Activation of Malonyl-CoA Decarboxylase in Rat Skeletal Muscle by Contraction and the AMP-activated Protein Kinase Activator 5-Aminoimidazole-4-carboxamide-1-β-d-ribofuranoside

Abstract

The role of malonyl-CoA, an inhibitor of carnitine palmitoyltransferase I, in regulating the oxidation of fatty acids in rat skeletal (1, 2) and cardiac (3, 4) muscle has been intensively investigated. Recent studies have demonstrated that its concentration in rat muscle is governed, at least in part, by changes in the activity of the muscle isoform of acetyl-CoA carboxylase (ACC ␤ ) 1 (5), the enzyme that catalyzes malonylCoA synthesis. Thus, in keeping with their observed effects on malonyl-CoA concentration and fatty acid oxidation, insulin and glucose appear to activate ACC ␤ in muscle by increasing the cytosolic concentration of citrate, an allosteric activator of ACC ␤ and a precursor of its substrate, cytosolic acetyl-CoA. Conversely, decreases in malonyl-CoA concentration and increases in fatty acid oxidation in muscle during exercise (contraction) have been linked to decreases in ACC ␤ activity, attributable to its phosphorylation and inhibition by the ␣ 2 isoform of AMP-activated protein kinase (AMPK) (5). AMPK can also be activated and the concentration of malonyl-CoA decreased by exposing resting muscle to 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), which is taken into the muscle and phosphorylated to form the 5Ј-AMP analogue ZMP (6).Whether a change in malonyl-CoA turnover contributes to the alterations in its concentration in muscle during exercise and other conditions is not known. In a lipogenic tissue such as liver, the de novo synthesis of fatty acids is thought to be the major mechanism by which malonyl-CoA is utilized. In contrast, in skeletal muscle fatty acid synthesis occurs at a very low rate, if at all (7), and attention has been focused on malonyl-CoA decarboxylase (MCD) for removal of malonyl-CoA (1). Evidence has been presented that MCD is present in both cardiac (8, 9) and skeletal (1, 10, 11) muscle. In skeletal muscle, its activity is similar to that of ACC (1). In heart, in which MCD activity is substantially greater than in skeletal muscle, a decrease in the K m of MCD for malonyl-CoA has been reported following an increase in its work load (9). On the other hand, no change in activity has been observed following ischemia-reperfusion of the heart, a situation in which AMPK is activated (8). The question of whether MCD is acutely regulated in skeletal muscle and, if so, how has not been studied previously.In this study, we describe the characteristics of purified MCD from rat skeletal muscle and contraction-induced changes in its maximal activity and affinity for malonyl-CoA. In addition, the effects of the AMPK activator 5-aminoimida-

Malonyl-CoA and carnitine in regulation of fat oxidation in human skeletal muscle during exercise

“…This suggests that altered muscle glycogen alone can influence ␣ 2 -AMPK activity in human skeletal muscle during exercise independently of adrenergic stimulation, in agreement with studies in rodent muscle (8). On this basis, AMPK could be a likely candidate mediating the effect of muscle glycogen on fat oxidation through regulation of ACC activity and malonylCoA formation, as suggested earlier (34,41). However, the similar ACC␤ Ser 221 phosphorylation and malonyl-CoA concentration between L-CHO and H-CHO in the present study (Fig.…”

“…Alternatively, the activity of MCD, the enzyme catalyzing the turnover of malonyl-CoA, may have differed between the two conditions. It has been suggested that AMPK phosphorylates and activates MCD during muscle contraction (19,34). Consequently, the higher ␣ 2 -AMPK activity in L-CHO than in H-CHO might have induced higher malonylCoA turnover in L-CHO via an effect on MCD.…”

“…This is likely the mechanism whereby fat oxidation is inhibited by high glucose availability in resting humans (3,27). AMPK in turn regulates the concentration of malonylCoA by phosphorylating and inhibiting ACC (28) and possibly by activating malonyl-CoA decarboxylase (MCD), the major enzyme regulating malonyl-CoA turnover in muscle (34). During muscle contractions in rodents, AMPK is activated and ACC is phosphorylated and consequently inhibited, leading to a decrease in muscle malonyl-CoA concentration, which may induce the increase in fat oxidation at the onset of contraction (28).…”

Normal mitochondrial function and increased fat oxidation capacity in leg and arm muscles in obese humans

“…In skeletal muscle cells, AMPK increases FA oxidation by inhibiting ACC through phosphorylation, which reduces intracellular malonyl coenzyme A levels and thereby relieves the inhibition of carnitine palmitoyltransferase-1; this ultimately increases the influx and oxidation of long-chain FAs into the mitochondria. 46 However, in the PO group, resting phosphorylated AMPK and phosphorylated ACC levels were comparable to those observed in the C group, despite higher adiponectin levels, implying that this cannot explain the fact that fat oxidation is not normalized during leg exercise in PO individuals. On the other hand, when levels of these molecules in arm and leg muscles were compared within each group, both PO and O subjects showed disproportionate levels between arm and leg muscle, whereas C subjects had comparable levels.…”

AMP-activated protein kinase control of energy metabolism in the ischemic heart

“…Phosphorylation of acetyl CoA carboxylase by AMPK has been well documented 12 and although controversial, it has been suggested that malonyl CoA decarboxylase is also a phosphorylation target of AMPK. 17 Therefore, AMPK plays a distinct and important role in regulating both malonyl-CoA levels and fatty acid oxidation in the heart.…”