PCYT2 controls muscle health and muscle aging

Authors
D Cikes, K Elsayad, E Sezgin et al


Lab
Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria

Journal
bioRxiv

Abstract
Muscle degeneration is the most prevalent cause for frailty and dependency in inherited diseases and ageing, affecting hundreds of millions of people. Elucidation of pathophysiological mechanisms, as well as effective treatments for muscle diseases represents an important goal in improving human health. Here, we show that phosphatidylethanolamine cytidyltransferase (PCYT2/ECT), the critical enzyme of the Kennedy branch of phosphatidylethanolamine (PE) synthesis pathway, has an essential role in muscle health and lifespan. Human genetic deficiency in PCYT2 causes a severe disease with failure to thrive and progressive weakness. Pcyt2 mutant zebrafish recapitulate patient phenotypes, indicating that the role of PCYT2/PE in muscle is evolutionary conserved. Muscle specific Pcyt2 knockout mice exhibited failure to thrive, impaired muscle development, progressive muscle weakness, muscle loss and accelerated ageing. Interestingly, from several organs tested, this pathology is muscle specific. Mechanistically, in muscle deficiency of PCYT2 triggers dramatic alterations of physicochemical properties of the myofiber membrane lipid bilayer, compromising membrane stability and durability under strain. We also show that PCYT2 activity declines in the aging muscles of humans and mice, and Pcyt2 gene-therapy in aged mice improved muscle strength. AAV-based delivery of PCYT2 also rescued muscle weakness in Pcyt2 knock-out mice, offering a feasible novel therapeutic avenue for rare disease patients and to alleviate muscle aging. Thus, PCYT2 plays a fundamental, specific, and conserved role in vertebrate muscle health, linking PCYT2 and PCYT2 synthesized PE lipids to severe muscle dystrophy, exercise intolerance and aging..

BIOSEB Instruments Used:
Grip strength test (BIO-GS3)

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