دورية أكاديمية
أعرض في EDS

Autophagic signaling promotes systems-wide remodeling in skeletal muscle upon oncometabolic stress by D2-HG.

التفاصيل البيبلوغرافية
العنوان: Autophagic signaling promotes systems-wide remodeling in skeletal muscle upon oncometabolic stress by D2-HG.
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.)
References: Trends Cancer. 2016 Sep;2(9):461-463. (PMID: 28459108)
Nat Chem Biol. 2017 May;13(5):494-500. (PMID: 28263965)
FASEB J. 2017 Jan;31(1):29-34. (PMID: 27682203)
J Vis Exp. 2013 Jun 02;(76):. (PMID: 23770643)
Nucleic Acids Res. 2019 Jan 8;47(D1):D607-D613. (PMID: 30476243)
Proc Natl Acad Sci U S A. 2016 Sep 13;113(37):10436-41. (PMID: 27582470)
Bioinformatics. 2008 Nov 1;24(21):2534-6. (PMID: 18606607)
Adv Exp Med Biol. 2017;1043:153-197. (PMID: 29224095)
Cancer Res. 2011 Mar 1;71(5):1710-20. (PMID: 21163868)
Cell Metab. 2015 Aug 4;22(2):304-11. (PMID: 26212717)
Proc Natl Acad Sci U S A. 2001 Dec 4;98(25):14440-5. (PMID: 11717410)
Nat Methods. 2007 Mar;4(3):207-14. (PMID: 17327847)
Lancet Oncol. 2011 May;12(5):489-95. (PMID: 21296615)
Cell Rep. 2016 Oct 18;17(4):1037-1052. (PMID: 27760311)
Behav Brain Res. 2001 Sep 28;124(1):33-46. (PMID: 11423164)
Nat Med. 2016 Oct;22(10):1120-1130. (PMID: 27571348)
Autophagy. 2014 May;10(5):930-2. (PMID: 24675140)
Cell Metab. 2023 Jul 11;35(7):1147-1162.e7. (PMID: 37311455)
J Endocrinol. 2015 Jun;225(3):135-45. (PMID: 25901042)
Sci Rep. 2019 Jul 12;9(1):10147. (PMID: 31300716)
Proteomics Clin Appl. 2014 Aug;8(7-8):578-589. (PMID: 24974818)
J Cell Physiol. 2019 Aug;234(10):18041-18052. (PMID: 30851071)
Nucleic Acids Res. 2019 Jan 8;47(D1):D590-D595. (PMID: 30321428)
Methods Mol Biol. 2007;357:87-90. (PMID: 17172681)
Circ Res. 2020 Jul 31;127(4):502-518. (PMID: 32366200)
J Physiol. 1986 Nov;380:441-51. (PMID: 3612570)
Cell Metab. 2017 Mar 7;25(3):572-579. (PMID: 28273479)
Cell Death Dis. 2014 Apr 17;5:e1179. (PMID: 24743734)
J Mol Cell Cardiol. 2015 Nov;88:64-72. (PMID: 26388263)
Hum Mutat. 2010 Mar;31(3):279-83. (PMID: 20020533)
Mol Cell. 2014 Mar 6;53(5):710-25. (PMID: 24560926)
Oxid Med Cell Longev. 2017;2017:3292087. (PMID: 28785374)
Nat Methods. 2012 Jun 28;9(7):676-82. (PMID: 22743772)
Acta Physiol Scand. 1987 Sep;131(1):119-27. (PMID: 3673605)
J Biol Chem. 2009 Mar 6;284(10):6322-8. (PMID: 19124466)
PLoS One. 2011;6(7):e22304. (PMID: 21829455)
Mol Metab. 2024 Jan;79:101857. (PMID: 38141850)
Clin Cancer Res. 2012 May 15;18(10):2817-27. (PMID: 22452944)
Mol Cell. 2015 Feb 5;57(3):456-66. (PMID: 25601754)
Aging (Albany NY). 2019 Jun 7;11(11):3418-3431. (PMID: 31173576)
Clin Nutr. 2008 Dec;27(6):793-9. (PMID: 18718696)
J Cell Biol. 2004 Dec 20;167(6):1147-59. (PMID: 15596539)
Blood. 2013 Jun 13;121(24):4917-24. (PMID: 23641016)
Genome Res. 2003 Nov;13(11):2498-504. (PMID: 14597658)
Nucleic Acids Res. 2020 Jan 8;48(D1):D498-D503. (PMID: 31691815)
Mol Oncol. 2024 Feb 27;:. (PMID: 38414161)
Nucleic Acids Res. 2004 Jan 1;32(Database issue):D115-9. (PMID: 14681372)
Genome Biol. 2004;5(10):R80. (PMID: 15461798)
Theor Biol Med Model. 2015 Sep 15;12:17. (PMID: 26370269)
Cell Metab. 2010 Mar 3;11(3):213-9. (PMID: 20197054)
BMC Bioinformatics. 2012 May 16;13:99. (PMID: 22591066)
Mol Cell. 2018 Feb 15;69(4):581-593.e7. (PMID: 29452638)
Nucleic Acids Res. 2019 Jan 8;47(D1):D442-D450. (PMID: 30395289)
Behav Res Methods. 2007 May;39(2):175-91. (PMID: 17695343)
Acta Physiol Scand. 2004 Jun;181(2):173-81. (PMID: 15180789)
Science. 2001 Nov 23;294(5547):1704-8. (PMID: 11679633)
Protein Sci. 2019 Nov;28(11):1947-1951. (PMID: 31441146)
Science. 2010 Oct 15;330(6002):336. (PMID: 20847235)
Biochem Biophys Res Commun. 2008 Oct 31;375(4):576-80. (PMID: 18722353)
Bioinformatics. 2004 Jun 12;20(9):1466-7. (PMID: 14976030)
Med Sci Sports Exerc. 2012 Sep;44(9):1653-62. (PMID: 22525764)
Proteomics. 2013 Jan;13(1):22-4. (PMID: 23148064)
Bioelectrochemistry. 2010 Oct;79(2):173-8. (PMID: 20413350)
J Inherit Metab Dis. 2012 Jul;35(4):571-87. (PMID: 22391998)
Nat Med. 2023 Jun;29(6):1358-1363. (PMID: 37248298)
Nat Methods. 2015 Feb;12(2):115-21. (PMID: 25633503)
Science. 2012 Apr 27;336(6080):474-7. (PMID: 22539722)
Nucleic Acids Res. 2000 Jan 1;28(1):27-30. (PMID: 10592173)
Autophagy. 2021 May;17(5):1157-1169. (PMID: 32264736)
BMC Syst Biol. 2012 Aug 29;6:114. (PMID: 22929619)
Cell Struct Funct. 1998 Feb;23(1):33-42. (PMID: 9639028)
Cancer Med. 2018 Aug;7(8):3695-3703. (PMID: 29971962)
Mol Cell. 2008 Nov 7;32(3):449-55. (PMID: 18995842)
Curr Opin Support Palliat Care. 2018 Dec;12(4):394-403. (PMID: 30102621)
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
الوصف
تدمد:2212-8778
DOI:10.1016/j.molmet.2024.101969