Autophagic signaling promotes systems-wide remodeling in skeletal muscle upon oncometabolic stress
Autophagic signaling promotes systems-wide remodeling in skeletal muscle upon oncometabolic stress
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.
Burks Helen B.、Tan Lin、Taegtmeyer Heinrich、Karlstaedt Anja、Salazar Rebecca L.、Raedschelders Koen、Schiffer Walter、McNavish Daniel、Gottlieb Roberta A.、Hanson Blake M.、Vitrac Heidi、Dinh An Q.、Soetkamp Daniel、Lorenzi Philip L.、Taylor David J.R.、Azinas Stavros、Spivia Weston、Gould Benjamin D.、Guzman Anna G.、Van Eyk Jennifer E.
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer CenterDepartment of Internal Medicine, Division of Cardiology, McGovern Medical School at The University of Texas Health Science Center at HoustonDepartment of Internal Medicine, Division of Cardiology, McGovern Medical School at The University of Texas Health Science Center at Houston||Department of Cardiology, Smidt Heart Institute, Cedars Sinai Medical CenterDepartment of Internal Medicine, Division of Cardiology, McGovern Medical School at The University of Texas Health Science Center at HoustonAdvanced Clinical Biosystems Research Institute, The Smidt Heart Institute, Cedars-Sinai Medical CenterDepartment of Internal Medicine, Washington University School of Medicine in St. LouisDepartment of Internal Medicine, Wake Forest School of MedicineDepartment of Cardiology, The Smidt Heart Institute, Cedars-Sinai Medical CenterCenter for Infectious Diseases, School of Public Health, The University of Texas Health Science Center at HoustonTosoh Bioscience LLCCenter for Infectious Diseases, School of Public Health, The University of Texas Health Science Center at HoustonAdvanced Clinical Biosystems Research Institute, The Smidt Heart Institute, Cedars-Sinai Medical CenterDepartment of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer CenterDepartment of Cardiology, The Smidt Heart Institute, Cedars-Sinai Medical CenterDepartment of Cell and Molecular biology, Uppsala UniversityAdvanced Clinical Biosystems Research Institute, The Smidt Heart Institute, Cedars-Sinai Medical CenterDepartment of Internal Medicine, Division of Cardiology, McGovern Medical School at The University of Texas Health Science Center at HoustonCenter for Stem Cell and Regeneration, Baylor College of MedicineAdvanced Clinical Biosystems Research Institute, The Smidt Heart Institute, Cedars-Sinai Medical Center
基础医学肿瘤学生物化学
OncometabolismAutophagyCachexiaSystems BiologyMetabolic adaptation
Burks Helen B.,Tan Lin,Taegtmeyer Heinrich,Karlstaedt Anja,Salazar Rebecca L.,Raedschelders Koen,Schiffer Walter,McNavish Daniel,Gottlieb Roberta A.,Hanson Blake M.,Vitrac Heidi,Dinh An Q.,Soetkamp Daniel,Lorenzi Philip L.,Taylor David J.R.,Azinas Stavros,Spivia Weston,Gould Benjamin D.,Guzman Anna G.,Van Eyk Jennifer E..Autophagic signaling promotes systems-wide remodeling in skeletal muscle upon oncometabolic stress[EB/OL].(2025-03-28)[2025-05-22].https://www.biorxiv.org/content/10.1101/2020.10.13.338202.点此复制
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