biostudies-literatureGao YNIAID NIH HHSNHLBI NIH HHSAmerican Heart Association IncNational Institutes of HealthLeukemia Research FoundationNational Heart Lung and Blood InstituteUniversity of Texas MD Anderson Cancer CenterCancer Prevention and Research Institute of TexasCedars-Sinai Health SystemBurroughs Wellcome FundNational Cancer InstituteNCI NIH HHSNIH HHS101969https://www.ebi.ac.uk/biostudies/studies/S-EPMC11278897biostudies-literatureUnknown86<h4>Objectives</h4>Cachexia is a metabolic disorder and comorbidity with cancer and heart failure. The syndrome impacts more than thirty million people worldwide, accounting for 20% of all cancer deaths. In acute myeloid leukemia, somatic mutations of the metabolic enzyme isocitrate dehydrogenase 1 and 2 cause the production of the oncometabolite D2-hydroxyglutarate (D2-HG). Increased production of D2-HG is associated with heart and skeletal muscle atrophy, but the mechanistic links between metabolic and proteomic remodeling remain poorly understood. Therefore, we assessed how oncometabolic stress by D2-HG activates autophagy and drives skeletal muscle loss.<h4>Methods</h4>We quantified genomic, metabolomic, and proteomic changes in cultured skeletal muscle cells and mouse models of IDH-muMolecular metabolismAutophagic signaling promotes systems-wide remodeling in skeletal muscle upon oncometabolic stress by D2-HG.PMC11278897S10 OD01230417POST33660221R00 HL141702K01 AI148593K01-AI148593R00-HL-141702S10OD012304-01R01-HL132075R01-HL-06148315RDM005P30 CA016672RP130397R01-HL144509R01 HL132075R01 HL144509R01 HL061483U01 CA235510U01CA235510Tan LSalazar RLSpivia WVitrac HKarlstaedt ADinh AQLorenzi PLHanson BMRaedschelders KTaegtmeyer HKim KMcNavish DAzinas SGould BDBurks HBGottlieb RAGao YTaylor DJRSoedkamp DVan Eyk JEGuzman AGSchiffer WfalseAutophagic signaling promotes systems-wide remodeling in skeletal muscle upon oncometabolic stress by D2-HG.<h4>Objectives</h4>Cachexia is a metabolic disorder and comorbidity with cancer and heart failure. The syndrome impacts more than thirty million people worldwide, accounting for 20% of all cancer deaths. In acute myeloid leukemia, somatic mutations of the metabolic enzyme isocitrate dehydrogenase 1 and 2 cause the production of the oncometabolite D2-hydroxyglutarate (D2-HG). Increased production of D2-HG is associated with heart and skeletal muscle atrophy, but the mechanistic links between metabolic and proteomic remodeling remain poorly understood. Therefore, we assessed how oncometabolic stress by D2-HG activates autophagy and drives skeletal muscle loss.<h4>Methods</h4>We quantified genomic, metabolomic, and proteomic changes in cultured skeletal muscle cells and mouse models of IDH-mu2024-01-01T00:00:00Z2024 Aug2026-06-01T09:02:17.989Z2025-08-31T03:05:22.251ZS-EPMC112788973890879310.1016/j.molmet.2024.101969