Autophagy is important for the preservation of energy status in response to energy deprivation. Glucose deprivation, a condition similar to myocardial ischemia, induces autophagy, while pharmacological inhibition of autophagy has been shown to reduce cellular survival in cultured cardiomyocytes [10
]. Such findings collectively support the notion of the cardioprotective roles of autophagy. It may serve to maintain energy production in response to energy deprivation, including acute ischemia, and also may be responsible for the clearance of long-lived proteins and dysfunctional organelles during chronic ischemia or reperfusion.
A state of nutrient deprivation, such as myocardial ischemia, induces macroautophagy activation. Macroautophagy degrades proteins and organelles, thereby generating fatty acids and amino acids that are all used for mitochondrial adenosine triphosphate (ATP) production, which promotes cardiomyocyte survival [10
Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is an energy sensing kinase, taking action when the cellular AMP-to-ATP ratio increases. AMPK activates autophagy by activating ULK1, a serine/threonine-protein kinase, and by relieving the mammalian target of rapamycin (mTOR)-mediated inhibition of macroautophagy [12
]. mTOR tightly regulates autophagy by inhibiting the ULK1 kinase complex and accordingly prevents autophagy activation, along with phosphorylation of the tuberous sclerosis complex (TSC). This signaling pathway is accordingly called AMPK-mTOR, and is considered critical in regulating the activation of autophagy under circumstances such as energy stress and glucose starvation (). The TSC-mTOR pathway can function in diabetic hearts. In diabetic hearts, phosphorylation of raptor at both Ser722 and Ser792 is decreased, and phosphorylation of mTOR at both Ser2448 and Thr2446 is increased. Also, 4 E binding protein 1 and p70 ribosomal protein S6 kinase 1, downstream effectors of mTOR, are increased [13
]. Studies collectively suggest that mTOR complex 1 (mTORC1) activation may be detrimental under cardiac energy deprivation, while mTORC1 inhibition is protective because of energy preservation [14
]. In addition, it has been revealed that mTORC1 activation may be responsible for cell growth.
Fig. 1 Regulation of cardiac autophagy and nutritional status, including overnutrition and undernutrition. mTOR, mammalian target of rapamycin; PI3K, phosphoinositide 3-kinase; TSC, tuberous sclerosis complex; AMPK, adenosine monophosphate-activated protein (more ...)
Rheb, a Ras homolog guanosine triphosphate-binding protein, is inhibited in response to energy deprivation for autophagy activation. In addition, suppression of autophagy activation by inhibiting Beclin-1 counteracts the protective action of Rheb protein for energy deprivation. The action of Rheb-regulated autophagy has been shown to be protective against nutrient starvation and ischemia in cardiomyocytes through the preservation of ATP content and the reduction of misfolded protein accumulation [14
Rheb controls the activation of autophagy partly through Atg7, where Atg7 overexpression induces autophagy and suppresses Rheb-induced cell death in response to glucose deprivation. In addition, mTORC1 may be involved in regulating autophagy through ULK1/2 regulation [15
], though its exact function remains to be elucidated.
Under a starvation state, such as in myocardial ischemia, AMPK acts as a checkpoint by suppressing cellular growth and promoting autophagy activation in cardiomyocytes. Therefore, the AMPK-mTOR pathway is certainly a crucial regulator of autophagy in such circumstances, as inhibition of AMPK reduces autophagy and increases cell death in cardiomyocytes [10
]. This phenomenon was also observed in transgenic mice with cardiac-specific expression of a dominant negative AMPK. This setting has shown reduced autophagy induction in states of fasting in vivo
], which suggests that AMPK-induced autophagy may be controlled by inhibiting the expression of mTOR in response to ischemia. One study has shown that glycogen synthase kinase (GSK)-3, an enzyme involved in gene transcription regulation, protein translation, and apoptosis, as well as hexose metabolism, may be a regulator of the mTOR pathway in cardiomyocytes [16
]. In addition, inhibition of GSK-3β has been reported to be cardioprotective [17
] by inhibiting mTOR signaling and thus activating autophagy via phosphorylation of TSC2 [21
]. The function of GSK-3β also includes the regulation of mTOR during both myocardial ischemia and reperfusion [20
In response to glucose deprivation, cardiomyocytes initiate the nuclear translocation of FoxO1 and FoxO3 to the nucleus where the transcription of genes responsible for autophagy are activated [23
]. FoxO3 overexpression in the heart is associated with increased autophagy, which may be related to the development of cardiac atrophy [25
], while genetic deletion of FoxO3 resulted in the development of cardiac hypertrophy [26
]. Under a starvation state, Sirtuin 1 (Sirt1), a NAD-dependent deacetylase, is up-regulated [27
]. Sirt1 mediates the deacetylation of FoxO1 and upregulation of Rab7, which functions as the center for mediating increased autophagic flux in response to starvation, which in turn maintains left ventricular function during these events [23
Atg13 binds to Atg1 and Atg17 in response to glucose deprivation, promoting the induction of autophagy at the phagophore assembly site. This complex can be found in yeast; the mammalian counterpart shows slight differences [29
]. During starvation, mTOR dissociates and promotes the activation of ULK1, which up-regulates autophagy by increasing the phosphorylation of mATG13 and focal adhesion kinase interacting protein of 200 kD (FIP200). A class III phosphoinositide 3-kinase (PI3K) complex is then recruited to the assembly site and Vps34 lipid kinase protein binds to the phagophore via Vps15. This complex contains Beclin1/ATG6 and ATG14, which control the induction of Vps34 lipid kinase protein. It is believed that this lipid kinase is an essential protein for recruiting additional ATG proteins, where they complete the autophagosome formation [30