Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
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.
Doi: 10.1172/JCI71171
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- Co-Autor*innen der Med Uni Graz
- Bugger Heiko Matthias
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- 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.
- 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