title: Macrophage migration inhibitory factor plays a permissive role in the maintenance of cardiac contractile function under starvation through regulation of autophagy.
abstract: OBJECTIVE
  The cytokine macrophage migration inhibitory factor (MIF) protects the heart through AMPK activation. Autophagy, a conserved pathway for bulk degradation of intracellular proteins and organelles, helps preserve and recycle energy and nutrients for cells to survive under starvation. This study was designed to examine the role of MIF in cardiac homeostasis and autophagy regulation following an acute starvation challenge.
  
  
  RESULTS
  Wild-type (WT) and MIF knockout mice were starved for 48 h. Echocardiographic data revealed little effect of starvation on cardiac geometry, contractile and intracellular Ca²⁺ properties. MIF deficiency unmasked an increase in left ventricular end-systolic diameter, a drop in fractional shortening associated with cardiomyocyte contractile and intracellular Ca²⁺ anomalies following starvation. Interestingly, the unfavourable effect of MIF deficiency was associated with interruption of starvation-induced autophagy. Furthermore, restoration of autophagy using rapamycin partially protected against starvation-induced cardiomyocyte contractile defects. In our in vitro model of starvation, neonatal mouse cardiomyocytes from WT and MIF-/- mice and H9C2 cells were treated with serum free-glucose free DMEM for 2 h. MIF depletion dramatically attenuated starvation-induced autophagic vacuole formation in neonatal mouse cardiomyocytes and exacerbated starvation-induced cell death in H9C2 cells.
  
  
  CONCLUSIONS
  In summary, these results indicate that MIF plays a permissive role in the maintenance of cardiac contractile function under starvation by regulation of autophagy.
authors.affiliation: Center for Cardiovascular Research and Alternative Medicine, School of Pharmacy, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA.
authors.forename: Xihui
authors.initials: X
authors.lastname: Xu
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Pacheco
authors.forename: Lin
authors.initials: L
authors.lastname: Leng
authors.forename: Richard
authors.initials: R
authors.lastname: Bucala
authors.forename: Jun
authors.initials: J
authors.lastname: Ren
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D019746:Intramolecular Oxidoreductases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008263:Macrophage Migration-Inhibitory Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D013217:Starvation / Q000000981:diagnostic imaging / Q000473:pathology* / Q000503:physiopathology*; D014463:Ultrasonography; D014617:Vacuoles / Q000473:pathology; D000099211:Phospholamban
chemical_list: D002118:Calcium; D002135:Calcium-Binding Proteins; D019746:Intramolecular Oxidoreductases; D008263:Macrophage Migration-Inhibitory Factors; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D020123:Sirolimus; D019831:Sodium-Calcium Exchanger; D000099211:Phospholamban; C076231:Mif protein, mouse; C506947:Atp2a2 protein, mouse
keywords: AMPK; Autophagy; MIF; Rapamycin; Starvation