{"doi":"10.1101/2020.10.13.338202","title":"Autophagic signaling promotes systems-wide remodeling in skeletal muscle upon oncometabolic stress","abstract":"Abstract 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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":131283,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9584,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":118090,"name":"Heidi Vitrac","orcid":"0000-0002-8858-4914","position":1,"is_corresponding":false},{"id":585223,"name":"Rebecca Salazar","orcid":null,"position":2,"is_corresponding":false},{"id":584731,"name":"Benjamin D. Gould","orcid":"0000-0001-5822-4160","position":3,"is_corresponding":false},{"id":585224,"name":"Daniel Soedkamp","orcid":null,"position":4,"is_corresponding":false},{"id":419680,"name":"Weston Spivia","orcid":"0000-0003-2764-7763","position":5,"is_corresponding":false},{"id":584732,"name":"Koen Raedschelders","orcid":"0000-0003-0835-4762","position":6,"is_corresponding":false},{"id":232752,"name":"An Q Dinh","orcid":"0000-0002-2965-9269","position":7,"is_corresponding":false},{"id":377781,"name":"Anna Guzman","orcid":null,"position":8,"is_corresponding":false},{"id":270244,"name":"Lin Tan","orcid":"0000-0002-9400-1754","position":9,"is_corresponding":false},{"id":584733,"name":"Stavros Azinas","orcid":"0000-0002-3744-9229","position":10,"is_corresponding":false},{"id":372386,"name":"D. Taylor","orcid":"0000-0003-4240-0988","position":11,"is_corresponding":false},{"id":584734,"name":"Walter Schiffer","orcid":"0000-0002-2046-1993","position":12,"is_corresponding":false},{"id":584735,"name":"Daniel McNavish","orcid":"0000-0001-9394-7110","position":13,"is_corresponding":false},{"id":585225,"name":"Helen B. Burks","orcid":null,"position":14,"is_corresponding":false},{"id":372389,"name":"Roberta A. Gottlieb","orcid":"0000-0002-1432-006X","position":15,"is_corresponding":false},{"id":235977,"name":"Philip L. Lorenzi","orcid":"0000-0003-0385-7774","position":16,"is_corresponding":false},{"id":232743,"name":"Blake Hanson","orcid":"0000-0003-2949-7818","position":17,"is_corresponding":false},{"id":112291,"name":"Jennifer E. Van Eyk","orcid":"0000-0001-9050-148X","position":18,"is_corresponding":false},{"id":293959,"name":"Heinrich Taegtmeyer","orcid":"0000-0002-5434-6360","position":19,"is_corresponding":false},{"id":293950,"name":"Anja Karlstaedt","orcid":"0000-0001-5689-3571","position":0,"is_corresponding":true}],"reference_count":84,"raw_metadata":null,"created_at":"2026-07-18T23:16:00.235845Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}