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

Insulin and IGF-1 receptor signaling pathways differentially modulate cardiac growth under resting conditions and following exercise training. These effects are mediated by insulin receptor substrates (IRS) 1 and 2, 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 (CIRS1KO) or IRS2 (CIRS2KO) 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, PI3K activation was blunted and pro-hypertrophic signaling intermediates, such as Akt and GSK3β, were dephosphorylated potentially on the basis of reduced Janus Kinase-mediated inhibition of PP2A. Exercise training increased PGC-1α protein content, mitochondrial capacity, fatty acid oxidation, and glycogen synthesis in 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 non-redundant roles in mediating the hypertrophic and metabolic response of the heart to exercise.