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31 May 2023
Published online 22 March 2023
An enzyme vital for the healthy development and maintenance of muscles appears to decline with age.
Deficiency of an enzyme vital for the integrity of the membranes that encase muscle fibres is behind age-related muscle wasting and an inherited genetic disorder that causes severe neurological and muscle problems, researchers have found.
In humans, genetic mutations affecting the function of the enzyme phosphatidylethanolamine cytidyltransferase (PCYT2) lead to a disorder known as hereditary spastic paraplegia, which causes developmental delay and muscle degeneration. However, the role that PCYT2 plays in muscle development and health is not well understood.
An international team of researchers led by Domagoj Cikes, from the Institute of Molecular Biotechnology of the Austrian Academy of Sciences, and including Fathiya al-Murshedi, from Sultan Qaboos University in Oman, engineered mice and zebrafish with muscle tissue deficient in PCYT2 to explore its effects.
They found that when the activity of PCYT2 is compromised, it affects the double layer of lipids that make up the bilayer membrane surrounding the muscle fibres. This leads to a membrane that is softer, less rigid, and allows more movement of molecules across it. “If you have a compromised stability in terms of the durability of this bilayer, then little by little it's going to get damaged and this damage is going to accumulate,” Cikes says.
The group also looked at the activity of the PCYT2 enzyme in the muscles of older non-engineered mice and in the leg muscles of older humans. They found activity and levels of PCTY2 decline naturally over time with age. Introducing the gene for PCYT2 into the muscles of the deficient mice partly reversed the degeneration.
Frédéric Vaz, from Amsterdam UMC in the Netherlands, says the study is “a very comprehensive survey of the problems without this enzyme.” Vaz, who was not involved with the study, also drew attention to possible effects of PCYT2 deficiency on other key lipids such as ether lipids, also products of PCYT2, which are also important for membrane rigidity in muscle.
Cikes, D. et al. PCYT2-regulated lipid biosynthesis is critical to muscle health and ageing. Nature Metabolism https://doi.org/10.1038/s42255-023-00766-2 (2023).