One study has shown that a lack of Atg5, a cardiac-specific protein that is required for the activation of autophagy, leads to cardiac hypertrophy, left ventricular dilatation, and contractile dysfunction, along with increased levels of ubiquitination [7]. This study also demonstrated that a reduced expression level of Atg7, a protein necessary for the formation of autophagosome, is responsible for reduced cellular viability and remarkable features of cardiomyocyte hypertrophy [7]. In addition, lysosomal-associated membrane protein 2 is thought to be involved in the pathogenesis of cardiomyopathy, as its deficiency has been shown to accumulate autophagic vacuoles and impair the autophagic degradation of dysfunctional proteins [8].

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 [10,11].

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 (Fig. 1). 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.

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 [10], 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 [17-20] by inhibiting mTOR signaling and thus activating autophagy via phosphorylation of TSC2 [21,22]. 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 [23,24]. 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 [27,28]. 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].

High fat diet-induced obesity activates the Rheb/mTORC1 pathway and reduces the activation of autophagy in the heart of mice [14]. Increased myocardial injury in these mice in response to prolonged ischemia suggests that an increased level of mTORC1 activity may be associated with an increased susceptibility. It has been demonstrated that reactivation of autophagy is a critical mechanism underlying the beneficial effects of mTORC1 inhibition in high fat diet-induced obesity, as shown in the failure of pharmacological mTORC1 inhibition to reduce ischemic injury by inhibiting Beclin-1. Physiological inhibition of the Rheb-mTORC1 signaling pathway during myocardial ischemia can be impaired in such conditions as obesity and metabolic syndrome, which consequently exacerbates myocardial injury. This Rheb-dependent mTORC1 pathway seems to be critical in regulating the activation of autophagy during ischemia in cardiomyocytes and its dysfunction is thereby associated with human diseases.

Nonobese mice with fructose-induced insulin resistance have shown activation of myocardial autophagy [32], while Ossabaw swine with excessive nutrition have shown inhibition of cardiac autophagy, which may be responsible for myocardial injury [33]. The expression of conjugated Atg12-Atg5 is increased in obesity and metabolic syndrome, as well as in defective hepatic autophagy of obese individuals [34], while unc-51-like kinase-1, Beclin-1, and LC3 conversion, which are indicative of autophagic activity, all decrease in metabolic syndrome, indicating the suppressed formation of nascent and mature autophagosomes. In addition, insulin resistance impairs the action of autophagy as highlighted by the up-regulation of the autophagy inhibitor mTOR in metabolic syndrome. On the other hand, Sirt1 is responsible for activating autophagy by inhibiting the expression mTOR [35]; its down-regulation may be associated with the inhibition of autophagy in metabolic syndrome. Inhibition of autophagy, in turn, leads to accumulation of dysfunctional cellular organelles and proteins that thereby result in apoptosis or cell death [36,37].