Energy-preserving effects of IGF-1 antagonize starvation-induced cardiac autophagy

Rodrigo Troncoso, Jose Miguel Vicencio, Valentina Parra, Andriy Nemchenko, Yuki Kawashima, Andrea Del Campo, Barbra Toro, Pavan K. Battiprolu, Pablo Aranguiz, Mario Chiong, Shoshana Yakar, Thomas G. Gillette, Joseph A Hill, Evan Dale Abel, Derek Leroith, Sergio Lavandero

Research output: Contribution to journalArticlepeer-review

86 Scopus citations

Abstract

Aims Insulin-like growth factor 1 (IGF-1) is known to exert cardioprotective actions. However, it remains unknown if autophagy, a major adaptive response to nutritional stress, contributes to IGF-1-mediated cardioprotection. Methods and results We subjected cultured neonatal rat cardiomyocytes, as well as live mice, to nutritional stress and assessed cell death and autophagic rates. Nutritional stress induced by serum/glucose deprivation strongly induced autophagy and cell death, and both responses were inhibited by IGF-1. The Akt/mammalian target of rapamycin (mTOR) pathway mediated the effects of IGF-1 upon autophagy. Importantly, starvation also decreased intracellular ATP levels and oxygen consumption leading to AMP-activated protein kinase (AMPK) activation; IGF-1 increased mitochondrial Ca 2+ uptake and mitochondrial respiration in nutrient-starved cells. IGF-1 also rescued ATP levels, reduced AMPK phosphorylation and increased p70 S6K phosphorylation, which indicates that in addition to Akt/mTOR, IGF-1 inhibits autophagy by the AMPK/mTOR axis. In mice harbouring a liver-specific igf1 deletion, which dramatically reduces IGF-1 plasma levels, AMPK activity and autophagy were increased, and significant heart weight loss was observed in comparison with wild-type starved animals, revealing the importance of IGF-1 in maintaining cardiac adaptability to nutritional insults in vivo. Conclusion Our data support the cardioprotective actions of IGF-1, which, by rescuing the mitochondrial metabolism and the energetic state of cells, reduces cell death and controls the potentially harmful autophagic response to nutritional challenges. IGF-1, therefore, may prove beneficial to mitigate damage induced by excessive nutrient-related stress, including ischaemic disease in multiple tissues.

Original languageEnglish (US)
Pages (from-to)320-329
Number of pages10
JournalCardiovascular Research
Volume93
Issue number2
DOIs
StatePublished - Feb 1 2012

Keywords

  • ATP
  • Akt
  • Heart
  • IGF-1
  • Macroautophagy
  • mTOR

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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