| Autor: |
Walter Schiffer, David J. R. Taylor, Daniel Soetkamp, Benjamin D. Gould, Jennifer E. Van Eyk, Anna Guzman, Weston R. Spivia, Lin Tan, Heinrich Taegtmeyer, Helen B. Burks, Blake Hanson, Anja Karlstaedt, Heidi Vitrac, Philip L. Lorenzi, Rebecca Salazar, Daniel McNavish, An Q Dinh, Roberta A. Gottlieb, Koen Raedschelders, Stavros Azinas |
| Rok vydání: |
2020 |
| Předmět: |
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| Popis: |
About 20-30% of cancer-associated deaths are due to complications from cachexia which is characterized by skeletal muscle atrophy. Metabolic reprogramming in cancer cells causes body-wide metabolic and proteomic remodeling, which remain poorly understood. Here, we present evidence that the oncometabolite D-2-hydroxylgutarate (D2-HG) impairs NAD+ redox homeostasis in skeletal myotubes, causing atrophy via deacetylation of LC3-II by the nuclear deacetylase Sirt1. Overexpression of p300 or silencing of Sirt1 abrogate its interaction with LC3, and subsequently reduced levels of LC3 lipidation. Using RNA-sequencing and mass spectrometry-based metabolomics and proteomics, we demonstrate that prolonged treatment with the oncometabolite D2-HG in mice promotes cachexia in vivo and increases the abundance of proteins and metabolites, which are involved in energy substrate metabolism, chromatin acetylation and autophagy regulation. We further show that D2-HG promotes a sex-dependent adaptation in skeletal muscle using network modeling and machine learning algorithms. Our multi-omics approach exposes new metabolic vulnerabilities in response to D2-HG in skeletal muscle and provides a conceptual framework for identifying therapeutic targets in cachexia. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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