Spermidine overrides INSR (insulin receptor)-IGF1R (insulin-like growth factor 1 receptor)-mediated inhibition of autophagy in the aging heart

Autophagy. 2022 Oct;18(10):2500-2502. doi: 10.1080/15548627.2022.2095835. Epub 2022 Jul 10.

Abstract

Although attenuated IGF1R (insulin-like growth factor 1 receptor) signaling has long been viewed to promote longevity in model organisms, adverse effects on the heart have been the subject of major concern. We observed that IGF1R is overexpressed in cardiac tissues from patients with end-stage non-ischemic heart failure, coupled to the activation of the IGF1R downstream effector AKT/protein kinase B and inhibition of ULK1 (unc-51 like autophagy activating kinase 1). Transgenic overexpression of human IGF1R in cardiomyocytes from mice initially induces physiological cardiac hypertrophy and superior function, but later in life confers a negative impact on cardiac health, causing macroautophagy/autophagy inhibition as well as impaired oxidative phosphorylation, thus reducing life expectancy. Treatment with the autophagy inducer and caloric restriction mimetic spermidine ameliorates most of these IGF1R-induced cardiotoxic effects in vivo. Moreover, inhibition of IGF1R signaling by means of a dominant-negative phosphoinositide 3-kinase (PI3K) mutant induces cardioprotective autophagy, restores myocardial bioenergetics and improves late-life survival. Hence, our results demonstrate that IGF1R exerts a dual biphasic impact on cardiac health, and that autophagy mediates the late-life geroprotective effects of IGF1R inhibition in the heart.

Keywords: Heart failure; IGF1R; PI3K; human; insulin signaling; longevity; mitochondrial dysfunction; mouse.

Publication types

  • Research Support, Non-U.S. Gov't
  • Comment

MeSH terms

  • Aging
  • Animals
  • Antigens, CD
  • Autophagy
  • Autophagy-Related Protein-1 Homolog
  • Humans
  • Insulin-Like Growth Factor I / metabolism
  • Mice
  • Myocytes, Cardiac / metabolism
  • Phosphatidylinositol 3-Kinase
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt* / metabolism
  • Receptor, IGF Type 1
  • Receptor, Insulin* / metabolism
  • Spermidine / pharmacology

Substances

  • Antigens, CD
  • IGF1R protein, human
  • Insulin-Like Growth Factor I
  • Phosphatidylinositol 3-Kinase
  • INSR protein, human
  • Receptor, IGF Type 1
  • Receptor, Insulin
  • Autophagy-Related Protein-1 Homolog
  • Proto-Oncogene Proteins c-akt
  • Spermidine

Grants and funding

This work was funded by the Austrian Science Fund (FWF) through grant P27637-B28 and the European Research Area Network on Cardiovascular Diseases (ERA-CVD) through grant I3301-MINOTAUR to S.S. M.A. acknowledges support from the European Society of Cardiology (ESC basic research fellowship), Austrian Society of Cardiology (Präsidentenstipendium-ÖKG), Medical University of Graz (Start Fund) and the European Commission (H2020-MSCA-IF, Nr. 101025118). G.K. is supported by the Ligue contre le Cancer (équipe labellisée); Agence National de la Recherche (ANR) – Projets blancs; AMMICa US23/CNRS UMS3655; Association pour la recherche sur le cancer (ARC); Association “Ruban Rose”; Cancéropôle Ile-de-France; Fondation pour la Recherche Médicale (FRM); a donation by Elior; Equipex Onco-Pheno-Screen; European Joint Programme on Rare Diseases (EJPRD); Gustave Roussy Odyssea, the European Union Horizon 2020 Projects Oncobiome and Crimson; Fondation Carrefour; High-end Foreign Expert Program in China (GDW20171100085), Institut National du Cancer (INCa); Inserm (HTE); Institut Universitaire de France; LabEx Immuno-Oncology (ANR-18-IDEX-0001); the Leducq Foundation; the RHU Torino Lumière; Seerave Foundation; SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); and SIRIC Cancer Research and Personalized Medicine (CARPEM). This study contributes to the IdEx Université de Paris ANR-18-IDEX-000; Austrian Science Fund (FWF).