Cytosolic citrate and malonyl-CoA regulation in rat muscle in vivo

In liver, insulin and glucose acutely increase the concentration of malonyl -CoA by dephosphorylating and activating acetyl-CoA carboxylase (ACC). In c ontrast, in incubated rat skeletal muscle, they appear to act by increasing the cytosolic concentration of citrate, an allosteric activator of ACC, as reflected by increases in the whole cell concentrations of citrate and mal ate [Saha, A. K., D. Vavvas, T. G. Kurowski, A. Apazidis, L. A. Witters, E. Shafrir, and N. B. Ruderman. Am. J. Physiol. 272 (Endocrinol. Metab. 35): E641-E648, 1997]. We report here that sustained increases in plasma insulin and glucose may also increase the concentration of malonyl-CoA in rat skel etal muscle in vivo by this mechanism. Thus 70 and 125% increases in malony l-CoA induced in skeletal muscle by infusions of glucose for 1 and 4 days, respectively, and a twofold increase in its concentration during a 90-min e uglycemic-hyperinsulinemic clamp were all associated with significant incre ases in the sum of whole cell concentrations of citrate and/or malate. Simi lar correlations were observed in muscle of the hyperinsulinemic fa lfa rat , in denervated muscle, and in muscle of rats infused with insulin for 5 h. In muscle of 48-h-starved rats 3 and 24 h after refeeding, increases in ma lonyl-CoA mere not accompanied by consistent increases in the concentration s of malate or citrate. However, they were associated with a decrease in th e whole cell concentration of long-chain fatty acyl-CoA (LCFA-CoA), an allo steric inhibitor of ACC. The results suggest that increases in the concentr ation of malonyl-CoA, caused in rat muscle in vivo by sustained increases i n plasma insulin and glucose or denervation, may be due to increases in the cytosolic concentration of citrate. In contrast, during refeeding after st arvation, the increase in malonyl-CoA in muscle is probably due to another mechanism.