Role of AMP-activated protein kinase in healthy and diseased hearts

Abstract

Dolinsky, Vernon W., and Jason R. B. Dyck. Role of AMP-activated protein kinase in healthy and diseased hearts. Am J Physiol Heart Circ Physiol 291: H2557-H2569, 2006. First published July 14, 2006 doi:10.1152/ajpheart.00329.2006.-The heart is capable of utilizing a variety of substrates to produce the necessary ATP for cardiac function. AMP-activated protein kinase (AMPK) has emerged as a key regulator of cellular energy homeostasis and coordinates multiple catabolic and anabolic pathways in the heart. During times of acute metabolic stresses, cardiac AMPK activation seems to be primarily involved in increasing energy-generating pathways to maintain or restore intracellular ATP levels. In acute situations such as mild ischemia or short durations of severe ischemia, activation of cardiac AMPK appears to be necessary for cardiac myocyte function and survival by stimulating ATP generation via increased glycolysis and accelerated fatty acid oxidation. Whereas AMPK activation may be essential for adaptation of cardiac energy metabolism to acute and/or minor metabolic stresses, it is unknown whether AMPK activation becomes maladaptive in certain chronic disease states and/or extreme energetic stresses. However, alterations in cardiac AMPK activity are associated with a number of cardiovascular-related diseases such as pathological cardiac hypertrophy, myocardial ischemia, glycogen storage cardiomyopathy, and Wolff-Parkinson-White syndrome, suggesting the possibility of a maladaptive role. Although the precise role AMPK plays in the diseased heart is still in question, it is clear that AMPK is a major regulator of cardiac energy metabolism. The consequences of alterations in AMPK activity and subsequent cardiac energy metabolism in the healthy and the diseased heart will be discussed. ischemia; cardiac hypertrophy; cardiac energy metabolism; glycogen THE HEART is capable of utilizing a variety of substrates to meet its immense demand for energy. Under normal physiological circumstances, cardiac function is dependent on the production of intracellular ATP derived primarily by the utilization of fatty acids, glucose, and lactate (123). A variety of transport proteins and regulatory enzymes control the uptake and subsequent metabolism of these energy substrates. Whereas many of these enzymes are regulated through substrate supply and/or energy demand, covalent modification of a number of these enzymes is also important. These regulatory mechanisms mediate substrate utilization and are essential for proper cardiac function.Fatty acids provide a concentrated supply of energy accounting for ϳ50 -75% of the myocardial acetyl CoA-derived ATP (84). Upon entering the cardiac myocyte, fatty acids are transported into the mitochondria and undergo ␤-oxidation to produce acetyl CoA that is eventually used to produce ATP. Glucose is transported into the cell via glucose transporters (GLUT) and can undergo glycolytic metabolism to generate pyruvate and ATP. This can occur in the absence of oxygen while still producing ATP. However, i...

Resveratrol protects ROS-induced cell death by activating AMPK in H9c2 cardiac muscle cells

“…AMPK phosphorylates a range of metabolic enzymes and has been shown to be implicated in various physiological functions including stress-induced cellular protection [10]. The physiological or stress conditions known to activate AMPK include exercise, nutritional starvation, heat shock, oxidative stress and ischemia/hypoxia [6]. In this study the activation of AMPK is connected to protection from cellular apoptosis processing; thus, AMPK plays a critical role in the protection against cellular death.…”

Recycle or die: The role of autophagy in cardioprotection

“…Generation of ATP via oxidative phoshorylation is inhibited during ischemia and reduced ATP levels have been shown to induce autophagy [1,10]. AMP kinase (AMPK) is involved in activating energy-generating pathways to maintain or restore ATP levels [54] and has been reported to upregulate autophagy [55][56][57]. AMPK is activated during ischemia and was recently shown to play a role in upregulaing autophagy during ischemia [10].…”

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.…”