Insulin-Like Growth Factor I Receptor Signaling Is Required for Exercise-Induced Cardiac Hypertrophy

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

doi:10.1210/me.2008-0265

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Insulin-Like Growth Factor I Receptor Signaling Is Required for Exercise-Induced Cardiac Hypertrophy

Journal article

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Insulin-Like Growth Factor I Receptor Signaling Is Required for Exercise-Induced Cardiac Hypertrophy

Jaetaek Kim, Adam R Wende, Sandra Sena, Heather A Theobald, Jamie Soto, Crystal Sloan, Benjamin E Wayment, Sheldon E Litwin, Martin Holzenberger, Derek LeRoith, …

Molecular endocrinology (Baltimore, Md.), Vol.22(11), pp.2531-2543

11/01/2008

DOI: 10.1210/me.2008-0265

PMCID: PMC2582541

PMID: 18801929

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Abstract

Abstract 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-γ coactivator-1α (PGC-1α) 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-β-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.

Details

Title: Subtitle: Insulin-Like Growth Factor I Receptor Signaling Is Required for Exercise-Induced Cardiac Hypertrophy
Creators: Jaetaek Kim - 1Program in Human Molecular Biology and Genetics and Division of Endocrinology, Metabolism, and Diabetes (J.K., A.R.W., S.S., H.A.T., J.S., C.S., E.D.A.), Salt Lake City, Utah 84112
Adam R Wende - 1Program in Human Molecular Biology and Genetics and Division of Endocrinology, Metabolism, and Diabetes (J.K., A.R.W., S.S., H.A.T., J.S., C.S., E.D.A.), Salt Lake City, Utah 84112
Sandra Sena - 1Program in Human Molecular Biology and Genetics and Division of Endocrinology, Metabolism, and Diabetes (J.K., A.R.W., S.S., H.A.T., J.S., C.S., E.D.A.), Salt Lake City, Utah 84112
Heather A Theobald - 1Program in Human Molecular Biology and Genetics and Division of Endocrinology, Metabolism, and Diabetes (J.K., A.R.W., S.S., H.A.T., J.S., C.S., E.D.A.), Salt Lake City, Utah 84112
Jamie Soto - 1Program in Human Molecular Biology and Genetics and Division of Endocrinology, Metabolism, and Diabetes (J.K., A.R.W., S.S., H.A.T., J.S., C.S., E.D.A.), Salt Lake City, Utah 84112
Crystal Sloan - 1Program in Human Molecular Biology and Genetics and Division of Endocrinology, Metabolism, and Diabetes (J.K., A.R.W., S.S., H.A.T., J.S., C.S., E.D.A.), Salt Lake City, Utah 84112
Benjamin E Wayment - 2Division of Cardiology (B.E.W., S.E.L.), University of Utah, Salt Lake City, Utah 84112
Sheldon E Litwin - 2Division of Cardiology (B.E.W., S.E.L.), University of Utah, Salt Lake City, Utah 84112
Martin Holzenberger - 4Institut National de la Santé et de la Recherche (INSERM), Centre de Recherche Saint-Antoine, Université Pierre-et-Marie Curie (M.H.), 75012 Paris, France
Derek LeRoith - 5Division of Endocrinology, Diabetes, and Bone Diseases (D.L.), Department of Medicine, The Mount Sinai School of Medicine, New York, New York 10029
E. Dale Abel - 1Program in Human Molecular Biology and Genetics and Division of Endocrinology, Metabolism, and Diabetes (J.K., A.R.W., S.S., H.A.T., J.S., C.S., E.D.A.), Salt Lake City, Utah 84112
Resource Type: Journal article
Publication Details: Molecular endocrinology (Baltimore, Md.), Vol.22(11), pp.2531-2543
DOI: 10.1210/me.2008-0265
PMID: 18801929
PMCID: PMC2582541
NLM abbreviation: Mol Endocrinol
ISSN: 0888-8809
eISSN: 1944-9917
Publisher: Oxford University Press
Language: English
Date published: 11/01/2008
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
Record Identifier: 9984025290002771

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