Insulin receptor substrate signaling suppresses neonatal autophagy in the heart

Christian Riehle, Adam R. Wende, Sandra Sena, Karla M. Pires, Renata O. Pereira, Yi Zhu, Heiko Bugger, Deborah Frank, Jack Bevins, Dong Chen, Cynthia N. Perry, Xiaocheng C. Dong, Steven Valdez, Monika Rech, Xiaoming Sheng, Bart C Weimer, Roberta A. Gottlieb, Morris F. White, E. D. Abel

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66 Scopus citations

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 ofmTOR 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.

Original languageEnglish (US)
Pages (from-to)5319-5333
Number of pages15
JournalJournal of Clinical Investigation
Volume123
Issue number12
DOIs
StatePublished - Dec 2 2013
Externally publishedYes

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ASJC Scopus subject areas

  • Medicine(all)

Cite this

Riehle, C., Wende, A. R., Sena, S., Pires, K. M., Pereira, R. O., Zhu, Y., Bugger, H., Frank, D., Bevins, J., Chen, D., Perry, C. N., Dong, X. C., Valdez, S., Rech, M., Sheng, X., Weimer, B. C., Gottlieb, R. A., White, M. F., & Abel, E. D. (2013). Insulin receptor substrate signaling suppresses neonatal autophagy in the heart. Journal of Clinical Investigation, 123(12), 5319-5333. https://doi.org/10.1172/JCI71171