| Insulin-like growth factor I receptor signaling is required for exercise-induced cardiac hypertrophy. | |
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MedLine Citation:
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PMID: 18801929 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The receptors for IGF-I (IGF-IR) and insulin (IR) have been implicated in physiological cardiac growth, but it is unknown whether IGF-IR or IR signaling are critically required. We generated mice with cardiomyocyte-specific knockout of IGF-IR (CIGF1RKO) and compared them with cardiomyocyte-specific insulin receptor knockout (CIRKO) mice in response to 5 wk exercise swim training. Cardiac development was normal in CIGF1RKO mice, but the hypertrophic response to exercise was prevented. In contrast, despite reduced baseline heart size, the hypertrophic response of CIRKO hearts to exercise was preserved. Exercise increased IGF-IR content in control and CIRKO hearts. Akt phosphorylation increased in exercise-trained control and CIRKO hearts and, surprisingly, in CIGF1RKO hearts as well. In exercise-trained control and CIRKO mice, expression of peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) and glycogen content were both increased but were unchanged in trained CIGF1RKO mice. Activation of AMP-activated protein kinase (AMPK) and its downstream target eukaryotic elongation factor-2 was increased in exercise-trained CIGF1RKO but not in CIRKO or control hearts. In cultured neonatal rat cardiomyocytes, activation of AMPK with 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) prevented IGF-I/insulin-induced cardiomyocyte hypertrophy. These studies identify an essential role for IGF-IR in mediating physiological cardiomyocyte hypertrophy. IGF-IR deficiency promotes energetic stress in response to exercise, thereby activating AMPK, which leads to phosphorylation of eukaryotic elongation factor-2. These signaling events antagonize Akt signaling, which although necessary for mediating physiological cardiac hypertrophy, is insufficient to promote cardiac hypertrophy in the absence of myocardial IGF-I signaling. |
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Authors:
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Jaetaek Kim; Adam R Wende; Sandra Sena; Heather A Theobald; Jamie Soto; Crystal Sloan; Benjamin E Wayment; Sheldon E Litwin; Martin Holzenberger; Derek LeRoith; E Dale Abel |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2008-09-18 |
Journal Detail:
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Title: Molecular endocrinology (Baltimore, Md.) Volume: 22 ISSN: 0888-8809 ISO Abbreviation: Mol. Endocrinol. Publication Date: 2008 Nov |
Date Detail:
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Created Date: 2008-10-28 Completed Date: 2009-06-11 Revised Date: 2011-05-05 |
Medline Journal Info:
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Nlm Unique ID: 8801431 Medline TA: Mol Endocrinol Country: United States |
Other Details:
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Languages: eng Pagination: 2531-43 Citation Subset: IM |
Affiliation:
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Program in Human Molecular Biology and Genetics, University of Utah, Salt Lake City, Utah 84112, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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AMP-Activated Protein Kinases
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metabolism Aminoimidazole Carboxamide / analogs & derivatives, pharmacology Animals Cardiomegaly / etiology*, pathology, physiopathology* Cell Enlargement / drug effects Cells, Cultured Male Mice Mice, Knockout Models, Cardiovascular Myocardial Contraction Myocytes, Cardiac / cytology, drug effects, metabolism Peptide Elongation Factor 2 / metabolism Physical Exertion Proto-Oncogene Proteins c-akt / metabolism Rats Receptor, IGF Type 1 / deficiency, genetics, physiology* Receptor, Insulin / deficiency, genetics, physiology Ribonucleotides / pharmacology Signal Transduction Swimming |
| Grant Support | |
ID/Acronym/Agency:
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5T32 HL007576/HL/NHLBI NIH HHS; R01 DK092065-07/DK/NIDDK NIH HHS; R01HL070070/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Peptide Elongation Factor 2; 0/Ribonucleotides; 3031-94-5/AICA ribonucleotide; 360-97-4/Aminoimidazole Carboxamide; EC 2.7.10.1/Receptor, IGF Type 1; EC 2.7.10.1/Receptor, Insulin; EC 2.7.11.1/AMP-Activated Protein Kinases; EC 2.7.11.1/Proto-Oncogene Proteins c-akt |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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