>Mechanism for increasing muscle endurance via the small molecules AICAR

AICAR is a nucleoside that is taken up into muscle and converted into the nucleotide ZMP, which mimics the effects of the natural ligand, 5′-AMP, on AMPK. The latter is produced by adenylate kinase acting on ADP generated from ATP during muscle contraction. Activated AMPK in the nucleus (an alphabetagamma heterotrimer) then promotes expression of oxidative genes, in part by upregulating PGC-1alpha and switching on promoters with binding sites for PPAR-delta and its partner RXR. PPAR-delta can also be activated by GW1516, which may mimic a natural ligand produced by increased muscle metabolism. These dual mechanisms trigger expression of genes (including genes involved in fatty acid oxidation) that increase ATP production and hence endurance.