title: IGF-IR signaling attenuates the age-related decline of diastolic cardiac function.
abstract: Insulin-like growth factor (IGF-I) signaling has been implicated to play an important role in regulation of cardiac growth, hypertrophy, and contractile function and has been linked to the development of age-related congestive heart failure. Here, we address the question to what extent cardiomyocyte-specific IGF-I signaling is essential for maintenance of the structural and functional integrity of the adult murine heart. To investigate the effects of IGF-I signaling in the adult heart without confounding effects due to IGF-I overexpression or adaptation during embryonic and early postnatal development, we inactivated the IGF-I receptor (IGF-IR) by a 4-hydroxytamoxifen-inducible Cre recombinase in adult cardiac myocytes. Efficient inactivation of the IGF-IR (iCMIGF-IRKO) as assessed by Western analysis and real-time PCR went along with reduced IGF-I-dependent Akt and GSK3β phosphorylation. Functional analysis by conductance manometry and MRI revealed no functional alterations in young adult iCMIGF-IRKO mice (age 3 mo). However, when induced in aging mice (11 mo) diastolic cardiac function was depressed. To address the question whether insulin signaling might compensate for the defective IGF-IR signaling, we inactivated β-cells by streptozotocin. However, the diabetes-associated functional depression was similar in control and iCMIGF-IRKO mice. Similarly, analysis of the cardiac gene expression profile on 44K microarrays did not reveal activation of overt adaptive processes. Endogenous IGF-IR signaling is required for conservation of cardiac function of the aging heart, but not for the integrity of cardiac structure and function of young hearts.
authors.affiliation: Institut für Herz- und Kreislaufphysiologie, Universitätsklinikum, Heinrich-Heine-Universität Düsseldorf, Dusseldorf, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Moellendorf
authors.forename: Claudia
authors.initials: C
authors.lastname: Kessels
authors.forename: Lena
authors.initials: L
authors.lastname: Peiseler
authors.forename: Annika
authors.initials: A
authors.lastname: Raupach
authors.forename: Christoph
authors.initials: C
authors.lastname: Jacoby
authors.forename: Nora
authors.initials: N
authors.lastname: Vogt
authors.forename: Antje
authors.initials: A
authors.lastname: Lindecke
authors.forename: Linda
authors.initials: L
authors.lastname: Koch
authors.forename: Jens
authors.initials: J
authors.lastname: Brüning
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Heger
authors.forename: Karl
authors.initials: K
authors.lastname: Köhrer
authors.forename: Axel
authors.initials: A
authors.lastname: Gödecke
mesh_terms: D000222:Adaptation, Physiological; D000375:Aging / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology; D020869:Gene Expression Profiling; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006321:Heart / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000502:physiology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D017526:Receptor, IGF Type 1; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3