Insulin receptor substrates are essential for the bioenergetic and hypertrophic
response of the heart to exercise training.
Authors Riehle C, Wende AR, Zhu Y, Oliveira KJ, Pereira RO, Jaishy BP, Bevins J, Valdez
S, Noh J, Kim BJ, Moreira AB, Weatherford ET, Manivel R, Rawlings TA, Rech M,
White MF, Abel ED
Submitted By Adam Wende on 3/4/2015
Status Published
Journal Molecular and cellular biology
Year 2014
Date Published 9/15/2014
Volume : Pages 34 : 3450 - 60
PubMed Reference 25002528
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 3ß (GSK3ß), 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-1a) protein content, mitochondrial capacity, fatty acid
oxidation, and glycogen synthesis in wild-type (WT) controls but not in IRS1-
and IRS2-deficient hearts. PGC-1a 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.

Investigators with authorship
E. Dale AbelUniversity of Iowa
Adam WendeUniversity of Alabama at Birmingham