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 ischemia 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, thereby protecting the heart during the ischemic stress. However, at clinically relevant high levels of fatty acids, ischemic-induced activation of AMPK also stimulates fatty acid oxidation during and following ischemia. This can contribute to ischemic injury secondary to an inhibition of glucose oxidation, which results in a decrease in cardiac efficiency As a result, the question of whether AMPK activation benefits or harms the ischemic 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 γ2 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 γ2 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. The issue of whether AMPK activation is beneficial or harmful to the hypertrophied heart has also not been completely resolved. Resolving these issues has important implications as to whether therapeutic approaches to protect the ischemic heart or decrease cardiac hypertrophy should be developed which either activate or inhibit AMPK.
06 - 07 Nov 2006
Society for Endocrinology