胰岛素样生长因子1受体
自噬
生物
蛋白激酶B
胰岛素受体
PI3K/AKT/mTOR通路
mTORC1型
细胞生物学
胰岛素样生长因子
内分泌学
内科学
受体
胰岛素
生长因子
信号转导
胰岛素抵抗
细胞凋亡
生物化学
医学
作者
Mahmoud Abdellatif,Frank Madeo,Guido Kroemer,Simon Sedej
出处
期刊:Autophagy
[Informa]
日期:2022-07-10
卷期号:18 (10): 2500-2502
被引量:6
标识
DOI:10.1080/15548627.2022.2095835
摘要
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.
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