Insulin receptor substrates are essential for the bioenergetic and hypertrophic response of the heart to exercise training

Christian Riehle; Adam R Wende; Yi Zhu; Karen J Oliveira; Renata O Pereira; Bharat P Jaishy; Jack Bevins; Steven Valdez; Junghyun Noh; Bum Jun Kim; Annie Bello Moreira; Eric T Weatherford; Rajkumar Manivel; Tenley A Rawlings; Monika Rech; Morris F White; E Dale Abel

doi:10.1128/MCB.00426-14

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Insulin receptor substrates are essential for the bioenergetic and hypertrophic response of the heart to exercise training

Journal article

Peer reviewed

Insulin receptor substrates are essential for the bioenergetic and hypertrophic response of the heart to exercise training

Christian Riehle, Adam R Wende, Yi Zhu, Karen J Oliveira, Renata O Pereira, Bharat P Jaishy, Jack Bevins, Steven Valdez, Junghyun Noh, Bum Jun Kim, …

Molecular and cellular biology, Vol.34(18), pp.3450-3460

09/15/2014

DOI: 10.1128/MCB.00426-14

PMCID: PMC4135616

PMID: 25002528

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Abstract

Insulin and insulin-like growth factor 1 (IGF-1) receptor signaling pathways differentially modulate cardiac growth under resting conditions and following exercise training. These effects are mediated by insulin receptor substrate 1 (IRS1) and IRS2, which also differentially regulate resting cardiac mass. To determine the role of IRS isoforms in mediating the hypertrophic and metabolic adaptations of the heart to exercise training, we subjected mice with cardiomyocyte-specific deletion of either IRS1 (CIRS1 knockout [CIRS1KO] mice) or IRS2 (CIRS2KO mice) to swim training. CIRS1KO hearts were reduced in size under basal conditions, whereas CIRS2KO hearts exhibited hypertrophy. Following exercise swim training in CIRS1KO and CIRS2KO hearts, the hypertrophic response was equivalently attenuated, phosphoinositol 3-kinase (PI3K) activation was blunted, and prohypertrophic signaling intermediates, such as Akt and glycogen synthase kinase 3β (GSK3β), were dephosphorylated potentially on the basis of reduced Janus kinase-mediated inhibition of protein phosphatase 2a (PP2A). Exercise training increased peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) protein content, mitochondrial capacity, fatty acid oxidation, and glycogen synthesis in wild-type (WT) controls but not in IRS1- and IRS2-deficient hearts. PGC-1α protein content remained unchanged in CIRS1KO but decreased in CIRS2KO hearts. These results indicate that although IRS isoforms play divergent roles in the developmental regulation of cardiac size, these isoforms exhibit nonredundant roles in mediating the hypertrophic and metabolic response of the heart to exercise.

Signal Transduction

Energy Metabolism

Heart - physiology

Insulin Receptor Substrate Proteins - physiology

Mice, Inbred C57BL

Gene Expression Regulation

Phosphatidylinositol 3-Kinases - metabolism

Mice, Knockout

Transcription Factors - metabolism

Animals

Glycogen - metabolism

Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha

Protein Isoforms

Mice

Swimming

Mitochondria - physiology

Details

Title: Subtitle: Insulin receptor substrates are essential for the bioenergetic and hypertrophic response of the heart to exercise training
Creators: Christian Riehle - Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA Division of Endocrinology, Metabolism and Diabetes and Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA
Adam R Wende - Division of Endocrinology, Metabolism and Diabetes and Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA
Yi Zhu - Division of Endocrinology, Metabolism and Diabetes and Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA
Karen J Oliveira - Division of Endocrinology, Metabolism and Diabetes and Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA
Renata O Pereira - Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA Division of Endocrinology, Metabolism and Diabetes and Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA
Bharat P Jaishy - Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA Division of Endocrinology, Metabolism and Diabetes and Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA
Jack Bevins - Division of Endocrinology, Metabolism and Diabetes and Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA
Steven Valdez - Division of Endocrinology, Metabolism and Diabetes and Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA
Junghyun Noh - Division of Endocrinology, Metabolism and Diabetes and Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA
Bum Jun Kim - Division of Endocrinology, Metabolism and Diabetes and Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA
Annie Bello Moreira - Division of Endocrinology, Metabolism and Diabetes and Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA
Eric T Weatherford - Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
Rajkumar Manivel - Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
Tenley A Rawlings - Division of Endocrinology, Metabolism and Diabetes and Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA
Monika Rech - Division of Endocrinology, Metabolism and Diabetes and Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA
Morris F White - Division of Endocrinology, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts, USA
E Dale Abel - Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA Division of Endocrinology, Metabolism and Diabetes and Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA DRCadmin@uiowa.edu
Resource Type: Journal article
Publication Details: Molecular and cellular biology, Vol.34(18), pp.3450-3460
DOI: 10.1128/MCB.00426-14
PMID: 25002528
PMCID: PMC4135616
NLM abbreviation: Mol Cell Biol
ISSN: 0270-7306
eISSN: 1098-5549
Publisher: United States
Grant note: K99 HL111322 / NHLBI NIH HHS P30 DK079626 / NIDDK NIH HHS R00 HL111322 / NHLBI NIH HHS R01 HL070070 / NHLBI NIH HHS T32 HL007576 / NHLBI NIH HHS R01 HL108379 / NHLBI NIH HHS UO1HL087947 / NHLBI NIH HHS R01 DK092065 / NIDDK NIH HHS U01 HL087947 / NHLBI NIH HHS R01DK092065 / NIDDK NIH HHS R01HL070070 / NHLBI NIH HHS R01HL108379 / NHLBI NIH HHS
Language: English
Date published: 09/15/2014
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: 9984024507902771

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