AMPK Regulation of Cardiac Metabolism in Heart Disease

AMP-activated protein kinase (AMPK) plays an important role in regulating cardiac metabolism, and once stimulated, AMPK turns on ATP-generating mechanisms believed to be essential in maintaining a normal heart function. AMPK is activated during various physiological or pathophysiological conditions. During cellular stresses, such as glucose deprivation, ischemia, hypoxia, and oxidative stress, ATP generation is compromised, leading to a rise in AMP/ATP ratio and activation of AMPK. During physiological conditions such as exercise, increased ATP consumption, rather than impaired ATP generation, changes the AMP/ATP ratio and stimulates AMPK. In cardiac muscle, AMPK promotes glucose uptake and glycolysis (through recruiting GLUT4 to the plasma membrane), fatty acid (FA) utilization (through its control of acetyl-CoA carboxylase), FA delivery (through its regulation of the FA transporter CD36 and lipoprotein lipase), and glycogen metabolism. Changes in metabolism have been closely linked to the development of heart disease. For example, in the heart, elevated FA use has been implicated in “lipotoxicity.” In addition to lipotoxicity, excessive FA compromises glucose oxidation, and glycogen accumulates, with attendant effects on cardiac contractility. Understanding the regulation of this important stress kinase is expected to shed light on how changes in cardiac metabolism play a crucial role in the development of heart disease.