title: Repetitive stimulation of autophagy-lysosome machinery by intermittent fasting preconditions the myocardium to ischemia-reperfusion injury.
abstract: Autophagy, a lysosomal degradative pathway, is potently stimulated in the myocardium by fasting and is essential for maintaining cardiac function during prolonged starvation. We tested the hypothesis that intermittent fasting protects against myocardial ischemia-reperfusion injury via transcriptional stimulation of the autophagy-lysosome machinery. Adult C57BL/6 mice subjected to 24-h periods of fasting, every other day, for 6 wk were protected from in-vivo ischemia-reperfusion injury on a fed day, with marked reduction in infarct size in both sexes as compared with nonfasted controls. This protection was lost in mice heterozygous null for Lamp2 (coding for lysosomal-associated membrane protein 2), which demonstrate impaired autophagy in response to fasting with accumulation of autophagosomes and SQSTM1, an autophagy substrate, in the heart. In lamp2 null mice, intermittent fasting provoked progressive left ventricular dilation, systolic dysfunction and hypertrophy; worsening cardiomyocyte autophagosome accumulation and lack of protection to ischemia-reperfusion injury, suggesting that intact autophagy-lysosome machinery is essential for myocardial homeostasis during intermittent fasting and consequent ischemic cardioprotection. Fasting and refeeding cycles resulted in transcriptional induction followed by downregulation of autophagy-lysosome genes in the myocardium. This was coupled with fasting-induced nuclear translocation of TFEB (transcription factor EB), a master regulator of autophagy-lysosome machinery; followed by rapid decline in nuclear TFEB levels with refeeding. Endogenous TFEB was essential for attenuation of hypoxia-reoxygenation-induced cell death by repetitive starvation, in neonatal rat cardiomyocytes, in-vitro. Taken together, these data suggest that TFEB-mediated transcriptional priming of the autophagy-lysosome machinery mediates the beneficial effects of fasting-induced autophagy in myocardial ischemia-reperfusion injury.
authors.affiliation: a Division of Cardiology and Center for Cardiovascular Research ; Department of Internal Medicine; Washington University School of Medicine ; St. Louis , MO USA.|b John Cochran VA Medical Center ; St. Louis , MO USA.
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Godar
authors.affiliation: a Division of Cardiology and Center for Cardiovascular Research ; Department of Internal Medicine; Washington University School of Medicine ; St. Louis , MO USA.|b John Cochran VA Medical Center ; St. Louis , MO USA.
authors.forename: Xiucui
authors.initials: X
authors.lastname: Ma
authors.affiliation: a Division of Cardiology and Center for Cardiovascular Research ; Department of Internal Medicine; Washington University School of Medicine ; St. Louis , MO USA.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Liu
authors.affiliation: a Division of Cardiology and Center for Cardiovascular Research ; Department of Internal Medicine; Washington University School of Medicine ; St. Louis , MO USA.
authors.forename: John T
authors.initials: JT
authors.lastname: Murphy
authors.affiliation: a Division of Cardiology and Center for Cardiovascular Research ; Department of Internal Medicine; Washington University School of Medicine ; St. Louis , MO USA.
authors.forename: Carla J
authors.initials: CJ
authors.lastname: Weinheimer
authors.affiliation: a Division of Cardiology and Center for Cardiovascular Research ; Department of Internal Medicine; Washington University School of Medicine ; St. Louis , MO USA.
authors.forename: Attila
authors.initials: A
authors.lastname: Kovacs
authors.affiliation: c Department of Genetics ; Washington University School of Medicine ; St. Louis , MO USA.
authors.forename: Seth D
authors.initials: SD
authors.lastname: Crosby
authors.affiliation: d Institut für Biochemie; Christian-Albrechts-Universität zu Kiel ; Kiel , Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Saftig
authors.affiliation: a Division of Cardiology and Center for Cardiovascular Research ; Department of Internal Medicine; Washington University School of Medicine ; St. Louis , MO USA.|b John Cochran VA Medical Center ; St. Louis , MO USA.
authors.forename: Abhinav
authors.initials: A
authors.lastname: Diwan
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D015687:Cell Hypoxia / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D005215:Fasting; D005247:Feeding Behavior; D005260:Female; D063990:Gene Ontology; D006579:Heterozygote; D052119:Lysosomal-Associated Membrane Protein 2 / Q000378:metabolism; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000000981:diagnostic imaging / Q000473:pathology* / Q000503:physiopathology / Q000517:prevention & control; D009206:Myocardium / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D010100:Oxygen / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014463:Ultrasonography; D015854:Up-Regulation / Q000187:drug effects; D020257:Ventricular Remodeling
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D052119:Lysosomal-Associated Membrane Protein 2; D017382:Reactive Oxygen Species; C484068:Tcfeb protein, mouse; D010100:Oxygen
keywords: autophagy; fasting; ischemia-reperfusion; lysosome; myocardial infarction