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

Research output: Contribution to journalArticlepeer-review

75 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)3450-3460
Number of pages11
JournalMolecular and cellular biology
Issue number18
StatePublished - 2014

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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