Activation of malonyl-CoA decarboxylase in rat skeletal muscle by contraction and the AMP-activated protein kinase activator 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside

Alterations in the concentration of malonyl-CoA, an inhibitor of carnitine palmitoyltransferase I, have been linked to the regulation of fatty acid ox idation in skeletal muscle. During contraction decreases in muscle malonyl- CoA concentration have been related to activation of AMP-activated protein kinase (AMPK), which phosphorylates and inhibits acetyl-CoA carboxylase (AC C), the rate-limiting enzyme in malonyl-CoA formation. We report here that the activity of malonyl-CoA decarboxylase (MCD) is increased in contracting muscle, Using either immunopurified enzyme or enzyme partially purified by (NH4)(2)SO4 precipitation, 2-3-fold increases in the V-max of MCD and a 40 % decrease in its K-m for malonyl-CoA (190 versus 119 mu M) were observed i n rat gastrocnemius muscle after 5 min of contraction, induced by electrica l stimulation of the sciatic nerve. The increase in MCD activity was marked ly diminished when immunopurified enzyme was treated with protein phosphata se 2A or when phosphatase inhibitors were omitted from the homogenizing sol ution and assay mixture. Incubation of extensor digitorum longus muscle for 1 h with 2 mM 5-aminoimidazole-4-carboxamide-1-beta-D-rib furanoside, a ce ll-permeable activator of AMPK, increased MCD activity g-fold, Here, too, a ddition of protein phosphatase 2A to the immunopellets reversed the increas e of MCD activity. The results strongly suggest that activation of AMPK dur ing muscle contraction leads to phosphorylation of MCD and an increase in i ts activity. They also suggest a dual control of malonyl-CoA concentration by ACC and MCD, via AMPK, during exercise.