AMPK alterations in cardiac physiology and pathology: enemy or ally?

Abstract

AMP-activated protein kinase (AMPK) has emerged as a key regulator of energy metabolism in the heart. The high energy demands of the heart are primarily met by the metabolism of both fatty acids and glucose, both processes being regulated by AMPK. During myocardial ischaemia a rapid activation of AMPK occurs, resulting in an activation of both glucose uptake and glycolysis, as well as an increase in fatty acid oxidation. This activation of AMPK has the potential to increase energy production and to inhibit apoptosis, thereby protecting the heart during the ischaemic stress. However, at clinically relevant high levels of fatty acids, ischaemic-induced activation of AMPK also stimulates fatty acid oxidation during and following ischaemia. This can contribute to ischaemic injury secondary to an inhibition of glucose oxidation, which results in a decrease in cardiac efficiency. In a number of other non-cardiac tissues, AMPK has been shown to have pro-apoptotic effects. As a result, the question of whether AMPK activation benefits or harms the ischaemic heart remains controversial. The role of AMPK in cardiac hypertrophy is also controversial. Activation of AMPK inhibits protein synthesis, and may be an adaptive response to pathological cardiac hypertrophy. However, none of mouse models of AMPK deficiency (excluding those that may involve the gamma2 subunit mutations) demonstrate increased cardiac mass, suggesting that AMPK is not essential for restriction of cardiac growth. In addition to the potential effects of AMPK on myofibrillar hypertrophy associated with pressure overload, there is also controversy with respect to the cardiac hypertrophy associated with the gamma2 subunit mutations. In the cardiac hypertrophy associated with glycogen overload, both activating and inactivating mutations of AMPK in mice are associated with a marked cardiac hypertrophy. This review will address the issue of whether AMPK activation acts as an enemy or ally to the ischaemic and hypertrophied heart. Resolving this issue has important implications as to whether therapeutic approaches to protect the ischaemic heart should be developed which either activate or inhibit AMPK.

Figure 1. Proposed pathways by which activation of AMPK can benefit or harm the ischaemic-reperfused heart

A, in the aerobic heart AMPK activation can activate or inhibit a number of processes that increase fatty acid oxidation and glycolysis. Ischaemia results in a rapid activation of AMPK in the heart. This results in a stimulation of glucose uptake, glycogenolysis and glycolysis. B, this can provide a potentially beneficial source of energy for the heart during an ischaemic-induced decrease in mitochondrial oxidative metabolism. AMPK activation also increases fatty acid oxidation, which unfortunately results in a parallel decrease in glucose oxidation rates. In the presence of low levels of fatty acids, this inhibition of glucose oxidation is minimal. C, in the presence of the high levels of fatty acids (which is seen in most clinical scenarios of ischaemia and reperfusion) a large decrease in glucose oxidation can increase proton production, due to an uncoupling of glycolysis from glucose oxidation. This can decrease cardiac efficiency and potentially contribute to ischaemic injury. Red symbols indicate inhibition, green symbols indicate activation, and grey symbols indicate possible direct or indirect targets of regulation.

Figure 2. The involvement of AMPK in the development of cardiac hypertrophy

Following the precipitating event, a number of mechanisms (including reduced myocardial perfusion) can promote cardiac myocyte growth. Hypertrophic growth can be adaptive (physiological hypertrophy) but can also become maladaptive (pathological hypertrophy). AMPK appears to have a dual role in the hypertrophic process, where in the early stages inhibition of AMPK may be necessary for cardiac growth (or if not directly involved in the pathway, pharmacological activation of AMPK in the early phase of cardiac hypertrophy may be able to prevent hypertrophic growth), while in the later stages AMPK activation may become essential for maintaining adequate ATP supply.

Figure 3. The PRKAG2 cardiac syndrome

Mutations in the γ₂ subunit of AMPK (the PRKAG2 gene) appear to cause both activating and inhibiting forms of cardiac AMPK. Various changes in the control of glucose utilization and storage ensue that result in a glycogen storage cardiomyopathy that is associated with the development of Wolff–Parkinson–White Syndrome and cardiac hypertrophy.