AICA RIBOSIDE INCREASES AMP-ACTIVATED PROTEIN-KINASE, FATTY-ACID OXIDATION, AND GLUCOSE-UPTAKE IN RAT MUSCLE

5-Aminoimidazole-4-carboxamide ribonucleoside (AICAR) has previously b een reported to be taken up into cells and phosphorylated to form ZMP, an analog of 5'-AMP. This study was designed to determine whether AIC AR can activate AMP-activated protein kinase (AMPK) in skeletal muscle with consequent phosphorylation of acetyl-CoA carboxylase (ACC), decr ease in malonyl-CoA, and increase in fatty acid oxidation. Rat hindlim bs were perfused with Krebs-Henseleit bicarbonate containing 4% bovine serum albumin, washed bovine red blood cells, 200 mu U/ml insulin, an d 10 mM glucose with or without AICAR (0.5-2.0 mM). Perfusion with med ium containing AICAR was found to activate AMPK in skeletal muscle, in activate ACC, and decrease malonyl-CoA. Hindlimbs perfused with 2 mM A ICAR for 45 min exhibited a 2.8-fold increase in fatty acid oxidation and a significant increase in glucose uptake. No difference was observ ed in oxygen uptake in AICAR vs. control hindlimb. These results provi de evidence that decreases in muscle content of malonyl-CoA can increa se the rate of fatty acid oxidation.