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(Circulation Research. 2007;100:474.)
© 2007 American Heart Association, Inc.

Reviews

AMP-Activated Protein Kinase in the Heart

Role During Health and Disease

Michael Arad, Christine E. Seidman, J.G. Seidman

From the Heart Institute (M.A.), Sheba Medical Center and Sackler School of Medicine, Tel Aviv University, Israel; Department of Genetics (C.E.S., J.G.S.), Harvard Medical School and Howard Hughes Medical Institute, Boston, Mass; and Cardiovascular Division (C.E.S.), Brigham and Women’s Hospital, Boston, Mass.

Correspondence to Jonathan G. Seidman, PhD, Department of Genetics, Harvard Medical School, 77 Ave Louis Pasteur, NRB 256, Boston, MA 02115. E-mail seidman{at}genetics.med.harvard.edu

This Review is part of a thematic series on AMP Kinase, which includes the following articles:

AMP-Activated Protein Kinase in the Heart: Role During Health and Disease
AMP-Activated Protein Kinase in Metabolic Control and Insulin Signaling

Bruce Kemp Guest Editor

AMP-activated protein kinase (AMPK) is a heterotrimeric enzyme that is expressed in most mammalian tissues including cardiac muscle. Among the multiple biological processes influenced by AMPK, regulation of fuel supply and energy-generating pathways in response to the metabolic needs of the organism is fundamental and likely accounts for the remarkable evolutionary conservation of this enzyme complex. By regulating the activity of acetyl–coenzyme A carboxylase, AMPK affects levels of malonyl–coenzyme A, a key energy regulator in the cell. AMPK is generally quiescent under normal conditions but is activated in response to hormonal signals and stresses sufficient to produce an increase in AMP/ATP ratio, such as hypoglycemia, strenuous exercise, anoxia, and ischemia. Once active, muscle AMPK enhances uptake and oxidative metabolism of fatty acids as well as increases glucose transport and glycolysis. Data from AMPK deficiency models suggest that AMPK activity might influence the pathophysiology and therapy of diabetes and increase heart tolerance to ischemia. Effects that are not as well understood include AMPK regulation of transcription. Different AMPK isoforms are found in distinct locations within the cell and have distinct functions in different tissues. A principal mode of AMPK activation is phosphorylation by upstream kinases (eg, LKB1). These kinases have a fundamental role in cell-cycle regulation and protein synthesis, suggesting involvement in a number of human disorders including cardiac hypertrophy, apoptosis, cancer, and atherosclerosis. The physiological role played by AMPK during health and disease is far from being clearly defined. Naturally occurring mutations affecting the nucleotide-sensing modules in the regulatory subunit of AMPK lead to enzyme dysregulation and inappropriate activation under resting conditions. Glycogen accumulation ensues, leading to human disease manifesting as cardiac hypertrophy, accessory atrioventricular connections, and degeneration of the physiological conduction system. Whether AMPK is a key participant or bystander in other disease states and whether its selective manipulation may significantly benefit these conditions remain important questions.

Key Words: AMPK • glycogen • metabolism • cardiomyopathy

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