FoxO3 induces reversible cardiac atrophy and autophagy in a transgenic mouse model

• Published in: Cardiovascular research 2011-09, Vol.91 (4), p.587-597
• Main Authors: SCHIPS, Tobias G, WIETELMANN, Astrid, HÖHN, Katharina, SCHIMANSKI, Silvia, WALTHER, Paul, BRAUN, Thomas, WIRTH, Thomas, MAIER, Harald J
• Format: Article
• Language: English
• Subjects: Animals; Atrophy; Autophagy; Biological and medical sciences; Body Weight; Cardiology. Vascular system; Disease Models, Animal; Forkhead Box Protein O3; Forkhead Transcription Factors - physiology; Medical sciences; Mice; Mice, Transgenic; Myocardium - pathology; Myocytes, Cardiac - pathology; Organ Size; Phenotype; Proto-Oncogene Proteins c-akt - physiology; Signal Transduction; TOR Serine-Threonine Kinases - physiology; Ventricular Remodeling
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1093/cvr/cvr144

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. 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. 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.