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Rapid Activation by 3,5,3'-L-Triiodothyronine of Adenosine 5'-Monophosphate-Activated Protein Kinase/Acetyl-Coenzyme A Carboxylase and Akt/Protein Kinase B Signaling Pathways: Relation to Changes in Fuel Metabolism and Myosin Heavy-Chain Protein Content in Rat Gastrocnemius Muscle in Vivo

Dipartimento di Scienze della Vita (P.d.L., R.S., F.C., A.L.), Seconda Università degli Studi di Napoli, 81100 Caserta, Italy; Dipartimento di Scienze Biologiche ed Ambientali (M.M., E.S., F.G.), Università degli Studi del Sannio, 82100 Benevento, Italy; and Dipartimento delle Scienze Biologiche (A.L.), Sez. Fisiologia ed Igiene, Università degli Studi di Napoli "Federico II," 80134 Napoli, Italy

Address all correspondence and requests for reprints to: Pieter de Lange or Antonia Lanni, Dipartimento di Scienze della Vita, Seconda Università degli Studi di Napoli, Via Vivaldi 43, 81100 Caserta, Italy. E-mail: pieter.delange{at}unina2.it; antonia.lanni{at}unina2.it.

T₃ stimulates metabolic rate in many tissues and induces changes in fuel use. The pathways by which T₃ induces metabolic/structural changes related to altered fuel use in skeletal muscle have not been fully clarified. Gastrocnemius muscle (isolated at different time points after a single injection of T₃ into hypothyroid rats), displayed rapid inductions of AMP-activated protein kinase (AMPK) phosphorylation (threonine 172; within 6 h) and acetyl-coenzyme A carboxylase phosphorylation (serine 79; within 12 h). As a consequence, increases occurred in mitochondrial fatty acid oxidation and carnitine palmitoyl transferase activity. Concomitantly, T₃ stimulated signaling toward increased glycolysis through a rapid increase in Akt/protein kinase B (serine 473) phosphorylation (within 6 h) and a directly related increase in the activity of phosphofructokinase. The kinase specificity of the above effects was verified by treatment with inhibitors of AMPK and Akt activity (compound C and wortmannin, respectively). In contrast, glucose transporter 4 translocation to the membrane (activated by T₃ within 6 h) was maintained when either AMPK or Akt activity was inhibited. The metabolic changes were accompanied by a decline in myosin heavy-chain Ib protein [causing a shift toward the fast-twitch (glycolytic) phenotype]. The increases in AMPK and acetyl-coenzyme A carboxylase phosphorylation were transient events, both levels declining from 12 h after the T₃ injection, but Akt phosphorylation remained elevated until at least 48h after the injection. These data show that in skeletal muscle, T₃ stimulates both fatty acid and glucose metabolism through rapid activations of the associated signaling pathways involving AMPK and Akt/protein kinase B.