Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz

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SHR Neuro Krebs Kardio Lipid

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.
Insulin receptor substrate signaling suppresses neonatal autophagy in the heart.
J Clin Invest. 2013; 123(12): 5319-5333. [OPEN ACCESS]
Web of Science PubMed PUBMED Central FullText FullText_MUG


Autor/innen der Med Uni Graz:
Bugger Heiko Matthias

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Number of Figures: 10
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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.
Find related publications in this database (using NLM MeSH Indexing)
Amino Acids - pharmacology
Animals -
Apoptosis -
Apoptosis Regulatory Proteins - deficiency
Autophagy - genetics
Autophagy - physiology
Beclin-1 -
Cardiomyopathy, Dilated - complications
Cardiomyopathy, Dilated - genetics
Cardiomyopathy, Dilated - pathology
Fetal Heart - pathology
Heart - growth & development
Heart Failure - etiology
Heart Failure - pathology
Insulin - physiology
Insulin Receptor Substrate Proteins - deficiency
Insulin Receptor Substrate Proteins - physiology
Insulin-Like Growth Factor I - physiology
Mice -
Mitochondria, Heart - physiology
Myocytes, Cardiac - metabolism
Oxidative Phosphorylation -
Phosphorylation -
Protein Processing, Post-Translational -
Receptor, IGF Type 1 - physiology
Signal Transduction - physiology
TOR Serine-Threonine Kinases - physiology

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