In aging and many diseases, muscles degenerate and there is a loss of function that can lead to many other health problems. As skeletal muscles break down, people can become frail and experience a general decline in their health. Scientists have now found that an enzyme called PCYT2 plays a critical role in muscle health. This enzyme is a crucial part of a lipid biosynthesis pathway, and if it is deficient, it could lead to muscle degeneration. The findings have been reported in Nature Metabolism.
PCYT2 is essential to a biochemical cascade in which ethanolamine-derived phospholipids, the phosphatidylethanolamines (PEs) are produced. Researchers used mouse and zebrafish models to assess the impact of mutations that reduced the activity of PCYT2. This reduction caused the hallmarks of muscle degeneration to appear in the models.
Lipids are an integral part of biological membranes, like the ones that surround cells. The membranes of neurons and neural tissues carry particularly high levels of lipids. Previous work has indicated that PE molecules can increase rigidity in liposomes. In this study, the researchers wanted to know more about how lipid species are related to cells that are subjected to a lot of physical stress, like muscles.
In muscles, a PCYT2 deficiency was found to impact the membrane of muscle cells and the function of energy-producing organelles called mitochondria.
There are people who carry genetic mutations that affect PCYT2. These individuals have complex hereditary spastic paraplegia, which is a severe disease that causes muscle weakness in the legs, stiffness, and muscle wasting that gets progressively worse. "However, given that the disease was just recently discovered, the underlying pathophysiological biology is vastly unknown," said co-corresponding study author Domagoj Cikes of the Institute of Molecular Biotechnology.
In mice, a loss of PCYT2 disrupted muscle growth and induced muscle deterioration. The study authors noted that the phenotype of the mice resembled rapid aging. PCYT2 reduction changed the function of mitochondria too. The mice could not be treated simply by restoring mitochondrial function, however. This led the researchers to look for another mechanism. They found that the lipid bilayer of cell membranes was also involved.
"This represents a novel pathophysiological mechanism that might also be present in other lipid-related disorders," said Cikes.
Additional work showed that PCYT2 activity declines when both humans and mice are aging. When the researchers exposed mice that modeled a loss of PCYT2 to active PCYT2 enzymes, muscle strength was restored in these mice. Active PCYT2 also improved muscle strength in aged mice.
The researchers used a technique called Brillouin Light Scattering (BLS) to assess the physical properties of membranes. Membranes were found to become more stiff in mouse models in which PCYT2 activity was reduced. This technique is outlined in the video above.
“Our current work demonstrates a fundamental, specific, and conserved role of PCYT2-mediated lipid synthesis in vertebrate muscle health and allows us to explore novel therapeutic avenues to improve muscle health in rare diseases and aging,” said corresponding study author Josef Penninger, the director of the Life Sciences Institute at the University of British Columbia.
Sources: IMBA - Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Nature Metabolism
