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

Autor: Cikes D; IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria. domagoj.cikes@imba.oeaw.ac.at., Elsayad K; Division of Anatomy, Center for Anatomy and Cell Biology and Medical Imaging Cluster (MIC), Vienna, Austria. kareem.elsayad@meduniwien.ac.at., Sezgin E; MRC Weatherall Institute of Molecular Medicine, MRC Human Immunology Unit, University of Oxford, Oxford, UK.; Science for Life Laboratory, Department of Women's and Children's Health, Karolinska Institutet, Solna, Sweden., Koitai E; Research Institute of Sport Science, University of Physical Education, Budapest, Hungary., Torma F; Research Institute of Sport Science, University of Physical Education, Budapest, Hungary., Orthofer M; IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria., Yarwood R; School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK., Heinz LX; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria., Sedlyarov V; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria., Miranda ND; Institute of Science and Technology Austria (IST Austria), Klosterneuburg, Austria., Taylor A; Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada., Grapentine S; Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada., Al-Murshedi F; Department of Genetics, College of Medicine, Sultan Qaboos University, Muscat, Sultanate of Oman., Abot A; Enterosys SAS, Prologue Biotech, Labège, France., Weidinger A; Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA, Vienna, Austria., Kutchukian C; Institut NeuroMyoGène, Université Claude Bernard Lyon 1, Villeurbanne, France., Sanchez C; Institut NeuroMyoGène, Université Claude Bernard Lyon 1, Villeurbanne, France., Cronin SJF; IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria., Novatchkova M; IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria., Kavirayani A; VBCF, Vienna BioCenter Core Facilities, Vienna BioCenter, Vienna, Austria., Schuetz T; IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria., Haubner B; IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria., Haas L; IMP Research Institute of Molecular Pathology, Vienna, Austria., Hagelkruys A; IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria., Jackowski S; St. Jude Children's Research Hospital, Memphis, TN, USA., Kozlov AV; Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA, Vienna, Austria., Jacquemond V; Institut NeuroMyoGène, Université Claude Bernard Lyon 1, Villeurbanne, France., Knauf C; INSERM U1220 Institut de Recherche en Santé Digestive, CHU Purpan, Université Toulouse III Paul Sabatier Toulouse, Toulouse, France., Superti-Furga G; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.; Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria., Rullman E; Division of Clinical Physiology, Department of Laboratory Medicine, Karolinska Institutet, and Unit of Clinical Physiology, Karolinska University Hospital, Stockholm, Sweden.; Cardiovascular Theme, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden., Gustafsson T; Division of Clinical Physiology, Department of Laboratory Medicine, Karolinska Institutet, and Unit of Clinical Physiology, Karolinska University Hospital, Stockholm, Sweden., McDermot J; Manchester Centre for Genomics Medicine, St Mary's Hospital, Manchester University Hospital Foundation Trust, Manchester, UK., Lowe M; School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK., Radak Z; Research Institute of Sport Science, University of Physical Education, Budapest, Hungary., Chamberlain JS; Department of Neurology, University of Washington, Seattle, WA, USA.; Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center, University of Washington, Seattle, WA, USA., Bakovic M; Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada., Banka S; Manchester Centre for Genomics Medicine, St Mary's Hospital, Manchester University Hospital Foundation Trust, Manchester, UK.; Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK., Penninger JM; IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria. josef.penninger@ubc.ca.; Department of Medical Genetics, Life Science Institute, University of British Columbia, Vancouver, British Columbia, Canada. josef.penninger@ubc.ca.
Jazyk: angličtina
Zdroj: Nature metabolism [Nat Metab] 2023 Mar; Vol. 5 (3), pp. 495-515. Date of Electronic Publication: 2023 Mar 20.
DOI: 10.1038/s42255-023-00766-2
Abstrakt: 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.
(© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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