Researchers at the Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences and the University of British Columbia (UBC) discovered how the enzyme PCYT2 affects muscle health in disease and aging in mouse models. The findings may lead to new therapies for muscle degeneration in inherited diseases and aging.

The study, published in Nature Metabolism in a paper titled, “Critical role of PCYT2 in muscle health and aging,” was led by Domagoj Cikes, PhD, a postdoctoral researcher at IMBA and Josef Penninger, MD, professor at IMBA and UBC.

“Muscle degeneration is the most prevalent cause for frailty and dependency in inherited diseases and aging,” wrote the researchers. “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.”

CYT2 is known as the bottleneck enzyme in a major synthesis pathway of ethanolamine-derived phospholipids, the phosphatidylethanolamines (PEs). Patient data and using laboratory mouse and zebrafish models, the researchers showed that mutations affecting PCYT2 are conserved hallmarks of muscle degeneration across vertebrates.

Following reports that PE-based molecules enhance the membrane rigidity of liposomes Cikes, the study’s co-corresponding author and a former postdoctoral researcher in the Penninger lab at IMBA, hypothesized that this lipid species would play an important role in tissues subjected to constant shear stress, such as muscle tissue. “This assumption prompted me to selectively deplete PCYT2 in muscle tissues of animal models and study the outcome. In parallel, clinicians reported patient cases of mutations affecting PCYT2. The patients presented a condition called complex hereditary spastic paraplegia, a severe, multi-symptomatic disease characterized by leg muscle weakness, stiffness, and muscle wasting that worsened with time. However, given that the disease was just recently discovered, the underlying pathophysiological biology is vastly unknown,” said Cikes.

The researchers demonstrated that the levels of functional PCYT2 are linked to human muscle health and affect the muscle tissues of mice and zebrafish.

PEs are also abundant in mitochondrial membranes. Therefore, the researchers examined how PCYT2 depletion in muscle tissues affects mitochondrial membrane homeostasis and found that PCYT2 depletion indeed altered mitochondrial function and muscle energetics. A mitochondrial therapeutic approach was not sufficient to rescue the phenotype in mice. “This prompted us to think that there must be an additional mechanism driving the pathology,” said Cikes. Indeed, the team showed that the organization of the cell membrane lipid bilayer played an additional role. “This represents a novel pathophysiological mechanism that might also be present in other lipid-related disorders,” said Cikes.

“Current knowledge on the biology of lipids is largely over-simplified. The whole lipid field is summarized into a handful of molecular families, such as cholesterols, triglycerides, phospholipids, and fatty acids. It is a vast and unexplored molecular universe where the function of most species in health and disease is unknown,” said Cikes. By shedding light on the central effect of a lipid biosynthesis pathway in muscle health, Cikes and the team wish to highlight the importance and discovery potential of lipid research. “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,” concluded Penninger.

“PCYT2 activity declines in aging 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 aging,” wrote the researchers. “Thus, PCYT2 plays a fundamental and conserved role in vertebrate muscle health, linking PCYT2 and PCYT2-synthesized lipids to severe muscle dystrophy and aging.”

 

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