RT Journal Article
SR Electronic
T1 Autophagic signaling promotes systems-wide remodeling in skeletal muscle upon oncometabolic stress
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.10.13.338202
DO 10.1101/2020.10.13.338202
A1 Anja Karlstaedt
A1 Heidi Vitrac
A1 Rebecca L. Salazar
A1 Benjamin D. Gould
A1 Daniel Soetkamp
A1 Weston Spivia
A1 Koen Raedschelders
A1 An Q. Dinh
A1 Anna G. Guzman
A1 Lin Tan
A1 Stavros Azinas
A1 David J.R. Taylor
A1 Walter Schiffer
A1 Daniel McNavish
A1 Helen B. Burks
A1 Roberta A. Gottlieb
A1 Philip L. Lorenzi
A1 Blake M. Hanson
A1 Jennifer E. Van Eyk
A1 Heinrich Taegtmeyer
YR 2021
UL http://biorxiv.org/content/early/2021/07/19/2020.10.13.338202.abstract
AB 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.Competing Interest StatementThe authors have declared no competing interest.