Activation of muscle fatty acid oxidation by AMPK AMP-activated protein kinase (AMPK), whether activated by exercise or by 5-aminoimidazole-4-carboxamide riboside (AICAR), phosphorylates and inactivates the ACC2 isoform of acetyl-CoA carboxylase (119) [which is associated with the mitochondrial membrane (1)], thus lowering malonyl-CoA. This relieves the inhibition of CPT1 (78), allowing fatty acids to enter mitochondria as carnitine esters (FA-carnitine). They are converted by carnitine:palmitoyl-CoA acyl transferase 2 (CPT2) back to fatty acyl-CoA (FA-CoA) esters in the mitochondrial matrix, where they are oxidized to generate ATP.
Metabolic changes known to be induced by AMPK in muscle, including stimulation of glucose and fatty acid uptake, fatty acid oxidation, and mitochondrial biogenesis, and inhibition of glycogen synthesis and, via inhibition of TOR, hypertrophy Question marks indicate that the direct target for AMPK responsible for the observed downstream effect is not known. The effect on fatty acid uptake has to date only been observed in cardiac muscle. The mechanisms of inhibition of fatty acid oxidation and the target of rapamycin (TOR) by AMPK is shown in more detail in FIGURES 1 AND 3.
Proposed mechanism of inhibition of TOR, and hence protein synthesis and muscle hypertrophy, by AMPK AMPK phosphorylates TSC2 (hamartin) at two sites (57). This is proposed to stimulate its GTPase activator protein (GAP) activity against the small G protein, Rheb, converting the latter to its GDP-bound form that no longer activates TOR. Two proteins downstream of TOR are 4E binding protein-1 (4EBP1) and S6kinase 1 (S6K1), and phosphorylation of both of these leads to stimulation of protein synthesis and hence muscle hypertrophy.