Long-chain ceramides are cell non-autonomous signals linking lipotoxicity to endoplasmic reticulum stress in skeletal muscle

Ben D. McNally, Dean F. Ashley, Lea Hänschke, Hélène N. Daou, Nicole T. Watt, Steven A. Murfitt, Amanda D. V. MacCannell, Anna Whitehead, T. Scott Bowen, Francis W. B. Sanders, Michele Vacca, Klaus K. Witte, Graeme R. Davies, Reinhard Bauer, Julian L. Griffin and Lee D. Roberts ()
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Ben D. McNally: Department of Biochemistry, University of Cambridge
Dean F. Ashley: Department of Biochemistry, University of Cambridge
Lea Hänschke: Life & Medical Sciences Institute (LIMES) Development, Genetics & Molecular Physiology Unit, University of Bonn
Hélène N. Daou: University of Leeds
Nicole T. Watt: University of Leeds
Steven A. Murfitt: Department of Biochemistry, University of Cambridge
Amanda D. V. MacCannell: University of Leeds
Anna Whitehead: University of Leeds
T. Scott Bowen: University of Leeds
Francis W. B. Sanders: Department of Biochemistry, University of Cambridge
Michele Vacca: Department of Biochemistry, University of Cambridge
Klaus K. Witte: University of Leeds
Graeme R. Davies: Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca
Reinhard Bauer: Life & Medical Sciences Institute (LIMES) Development, Genetics & Molecular Physiology Unit, University of Bonn
Julian L. Griffin: Department of Biochemistry, University of Cambridge
Lee D. Roberts: University of Leeds

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract The endoplasmic reticulum (ER) regulates cellular protein and lipid biosynthesis. ER dysfunction leads to protein misfolding and the unfolded protein response (UPR), which limits protein synthesis to prevent cytotoxicity. Chronic ER stress in skeletal muscle is a unifying mechanism linking lipotoxicity to metabolic disease. Unidentified signals from cells undergoing ER stress propagate paracrine and systemic UPR activation. Here, we induce ER stress and lipotoxicity in myotubes. We observe ER stress-inducing lipid cell non-autonomous signal(s). Lipidomics identifies that palmitate-induced cell stress induces long-chain ceramide 40:1 and 42:1 secretion. Ceramide synthesis through the ceramide synthase 2 de novo pathway is regulated by UPR kinase Perk. Inactivation of CerS2 in mice reduces systemic and muscle ceramide signals and muscle UPR activation. The ceramides are packaged into extracellular vesicles, secreted and induce UPR activation in naïve myotubes through dihydroceramide accumulation. This study furthers our understanding of ER stress by identifying UPR-inducing cell non-autonomous signals.

Date: 2022
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DOI: 10.1038/s41467-022-29363-9

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