UCP-3 expression in skeletal muscle: effects of exercise, hypoxia, and AMP-activated protein kinase

Uncoupling protein 3 (UCP-3), a member of the mitochondrial transporter sup erfamily, is expressed primarily in skeletal muscle where it may play a rol e in altering metabolic function under conditions of fuel depletion caused, for example, by fasting and exercise. Here, we show that treadmill running by rats rapidly (30 min) induces skeletal muscle UCP-3 mRNA expression (se venfold after 200 min), as do hypoxia and swimming in a comparably rapid an d substantial fashion. The expression of the mitochondrial transporters, ca rnitine palmitoyltransferase 1 and the tricarboxylate carrier, is unaffecte d under these conditions. Hypoxia and exercise-mediated induction of UCP-3 mRNA result in a corresponding four- to sixfold increase in rat UCP-3 prote in. We treated extensor digitorum longus (EDL) muscle with 5'-amino-4-imida zolecarboxamide ribonucleoside (AICAR), a compound that activates AMP-activ ated protein kinase (AMPK), an enzyme known to be stimulated during exercis e and hypoxia. Incubation of rat EDL muscle in vitro for 30 min with 2 mM A ICAR causes a threefold increase in UCP-3 mRNA and a 1.5-fold increase of U CP-3 protein compared with untreated muscle. These data are consistent with the notion that activation of AMPK, presumably as a result of fuel depleti on, rapidly regulates UCP-3 gene expression.