By Institute of Molecular Biotechnology of the Austrian Academy of Sciences
April 14, 2023
Muscle membrane-derived Giant Plasma Membrane Vesicles (GPMVs). These separated big membrane systems, coupled with innovative microscopy applications, enabled a close analysis of the architecture of the otherwise difficult-to-study cell membrane lipid bilayer, providing insight into an unknown pathological system of a just recently discovered, extreme human inherited illness. Credit: Cikes/IMBA.
The most prevalent reason for frailty in genetic diseases and aging is muscle degeneration, which might originate from a lack of an important enzyme in the lipid biosynthesis path. A team of researchers at the Austrian Academy of Sciences Institute of Molecular Biotechnology (IMBA) has studied how the enzyme PCYT2 influences muscle health in disease and aging using lab mouse designs. The outcomes of their study were just recently released in the journal Nature Metabolism.
The degeneration of muscles in acquired diseases and aging is a worldwide issue affecting hundreds of countless individuals. The decrease of skeletal muscles, which work as the bodys source of protein, leads to a condition understood as frailty, defined by overall physiological deterioration. A research group led by Domagoj Cikes at the Institute of Molecular Biotechnology (IMBA) and Josef Penninger at IMBA and the University of British Columbia (UBC) have actually now revealed the essential function played by the enzyme PCYT2 in muscle health.
PCYT2 is referred to as the bottleneck enzyme in a significant synthesis path of ethanolamine-derived phospholipids, the phosphatidylethanolamines (PEs). Based on patient data and utilizing laboratory mouse and zebrafish models, they reveal that anomalies affecting PCYT2, or its decreased activity, are saved hallmarks of muscle degeneration throughout vertebrates. Specifically, they demonstrate that PCYT2 deficiency in muscles affects mitochondrial function and the physicochemical properties of the myofiber membrane.
Josef Penninger and Domagoj Cikes. Credit: IMBA
Membrane rigidness, aging, and conservation in vertebrates
Lipids are everywhere present in biological membranes and exist at especially high concentrations in the membranes of afferent neuron and neural tissues. Following reports that PE-based molecules boost the membrane rigidity of liposomes, Domagoj Cikes, the studys co-corresponding author and a previous postdoctoral scientist in the Penninger lab at IMBA, hypothesized that this lipid species might play an important function in tissues subjected to continuous shear tension, such as muscle tissue.
” This assumption triggered me to selectively deplete PCYT2 in muscle tissues of animal designs and study the result. The clients provided a condition called complex hereditary spastic paraplegia, an extreme, multi-symptomatic illness defined by leg muscle weak point, tightness, and muscle losing that gotten worse with time.
The scientists demonstrated that the levels of functional PCYT2 are connected to human muscle health and affect the muscle tissues of mice and zebrafish. The mouse models in specific revealed striking and serious phenotypes of muscle development retardation and fast degeneration upon PCYT2 deficiency.
Muscle membrane-derived Giant Plasma Membrane Vesicles (GPMVs). Credit: Cikes/IMBA
PEs are likewise plentiful in mitochondrial membranes. The scientists analyzed how PCYT2 exhaustion in muscle tissues impacts mitochondrial membrane homeostasis and found that PCYT2 exhaustion certainly modified mitochondrial function and muscle energetics. A mitochondrial restorative approach was not sufficient to rescue the phenotype in mice.
” This triggered us to believe that there need to be an additional mechanism driving the pathology,” says Cikes. The group showed that the company of the cell membrane lipid bilayer played an extra role. “This represents a novel pathophysiological system that might likewise be present in other lipid-related disorders,” says Cikes.
In addition, the team showed that PCYT2 activity reduced throughout aging in mice and people. Using a targeted delivery method of active PCYT2, the scientists had the ability to save muscle weak point in PCYT2-depleted mouse models and enhance muscle strength in old mice.
Technical advances to understand the biology and pathophysiology
Having connected muscle health in vertebrates with PEs and muscle membrane structure, the researchers studied the function of lipid species in biological membranes. As biological deal with lipids is especially tough, they likewise required to think about methods to advance the offered research study applications. By adapting a strategy developed by Kareem Elsayad at the Vienna BioCenter Core Facilities (VBCF) to determine tissue tightness using Brillouin Light Scattering (BLS), the scientists had the ability to take a look at the physical residential or commercial properties of biological membranes. With this strategy, the group demonstrated a considerable reduction in membrane surface tightness when PCYT2 was diminished in mouse muscles.
” In addition, our existing work makes another leap forward in the field of lipid biology, as we were able to peek into the lipid bilayer of cell membranes and examine the regional residential or commercial properties of structural lipids,” states Cikes. The technique is based on separating Giant Plasma Membrane Vesicles (GPMVs) from biological tissues and studying the physicochemical properties and geometry of the membrane bilayer by methods of an intercalating color. This approach enables the researchers to examine how well the lipids in the bilayer are matched and whether they observe spaces, hydrophilic components, and leakages through the membrane.
The biology of lipids– crucial, yet understudied
” Current understanding on the biology of lipids is largely over-simplified. The whole lipid field is summed up into a handful of molecular households, such as cholesterols, triglycerides, phospholipids, and fatty acids.
By clarifying the central effect of a lipid biosynthesis path in muscle health, Cikes and the group dream to highlight the importance and discovery potential of lipid research study.
” Our present work shows a fundamental, specific, and conserved function of PCYT2-mediated lipid synthesis in vertebrate muscle health and permits us to check out novel restorative opportunities to enhance muscle health in unusual diseases and aging,” concludes Penninger.
Recommendation: “PCYT2-regulated lipid biosynthesis is important to muscle health and ageing” by Domagoj Cikes, Kareem Elsayad, Erdinc Sezgin, Erika Koitai, Torma Ferenc, Michael Orthofer, Rebecca Yarwood, Leonhard X. Heinz, Vitaly Sedlyarov, Nasser Darwish Miranda, Adrian Taylor, Sophie Grapentine, Fathiya al-Murshedi, Anne Abot, Adelheid Weidinger, Candice Kutchukian, Colline Sanchez, Shane J. F. Cronin, Maria Novatchkova, Anoop Kavirayani, Thomas Schuetz, Bernhard Haubner, Lisa Haas, Astrid Hagelkruys, Suzanne Jackowski, Andrey Kozlov, Vincent Jacquemond, Claude Knauf, Giulio Superti-Furga, Eric Rullman, Thomas Gustafsson, John McDermot, Martin Lowe, Zsolt Radak, Jeffrey S. Chamberlain, Marica Bakovic, Siddharth Banka and Josef M. Penninger, 20 March 2023, Nature Metabolism.DOI: 10.1038/ s42255-023-00766-2.
Josef Penninger was the founding director of IMBA and is currently the director of the Life Sciences Institute at the University of British Columbia (UBC), Vancouver, Canada.
The clients presented a condition called complex genetic spastic paraplegia, an extreme, multi-symptomatic illness characterized by leg muscle muscle, weakness, and stiffness wasting that intensified with time. The researchers demonstrated that the levels of practical PCYT2 are connected to human muscle health and affect the muscle tissues of mice and zebrafish. The scientists examined how PCYT2 depletion in muscle tissues impacts mitochondrial membrane homeostasis and found that PCYT2 depletion indeed altered mitochondrial function and muscle energetics. Having linked muscle health in vertebrates with PEs and muscle membrane structure, the researchers studied the role of lipid types in biological membranes. With this strategy, the group demonstrated a significant decrease in membrane surface stiffness when PCYT2 was diminished in mouse muscles.
