Insulin receptor substrate signaling suppresses neonatal autophagy in the heart.
Authors Riehle C, Wende AR, Sena S, Pires KM, Pereira RO, Zhu Y, Bugger H, Frank D,
Bevins J, Chen D, Perry CN, Dong XC, Valdez S, Rech M, Sheng X, Weimer BC,
Gottlieb RA, White MF, Abel ED
Submitted By E. Dale Abel on 3/4/2015
Status Published
Journal The Journal of clinical investigation
Year 2013
Date Published 12/1/2013
Volume : Pages 123 : 5319 - 5333
PubMed Reference 24177427
Abstract The induction of autophagy in the mammalian heart during the perinatal period is
an essential adaptation required to survive early neonatal starvation; however,
the mechanisms that mediate autophagy suppression once feeding is established
are not known. Insulin signaling in the heart is transduced via insulin and
IGF-1 receptors (IGF-1Rs). We disrupted insulin and IGF-1R signaling by
generating mice with combined cardiomyocyte-specific deletion of Irs1 and Irs2.
Here we show that loss of IRS signaling prevented the physiological suppression
of autophagy that normally parallels the postnatal increase in circulating
insulin. This resulted in unrestrained autophagy in cardiomyocytes, which
contributed to myocyte loss, heart failure, and premature death. This process
was ameliorated either by activation of mTOR with aa supplementation or by
genetic suppression of autophagic activation. Loss of IRS1 and IRS2 signaling
also increased apoptosis and precipitated mitochondrial dysfunction, which were
not reduced when autophagic flux was normalized. Together, these data indicate
that in addition to prosurvival signaling, insulin action in early life mediates
the physiological postnatal suppression of autophagy, thereby linking nutrient
sensing to postnatal cardiac development.

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