title: FoxO3 induces reversible cardiac atrophy and autophagy in a transgenic mouse model.
abstract: OBJECTIVE
  The transcription factor FoxO3 contributes to anti-hypertrophic signalling in the heart presumably by regulating autophagic-lysosomal and ubiquitin-proteasomal pathways. We wanted to study FoxO3 function in the adult heart in vivo by expressing a constitutively active mutant of FoxO3 in transgenic mice.
  
  
  RESULTS
  We generated transgenic mice in which a tetracycline-regulated constitutively active FoxO3 transgene (FoxO3-CA) is controlled by the heart-specific α-myosin heavy chain promoter. Cardiac-specific expression in adult mice resulted in a decrease in heart weight by 25% and a reduction in stroke volume and cardiac output. The decrease in heart size was due to a reduction in the size of individual cardiomyocytes, whereas there was no evidence for increased cell death. FoxO3 activation was accompanied by the initiation of a foetal gene programme with increased expression of β-myosin heavy chain and natriuretic peptides, and by the activation of AKT and mammalian target of rapamycin signalling. As shown by electron microscopy, FoxO3-CA massively stimulated destruction of sarcomeres and autophagy, and induced expression of LC3-II and BNIP3. When FoxO3-CA expression was shut off in affected mice, cardiac atrophy and dysfunction as well as molecular markers were normalized within 1 month. FoxO3-CA expression did not counteract hypertrophy induced by transverse aortic constriction.
  
  
  CONCLUSIONS
  Heart-specific expression of constitutively active FoxO3 leads to reversible heart atrophy. The reversibility of the phenotype suggests a remarkable ability of the adult myocardium to respond to different regulatory cues.
authors.affiliation: Institute of Physiological Chemistry, University of Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany.
authors.forename: Tobias G
authors.initials: TG
authors.lastname: Schips
authors.forename: Astrid
authors.initials: A
authors.lastname: Wietelmann
authors.forename: Katharina
authors.initials: K
authors.lastname: Höhn
authors.forename: Silvia
authors.initials: S
authors.lastname: Schimanski
authors.forename: Paul
authors.initials: P
authors.lastname: Walther
authors.forename: Thomas
authors.initials: T
authors.lastname: Braun
authors.forename: Thomas
authors.initials: T
authors.lastname: Wirth
authors.forename: Harald J
authors.initials: HJ
authors.lastname: Maier
mesh_terms: D000818:Animals; D001284:Atrophy; D001343:Autophagy; D001835:Body Weight; D004195:Disease Models, Animal; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000473:pathology; D009929:Organ Size; D010641:Phenotype; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000502:physiology; D020257:Ventricular Remodeling
chemical_list: D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases