Unknown,Transcriptomics,Genomics,Proteomics

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IGF1-receptor signalling attenuates the age-related decline of diastolic cardiac function

ABSTRACT: Insulin-like growth factor (IGF1R) signalling 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 IGF1 signalling is essential for maintenance of the structural and functional integrity of the adult murine heart. To investigate the effects of IGF1 signalling in the adult heart without confounding effects due to IGF1 over-expression or adaptation during embryonic and early post-natal development, we inactivated the IGF1R by a 4-hydroxy tamoxifen inducible Cre recombinase in adult cardiac myocytes. Efficient inactivation of the IGF1R (iCMIGF1RKO) as assessed by Western analysis and real-time PCR went along with reduced IGF1-dependent AKT and GSK3Î²-phosphorylation. Functional analysis by conductance manometry and magnetic resonance imaging (MRI) revealed no functional alterations in young adult iCMIGF1RKO mice (age 3 month). However, when induced in aged mice (11 month) diastolic cardiac function was depressed. To address the question if insulin signalling might compensate for the defective IGF1R signalling we inactivated Î²-cells by streptozotocin. However, the diabetes associated functional depression was similar in controls and iCMIGF1RKO mice. Similarly, analysis of the cardiac gene expression profile on 44K microarrays did not reveal activation of overt adaptive processes. Endogenous IGF1 receptor signalling is required for conservation of cardiac function of the aging heart, but not for the integrity of cardiac structure and function of young hearts. Four samples of each group: the control group, positive for Cre recombinase, but negative for the floxed IGF-1R and the experimental group with double transgenic mice (merCremer/+ IGFloxP/IGFloxP).

ORGANISM(S): Mus musculus

SUBMITTER: Antje Lindecke

PROVIDER: E-GEOD-32936 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:The abstract of the manuscript titled "Signalling pathways involved in adult heart formation revealed by gene expression profiling in Drosophila" is given below: "Drosophila provides a powerful system for defining the complex genetic programs that drive organogenesis. Under control of the steroid hormone ecdysone, the adult heart in Drosophila forms during metamorphosis by a remodelling of the larval cardiac organ. Here, we evaluated the extent to which transcriptional signatures revealed by genomic approaches can provide new insights into the molecular pathways that underlie heart organogenesis. Whole-genome expression profiling at 8 successive time-points covering adult heart formation revealed a highly dynamic temporal map of gene expression through 13 transcript clusters with distinct expression kinetics. A functional atlas of the transcriptome profile strikingly points to the genomic transcriptional response of the ecdysone cascade, and a sharp regulation of key components belonging to a few evolutionary conserved signalling pathways. A reverse genetic analysis provided evidence that these specific signalling pathways are involved in discrete steps of adult heart formation. In particular, the Wnt signalling pathway is shown to participate in inflow tract and cardiomyocyte differentiation, while activation of the PDGF-VEGF pathway is required for cardiac valve formation. Thus, a detailed temporal map of gene expression can reveal signalling pathways responsible for specific developmental programs and provides here substantial grasp into heart formation." Keywords: Time-course analysis Total RNAs were prepared from dissected cardiac tubes of Drosophila staged pupae at 8 successive time-points 21, 24, 27, 30, 33, 36, 42 and 48 hours after puparium formation covering adult heart organogenesis. For each time-point sample, 5 cardiac tubes were hand dissected from staged individuals. Four independent biological replicates were analyzed to confer a high reproducibility and statistical significance of the expression data. PolyA+ RNAs were linearly amplified (32 amplifications), labelled (32 with Cy3 and 32 with Cy5), and used for hybridization on Drosophila high-density oligonucleotide (INDAC) dual-channel microarrays (32 arrays) according to a loop-design dedicated to time-course experiments. Given the same number of arrays (8), a simple loop design is more efficient than a reference design: direct comparisons, smallest variance for log ratios, balancing varieties with dye-swapping (including technical replicates) and no reference sample needed (which has no intrinsic interest in our study). A graphical representation of the loop design used on this study is showed in the associated manuscript.

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IGF1-receptor signalling attenuates the age-related decline of diastolic cardiac function

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