: '2' keyword: - Endocrinology - Genetics - Molecular Biology - Biochemistry language: - iso: eng oa_version: None page: 153-158 pmid: 1 publication: DNA Sequence publication_identifier: issn: - 1042-5179 publication_status: published publisher: Informa UK Limited quality_controlled: '1' scopus_import: '1' status: public title: A new geranylgeranyl Diphosphate synthase gene from Ginkgo biloba, which intermediates the biosynthesis of the key precursor for ginkgolides type: journal_article user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87 volume: 15 year: '2004' ...