AMP-Activated Protein Kinase in the Heart

Abstract

Abstract-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. (Circ Res. 2007;100:474-488.)

The role of autophagy in the heart

“…67 AMP binding facilitates AMPK activation by upstream kinases, such as LKB1 and Ca 2 þ /calmodulin-dependent protein kinase kinase b. 68 In addition, LKB1 can phosphorylate the a-subunit of AMPK at Thr172 independently of AMP in response to hypoxia. 69 Earlier, we have shown that AMPK plays an essential role in mediating autophagy in response to myocardial ischemia/hypoxia.…”

A preferred AMPK phosphorylation site adjacent to the inhibitory loop of cardiac and skeletal troponin I

“…1 Once activated, AMPK stimulates ATP-producing pathways and inhibits ATP-consuming pathways, resulting in an effort to maintain high cellular ATP levels. In skeletal and cardiac muscle, AMPK has been shown to stimulate glucose uptake, glycolysis, fatty acid oxidation, and mitochondrial biogenesis and to inhibit biosynthesis of lipids, glycogen, cholesterol, and proteins [2][3][4][5][6] by phosphorylation of key metabolic enzymes and activation of transcription factors. 7 Newer roles for AMPK now include regulation of cell growth and proliferation, development of cell polarity, and global regulation of food intake.…”

“…7 Newer roles for AMPK now include regulation of cell growth and proliferation, development of cell polarity, and global regulation of food intake. 7,8 Despite extensive research on the physiological role of AMPK in the metabolism of heart and skeletal muscle, [3][4][5][6]9,10 the ability of AMPK to phosphorylate myofilament proteins and, thereby, regulate the contractile apparatus in striated muscle remains unclear.…”

“…26 Multiple studies suggested that AMPK is the most important regulator of energy consumption in the heart. 3,5,6 Hence, we reasoned that AMPK, a critical regulator of cardiac energetics, may be able to regulate energy consumption by the contractile apparatus through altering the phosphorylation status of cTnI.…”

Activation of AMPK inhibits cardiomyocyte hypertrophy by modulating of the FOXO1/MuRF1 signaling pathway in vitro

“…In cardiomyocytes, these processes may determine the balance between prohypertrophic and antihypertrophic signals [30] . As a sensor of cellular energy status, AMPK responds to an increase in the ratio of AMP to ATP, which can be observed in response to starvation, exercise, and muscle contraction [20,32] . AMPK activation can influence the metabolism of cardiomyocytes by increasing glucose transport and glycolysis, as well as by regulating the oxidative phosphorylation of fatty acids [32] .…”