title: Dexamethasone-induced autophagy mediates muscle atrophy through mitochondrial clearance.
abstract: Glucocorticoids, such as dexamethasone, enhance protein breakdown via ubiquitin-proteasome system. However, the role of autophagy in organelle and protein turnover in the glucocorticoid-dependent atrophy program remains unknown. Here, we show that dexamethasone stimulates an early activation of autophagy in L6 myotubes depending on protein kinase, AMPK, and glucocorticoid receptor activity. Dexamethasone increases expression of several autophagy genes, including ATG5, LC3, BECN1, and SQSTM1 and triggers AMPK-dependent mitochondrial fragmentation associated with increased DNM1L protein levels. This process is required for mitophagy induced by dexamethasone. Inhibition of mitochondrial fragmentation by Mdivi-1 results in disrupted dexamethasone-induced autophagy/mitophagy. Furthermore, Mdivi-1 increases the expression of genes associated with the atrophy program, suggesting that mitophagy may serve as part of the quality control process in dexamethasone-treated L6 myotubes. Collectively, these data suggest a novel role for dexamethasone-induced autophagy/mitophagy in the regulation of the muscle atrophy program.
authors.affiliation: Advanced Center for Chronic Disease (ACCDiS); University of Chile; Santiago, Chile; Center for Molecular Studies of the Cell; Faculty of Chemical & Pharmaceutical Sciences & Faculty of Medicine; University of Chile; Santiago, Chile.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Troncoso
authors.affiliation: Advanced Center for Chronic Disease (ACCDiS); University of Chile; Santiago, Chile; Center for Molecular Studies of the Cell; Faculty of Chemical & Pharmaceutical Sciences & Faculty of Medicine; University of Chile; Santiago, Chile.
authors.forename: Felipe
authors.initials: F
authors.lastname: Paredes
authors.affiliation: Advanced Center for Chronic Disease (ACCDiS); University of Chile; Santiago, Chile; Center for Molecular Studies of the Cell; Faculty of Chemical & Pharmaceutical Sciences & Faculty of Medicine; University of Chile; Santiago, Chile; Department of Internal Medicine (Cardiology Division); University of Texas Southwestern Medical Center; Dallas, TX USA.
authors.forename: Valentina
authors.initials: V
authors.lastname: Parra
authors.affiliation: Advanced Center for Chronic Disease (ACCDiS); University of Chile; Santiago, Chile; Center for Molecular Studies of the Cell; Faculty of Chemical & Pharmaceutical Sciences & Faculty of Medicine; University of Chile; Santiago, Chile.
authors.forename: Damián
authors.initials: D
authors.lastname: Gatica
authors.affiliation: Advanced Center for Chronic Disease (ACCDiS); University of Chile; Santiago, Chile; Center for Molecular Studies of the Cell; Faculty of Chemical & Pharmaceutical Sciences & Faculty of Medicine; University of Chile; Santiago, Chile.
authors.forename: César
authors.initials: C
authors.lastname: Vásquez-Trincado
authors.affiliation: Advanced Center for Chronic Disease (ACCDiS); University of Chile; Santiago, Chile; Center for Molecular Studies of the Cell; Faculty of Chemical & Pharmaceutical Sciences & Faculty of Medicine; University of Chile; Santiago, Chile.
authors.forename: Clara
authors.initials: C
authors.lastname: Quiroga
authors.affiliation: Advanced Center for Chronic Disease (ACCDiS); University of Chile; Santiago, Chile; Center for Molecular Studies of the Cell; Faculty of Chemical & Pharmaceutical Sciences & Faculty of Medicine; University of Chile; Santiago, Chile.
authors.forename: Roberto
authors.initials: R
authors.lastname: Bravo-Sagua
authors.affiliation: Advanced Center for Chronic Disease (ACCDiS); University of Chile; Santiago, Chile; Center for Molecular Studies of the Cell; Faculty of Chemical & Pharmaceutical Sciences & Faculty of Medicine; University of Chile; Santiago, Chile.
authors.forename: Camila
authors.initials: C
authors.lastname: López-Crisosto
authors.affiliation: Advanced Center for Chronic Disease (ACCDiS); University of Chile; Santiago, Chile; Center for Molecular Studies of the Cell; Faculty of Chemical & Pharmaceutical Sciences & Faculty of Medicine; University of Chile; Santiago, Chile.
authors.forename: Andrea E
authors.initials: AE
authors.lastname: Rodriguez
authors.affiliation: Advanced Center for Chronic Disease (ACCDiS); University of Chile; Santiago, Chile; Center for Molecular Studies of the Cell; Faculty of Chemical & Pharmaceutical Sciences & Faculty of Medicine; University of Chile; Santiago, Chile.
authors.forename: Alejandra P
authors.initials: AP
authors.lastname: Oyarzún
authors.affiliation: Equipe 11 labellisée pas la Ligue Nationale contre le Cancer; INSERM; Centre de Recherche des Cordeliers; Paris, France; Metabolomics and Cell Biology Platforms; Institut Gustave Roussy; Villejuif, France; Pôle de Biologie; Hôpital Européen Georges Pompidou; AP-HP; Paris, France; Université Paris Descartes; Paris Sorbonne Cité; Paris, France.
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
authors.affiliation: Advanced Center for Chronic Disease (ACCDiS); University of Chile; Santiago, Chile; Center for Molecular Studies of the Cell; Faculty of Chemical & Pharmaceutical Sciences & Faculty of Medicine; University of Chile; Santiago, Chile; Department of Internal Medicine (Cardiology Division); University of Texas Southwestern Medical Center; Dallas, TX USA.
authors.forename: Sergio
authors.initials: S
authors.lastname: Lavandero
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; D002460:Cell Line; D003907:Dexamethasone / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D034281:Dynamins / Q000235:genetics / Q000378:metabolism; D005938:Glucocorticoids / Q000633:toxicity*; D006360:Heat-Shock Proteins / Q000172:deficiency / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008931:Mitochondria, Muscle / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D063306:Mitophagy / Q000187:drug effects; D018485:Muscle Fibers, Skeletal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009133:Muscular Atrophy / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D052999:Quinazolinones / Q000494:pharmacology; D034622:RNA Interference; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000819:agonists / Q000378:metabolism; D000071456:Sequestosome-1 Protein; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection
chemical_list: D055372:AMP-Activated Protein Kinases; D051017:Apoptosis Regulatory Proteins; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; D003907:Dexamethasone; D034281:Dynamins; D005938:Glucocorticoids; D006360:Heat-Shock Proteins; D008869:Microtubule-Associated Proteins; D011506:Proteins; D052999:Quinazolinones; D011965:Receptors, Glucocorticoid; D000071456:Sequestosome-1 Protein; C549041:3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone; C545865:Atg5 protein, rat; C512829:Becn1 protein, rat; C526109:Anxa3 protein, rat; C491079:Sqstm1 protein, rat; C519851:Dnm1l protein, rat
keywords: autophagy; dexamethasone; glucocorticoid; mitophagy; muscle atrophy