Spermidine overrides INSR (insulin receptor)-IGF1R (insulin-like growth factor 1 receptor)-mediated inhibition of autophagy in the aging heart - Centre de recherche des Cordeliers Access content directly
Journal Articles Autophagy Year : 2022

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

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.
Fichier principal
Vignette du fichier
Abdellatif et al_Autophagy punctum_2022_clean.pdf (632.94 Ko) Télécharger le fichier
Origin Files produced by the author(s)

Dates and versions

hal-04596675 , version 1 (06-06-2024)

Identifiers

Cite

Mahmoud Abdellatif, Frank Madeo, Guido Kroemer, Simon Sedej. Spermidine overrides INSR (insulin receptor)-IGF1R (insulin-like growth factor 1 receptor)-mediated inhibition of autophagy in the aging heart. Autophagy, 2022, 18 (10), pp.2500-2502. ⟨10.1080/15548627.2022.2095835⟩. ⟨hal-04596675⟩
33 View
6 Download

Altmetric

Share

Gmail Mastodon Facebook X LinkedIn More