Regulation of cardiac autophagy by insulin‐like growth factor 1

Abstract

Insulin-like growth factor-1 (IGF-1) signaling is a key pathway in the control of cell growth and survival. Three critical nodes in the IGF-1 signaling pathway have been described in cardiomyocytes: protein kinase Akt/mammalian target of rapamycin (mTOR), Ras/Raf/extracellular signal-regulated kinase (ERK), and phospholipase C (PLC)/inositol 1,4,5-triphosphate (InsP 3 )/ Ca 21 . The Akt/mTOR and Ras/Raf/ERK signaling arms govern survival in the settings of cardiac stress and hypertrophic growth. By contrast, PLC/InsP 3 /Ca 21 functions to regulate metabolic adaptability and gene transcription. Autophagy is a catabolic process involved in protein degradation, organelle turnover, and nonselective breakdown of cytoplasmic components during nutrient starvation or stress. In the heart, autophagy is observed in a variety of human pathologies, where it can be either adaptive or maladaptive, depending on the context. We proposed the hypothesis that IGF-1 protects the heart by rescuing the mitochondrial metabolism and the energetics state, reducing cell death and controls the potentially exacerbate autophagic response to nutritional stress. In light of the importance of IGF-1 and autophagy in the heart, we review here IGF-1 signaling and autophagy regulation in the context of cardiomyocyte nutritional stress. V C 2013 IUBMB Life, 65(7): [593][594][595][596][597][598][599][600][601] 2013

MiR-28 inhibits cardiomyocyte survival through suppressing PDK1/Akt/mTOR signaling

“…As a critical player in the nodal point of multiple signaling pathways, the protein kinase Akt responds to multiple upstream signals and regulates important cellular processes such as cell proliferation, energy metabolism, and autophagy (Troncoso et al 2013;Yao et al 2014). One of the most well-defined downstream targets of Akt is mTOR.…”

A time to reap, a time to sow: Mitophagy and biogenesis in cardiac pathophysiology

“…Mitophagy can be regulated by several different energy sensing stimuli: the availability of AAs in a cell regulates mTOR activity; the glucose level in blood regulates release of insulin and glucagon which have opposing effects on autophagy; and conditions such as metabolic syndrome and caloric restriction regulate autophagy and mitophagy. Insulin suppresses macroautophagy by activating the phosphatidyl-inositol triphosphate (PIP 3 ) cascade leading to phosphorylation and activation of Akt and subsequently mTOR, which inhibits autophagy [122]. Usually high insulin is followed by an increase in AAs in the cytosol, which also activates mTOR, reinforcing the same pathway.…”

Novel players in cardioprotection: Insulin like growth factor-1, angiotensin-(1–7) and angiotensin-(1–9)

“…This effect also emerges as a therapeutic target of clinical relevance on CV biology [43]. Recently, Troncoso et al showed that IGF-1 negatively modulates nutrient deprivationinduced cardiac autophagy involving activation of the Akt/mTOR and AMPK/mTOR signaling pathways, which in turn promoted the mitochondrial activity [44,45]. Despite the apparent physiological association between IGF-1 and insulin axis they activate differentially the Akt1 and Akt2 isoforms, respectively.…”

“…Akt1 is associated with normal cardiac growth, whereas Akt2 is linked to cardiomyocyte survival and metabolism [46]. Interestingly, both insulin and IGF-1 increase the mitochondrial activity in cultured rat cardiomyocytes [45,47] raising new questions regarding the complex interplay between their downstream signaling pathways. In this context, the manipulation of the ratio IGF-1R/IR affects hybrid receptor formation and insulin sensitivity in endothelial cells [48,49].…”