title: Improvement of cardiac functions by chronic metformin treatment is associated with enhanced cardiac autophagy in diabetic OVE26 mice.
abstract: OBJECTIVE
  Autophagy is a critical cellular system for removal of aggregated proteins and damaged organelles. Although dysregulated autophagy is implicated in the development of heart failure, the role of autophagy in the development of diabetic cardiomyopathy has not been studied. We investigated whether chronic activation of the AMP-activated protein kinase (AMPK) by metformin restores cardiac function and cardiomyocyte autophagy in OVE26 diabetic mice.
  
  
  METHODS
  OVE26 mice and cardiac-specific AMPK dominant negative transgenic (DN)-AMPK diabetic mice were treated with metformin or vehicle for 4 months, and cardiac autophagy, cardiac functions, and cardiomyocyte apoptosis were monitored.
  
  
  RESULTS
  Compared with control mice, diabetic OVE26 mice exhibited a significant reduction of AMPK activity in parallel with reduced cardiomyocyte autophagy and cardiac dysfunction in vivo and in isolated hearts. Furthermore, diabetic OVE26 mouse hearts exhibited aggregation of chaotically distributed mitochondria between poorly organized myofibrils and increased polyubiquitinated protein and apoptosis. Inhibition of AMPK by overexpression of a cardiac-specific DN-AMPK gene reduced cardiomyocyte autophagy, exacerbated cardiac dysfunctions, and increased mortality in diabetic mice. Finally, chronic metformin therapy significantly enhanced autophagic activity and preserved cardiac functions in diabetic OVE26 mice but not in DN-AMPK diabetic mice.
  
  
  CONCLUSIONS
  Decreased AMPK activity and subsequent reduction in cardiac autophagy are important events in the development of diabetic cardiomyopathy. Chronic AMPK activation by metformin prevents cardiomyopathy by upregulating autophagy activity in diabetic OVE26 mice. Thus, stimulation of AMPK may represent a novel approach to treat diabetic cardiomyopathy.
authors.affiliation: Section of Molecular Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA. zxie@ouhsc.edu
authors.forename: Zhonglin
authors.initials: Z
authors.lastname: Xie
authors.forename: Kai
authors.initials: K
authors.lastname: Lau
authors.forename: Bonnie
authors.initials: B
authors.lastname: Eby
authors.forename: Pedro
authors.initials: P
authors.lastname: Lozano
authors.forename: Chaoyong
authors.initials: C
authors.lastname: He
authors.forename: Becky
authors.initials: B
authors.lastname: Pennington
authors.forename: Hongliang
authors.initials: H
authors.lastname: Li
authors.forename: Shradha
authors.initials: S
authors.lastname: Rathi
authors.forename: Yunzhou
authors.initials: Y
authors.lastname: Dong
authors.forename: Rong
authors.initials: R
authors.lastname: Tian
authors.forename: David
authors.initials: D
authors.lastname: Kem
authors.forename: Ming-Hui
authors.initials: MH
authors.lastname: Zou
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000235:genetics / Q000502:physiology; D000071186:Beclin-1; D015153:Blotting, Western; D009202:Cardiomyopathies / Q000378:metabolism; D004452:Echocardiography; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D008687:Metformin / Q000627:therapeutic use*; D051379:Mice; D046529:Microscopy, Electron, Transmission; D009206:Myocardium / Q000166:cytology / Q000378:metabolism* / Q000648:ultrastructure; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000648:ultrastructure; D014402:Tuberous Sclerosis / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D007004:Hypoglycemic Agents; D008687:Metformin; C534978:Prkaa2 protein, mouse; D055372:AMP-Activated Protein Kinases