Key enzyme in muscle health and degeneration
Using a targeted delivery technique of active enzyme PCYT2, researchers were able to rescue muscle weakness in PCYT2-depleted mouse models and improve muscle strength in old mice, opening this up as a potential therapy for SPG82.
Muscle degeneration, the most prevalent cause of frailty in hereditary diseases and aging, could be caused by a deficiency in one key enzyme in a lipid biosynthesis pathway.
Researchers at the Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences demonstrate that PCYT2 deficiency in muscles affects mitochondrial function and the physicochemical properties of the myofiber membrane.
The researchers demonstrated that the levels of functional PCYT2 are linked to human muscle health and affect the muscle tissues of mice and zebrafish. The mouse models in particular showed striking and severe phenotypes of muscle growth retardation and quick deterioration upon PCYT2 depletion.
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.
SOURCE: Nat Metab. 2023 Mar;5(3):495-515. doi: 10.1038/s42255-023-00766-2. Epub 2023 Mar 20. PMID: 36941451 © 2023. The Author(s), under exclusive licence to Springer Nature Limited.
PCYT2-regulated lipid biosynthesis is critical to muscle health and ageing
Domagoj Cikes 1 , Kareem Elsayad 2 , Erdinc Sezgin 3 4 , Erika Koitai 5 , Ferenc Torma 5 , Michael Orthofer 6 , Rebecca Yarwood 7 , Leonhard X Heinz 8 , Vitaly Sedlyarov 8 , Nasser Darwish Miranda 9 , Adrian Taylor 10 , Sophie Grapentine 10 , Fathiya Al-Murshedi 11 , Anne Abot 12 , Adelheid Weidinger 13 , Candice Kutchukian 14 , Colline Sanchez 14 , Shane J F Cronin 6 , Maria Novatchkova 6 , Anoop Kavirayani 15 , Thomas Schuetz 6 , Bernhard Haubner 6 , Lisa Haas 16 , Astrid Hagelkruys 6 , Suzanne Jackowski 17 , Andrey V Kozlov 13 , Vincent Jacquemond 14 , Claude Knauf 18 , Giulio Superti-Furga 8 19 , Eric Rullman 20 21 , Thomas Gustafsson 20 , John McDermot 22 , Martin Lowe 7 , Zsolt Radak 5 , Jeffrey S Chamberlain 23 24 , Marica Bakovic 10 , Siddharth Banka 22 25 , Josef M Penninger 26 27
SOURCE: ScienceDaily, 20 March 2023.
Muscle health depends on lipid synthesis
IMBA – Institute of Molecular Biotechnology of the Austrian Academy of Sciences