PT  - JOURNAL ARTICLE
AU  - Anja Karlstaedt
AU  - Heidi Vitrac
AU  - Rebecca L. Salazar
AU  - Benjamin D. Gould
AU  - Daniel Soedkamp
AU  - Weston Spivia
AU  - Koen Raedschelders
AU  - An Q. Dinh
AU  - Anna Guzman
AU  - Lin Tan
AU  - Stavros Azinas
AU  - David Taylor
AU  - Walter Schiffer
AU  - Daniel McNavish
AU  - Helen B. Burks
AU  - Roberta A. Gottlieb
AU  - Philip L. Lorenzi
AU  - Blake M. Hanson
AU  - Jennifer E. Van Eyk
AU  - Heinrich Taegtmeyer
TI  - Oncometabolism Drives Autophagy Activation in Skeletal Muscle
AID  - 10.1101/2020.10.13.338202
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.10.13.338202
4099  - http://biorxiv.org/content/early/2020/10/14/2020.10.13.338202.short
4100  - http://biorxiv.org/content/early/2020/10/14/2020.10.13.338202.full
AB  - Metabolic rewiring is a well-established feature of muscle cells and a hallmark of cancer. In isocitrate dehydrogenase 1 and 2 mutant tumors, increased production of the oncometabolite D-2-hydroxyglutarate (D2-HG) is associated with myopathy. The connection between metabolic changes and proteomic remodeling in skeletal muscle remains poorly understood. We demonstrate that D2-HG impairs NAD+ redox homeostasis in myocytes, causing activation of autophagy via de-acetylation of microtubule-associated protein 1 light chain 3-II (LC3-II) by the nuclear deacetylase Sirt1. We integrated multi-omics data from mice treated with D2-HG and demonstrate that autophagy activation leads to skeletal muscle atrophy and sex-dependent metabolic and proteomic remodeling. We also characterized protein and metabolite interactions linking energy-substrate metabolism with chromatin organization and autophagy regulation. Collectively, our multi-omics approach exposes mechanisms by which the oncometabolite D2-HG induces metabolic and proteomic remodeling in skeletal muscle, and provides a conceptual framework for identifying potential therapeutic targets in cachexia.Competing Interest StatementThe authors have declared no competing interest.