title: Insulin receptor substrate signaling suppresses neonatal autophagy in the heart.
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.
authors.forename: Christian
authors.initials: C
authors.lastname: Riehle
authors.forename: Adam R
authors.initials: AR
authors.lastname: Wende
authors.forename: Sandra
authors.initials: S
authors.lastname: Sena
authors.forename: Karla Maria
authors.initials: KM
authors.lastname: Pires
authors.forename: Renata Oliveira
authors.initials: RO
authors.lastname: Pereira
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhu
authors.forename: Heiko
authors.initials: H
authors.lastname: Bugger
authors.forename: Deborah
authors.initials: D
authors.lastname: Frank
authors.forename: Jack
authors.initials: J
authors.lastname: Bevins
authors.forename: Dong
authors.initials: D
authors.lastname: Chen
authors.forename: Cynthia N
authors.initials: CN
authors.lastname: Perry
authors.forename: Xiaocheng C
authors.initials: XC
authors.lastname: Dong
authors.forename: Steven
authors.initials: S
authors.lastname: Valdez
authors.forename: Monika
authors.initials: M
authors.lastname: Rech
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Sheng
authors.forename: Bart C
authors.initials: BC
authors.lastname: Weimer
authors.forename: Roberta A
authors.initials: RA
authors.lastname: Gottlieb
authors.forename: Morris F
authors.initials: MF
authors.lastname: White
authors.forename: E Dale
authors.initials: ED
authors.lastname: Abel
mesh_terms: D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency; D001343:Autophagy / Q000235:genetics / Q000502:physiology; D000071186:Beclin-1; D002311:Cardiomyopathy, Dilated / Q000150:complications / Q000235:genetics / Q000473:pathology; D005318:Fetal Heart / Q000473:pathology; D006321:Heart / Q000254:growth & development*; D006333:Heart Failure / Q000209:etiology / Q000473:pathology; D007328:Insulin / Q000502:physiology; D055504:Insulin Receptor Substrate Proteins / Q000172:deficiency / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000502:physiology; D051379:Mice; D008929:Mitochondria, Heart / Q000502:physiology; D032383:Myocytes, Cardiac / Q000378:metabolism*; D010085:Oxidative Phosphorylation; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017526:Receptor, IGF Type 1 / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000502:physiology
chemical_list: D000596:Amino Acids; D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; C526298:Irs2 protein, mouse; C519530:insulin-like growth factor-1, mouse; D007334:Insulin-Like Growth Factor I; C546843:mTOR protein, mouse; D017526:Receptor, IGF Type 1; D058570:TOR Serine-Threonine Kinases