title: Energy-preserving effects of IGF-1 antagonize starvation-induced cardiac autophagy.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Centro de Estudios Moleculares de Célula, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago 838-0492, Chile.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Troncoso
authors.forename: Jose Miguel
authors.initials: JM
authors.lastname: Vicencio
authors.forename: Valentina
authors.initials: V
authors.lastname: Parra
authors.forename: Andriy
authors.initials: A
authors.lastname: Nemchenko
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kawashima
authors.forename: Andrea
authors.initials: A
authors.lastname: Del Campo
authors.forename: Barbra
authors.initials: B
authors.lastname: Toro
authors.forename: Pavan K
authors.initials: PK
authors.lastname: Battiprolu
authors.forename: Pablo
authors.initials: P
authors.lastname: Aranguiz
authors.forename: Mario
authors.initials: M
authors.lastname: Chiong
authors.forename: Shoshana
authors.initials: S
authors.lastname: Yakar
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Gillette
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Hill
authors.forename: Evan Dale
authors.initials: ED
authors.lastname: Abel
authors.forename: Derek
authors.initials: D
authors.lastname: Leroith
authors.forename: Sergio
authors.initials: S
authors.lastname: Lavandero
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000502:physiology; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004734:Energy Metabolism / Q000187:drug effects*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000502:physiology
chemical_list: D007334:Insulin-Like Growth Factor I; D000255:Adenosine Triphosphate; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D002118:Calcium