AICA riboside increases AMP-activated protein kinase, fatty acid oxidation, and glucose uptake in rat muscle

TLDR

AICAR is taken up by cells and phosphorylated to ZMP, an AMP analog. The study aimed to test whether AICAR activates AMPK in skeletal muscle, thereby phosphorylating ACC, lowering malonyl‑CoA, and boosting fatty‑acid oxidation. Rat hindlimbs were perfused with Krebs‑Henseleit bicarbonate, 4 % BSA, washed red blood cells, 200 µU ml⁻¹ insulin, 10 mM glucose, with or without 0.5–2.0 mM AICAR. AICAR perfusion activated AMPK, inactivated ACC, decreased malonyl‑CoA, increased fatty‑acid oxidation 2.8‑fold and glucose uptake at 2 mM, while oxygen consumption remained unchanged, indicating that reduced malonyl‑CoA enhances fatty‑acid oxidation.

Abstract

5-Aminoimidazole-4-carboxamide ribonucleoside (AICAR) has previously been reported to be taken up into cells and phosphorylated to form ZMP, an analog of 5′-AMP. This study was designed to determine whether AICAR can activate AMP-activated protein kinase (AMPK) in skeletal muscle with consequent phosphorylation of acetyl-CoA carboxylase (ACC), decrease in malonyl-CoA, and increase in fatty acid oxidation. Rat hindlimbs were perfused with Krebs-Henseleit bicarbonate containing 4% bovine serum albumin, washed bovine red blood cells, 200 μU/ml insulin, and 10 mM glucose with or without AICAR (0.5–2.0 mM). Perfusion with medium containing AICAR was found to activate AMPK in skeletal muscle, inactivate ACC, and decrease malonyl-CoA. Hindlimbs perfused with 2 mM AICAR for 45 min exhibited a 2.8-fold increase in fatty acid oxidation and a significant increase in glucose uptake. No difference was observed in oxygen uptake in AICAR vs. control hindlimb. These results provide evidence that decreases in muscle content of malonyl-CoA can increase the rate of fatty acid oxidation.