دورية أكاديمية
Autophagic signaling promotes systems-wide remodeling in skeletal muscle upon oncometabolic stress by D2-HG.
العنوان: | Autophagic signaling promotes systems-wide remodeling in skeletal muscle upon oncometabolic stress by D2-HG. |
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المؤلفون: | Gao Y; Department of Cardiology, Smidt Heart Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA., Kim K; Department of Cardiology, Smidt Heart Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA., Vitrac H; Department of Biochemistry, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Bruker Daltonics, Billerica, MA, USA., Salazar RL; Department of Internal Medicine, Division of Cardiology, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, TX 77030, USA., Gould BD; Department of Internal Medicine, Division of Cardiology, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, TX 77030, USA., Soedkamp D; Department of Cardiology, Smidt Heart Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA; Advanced Clinical Biosystems Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA., Spivia W; Department of Cardiology, Smidt Heart Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA; Advanced Clinical Biosystems Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA., Raedschelders K; Department of Cardiology, Smidt Heart Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA; Advanced Clinical Biosystems Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA., Dinh AQ; Center for Infectious Diseases, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA., Guzman AG; Center for Stem Cell and Regeneration, Baylor College of Medicine, Houston, TX, 77030, USA., Tan L; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77054, USA., Azinas S; Department of Biochemistry, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Department of Cell and Molecular Biology, Uppsala University, Sweden., Taylor DJR; Department of Cardiology, Smidt Heart Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA., Schiffer W; Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, 27101, USA., McNavish D; Department of Internal Medicine, Division of Cardiology, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, TX 77030, USA., Burks HB; Department of Internal Medicine, Division of Cardiology, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, TX 77030, USA., Gottlieb RA; Department of Cardiology, Smidt Heart Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA., Lorenzi PL; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77054, USA., Hanson BM; Center for Infectious Diseases, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA., Van Eyk JE; Advanced Clinical Biosystems Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA., Taegtmeyer H; Department of Biochemistry, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, TX 77030, USA., Karlstaedt A; Department of Cardiology, Smidt Heart Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA. Electronic address: anja.karlstaedt@csmc.edu. |
المصدر: | Molecular metabolism [Mol Metab] 2024 Aug; Vol. 86, pp. 101969. Date of Electronic Publication: 2024 Jun 21. |
نوع المنشور: | Journal Article |
اللغة: | English |
بيانات الدورية: | Publisher: Elsevier GmbH Country of Publication: Germany NLM ID: 101605730 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2212-8778 (Electronic) Linking ISSN: 22128778 NLM ISO Abbreviation: Mol Metab Subsets: MEDLINE |
أسماء مطبوعة: | Original Publication: [München] : Elsevier GmbH, 2012- |
مواضيع طبية MeSH: | Muscle, Skeletal*/metabolism , Autophagy* , Signal Transduction* , Glutarates*/metabolism, Animals ; Mice ; Male ; Isocitrate Dehydrogenase/metabolism ; Isocitrate Dehydrogenase/genetics ; Cachexia/metabolism ; Female ; Sirtuin 1/metabolism ; Sirtuin 1/genetics ; Mice, Inbred C57BL |
مستخلص: | Objectives: 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. Methods: We quantified genomic, metabolomic, and proteomic changes in cultured skeletal muscle cells and mouse models of IDH-mutant leukemia using RNA sequencing, mass spectrometry, and computational modeling. Results: D2-HG impairs NADH redox homeostasis in myotubes. Increased NAD+ levels drive activation of nuclear deacetylase Sirt1, which causes deacetylation and activation of LC3, a key regulator of autophagy. Using LC3 mutants, we confirm that deacetylation of LC3 by Sirt1 shifts its distribution from the nucleus into the cytosol, where it can undergo lipidation at pre-autophagic membranes. Sirt1 silencing or p300 overexpression attenuated autophagy activation in myotubes. In vivo, we identified increased muscle atrophy and reduced grip strength in response to D2-HG in male vs. female mice. In male mice, glycolytic intermediates accumulated, and protein expression of oxidative phosphorylation machinery was reduced. In contrast, female animals upregulated the same proteins, attenuating the phenotype in vivo. Network modeling and machine learning algorithms allowed us to identify candidate proteins essential for regulating oncometabolic adaptation in mouse skeletal muscle. Conclusions: 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 Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Copyright © 2024 The Author(s). Published by Elsevier GmbH.. All rights reserved.) |
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فهرسة مساهمة: | Keywords: Autophagy; Cachexia; Oncometabolism; Systems biology |
المشرفين على المادة: | 2889-31-8 (alpha-hydroxyglutarate) 0 (Glutarates) EC 1.1.1.41 (Isocitrate Dehydrogenase) EC 3.5.1.- (Sirtuin 1) EC 1.1.1.41 (isocitrate dehydrogenase 2, mouse) |
تواريخ الأحداث: | Date Created: 20240622 Date Completed: 20240720 Latest Revision: 20240728 |
رمز التحديث: | 20240728 |
مُعرف محوري في PubMed: | PMC11278897 |
DOI: | 10.1016/j.molmet.2024.101969 |
PMID: | 38908793 |
قاعدة البيانات: | MEDLINE |
تدمد: | 2212-8778 |
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DOI: | 10.1016/j.molmet.2024.101969 |