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Caffeine activates 5′AMP-activated protein kinase (AMPK), a signalling intermediary implicated in the regulation of glucose, lipid and energy metabolism in skeletal muscle. Skeletal muscle expresses two catalytic α subunits of AMPK, α1 and α2, but the isoform specificity of caffeine-induced AMPK activation is unclear. The aim of this study was to determine which α isoform is preferentially activated by caffeine in vitro and in vivo using rat skeletal muscle.Rat epitrochlearis muscle was isolated and incubated in vitro in the absence or presence of caffeine. In another experiment, the muscle was dissected after intravenous injection of caffeine. Isoform-specific AMPK activity, the phosphorylation status of AMPKα Thr172 and acetyl-CoA carboxylase (ACC) Ser79, the concentrations of ATP, phosphocreatine (PCr) and glycogen, and 3-O-methyl-D-glucose (3MG) transport activity were estimated.Incubation of isolated epitrochlearis muscle with 1 mM of caffeine for 15 min increased AMPKα1 activity, but not AMPKα2 activity; concentrations of ATP, PCr and glycogen were not affected. Incubation with 3 mM of caffeine activated AMPKα2 and reduced PCr and glycogen concentrations. Incubation with 1 mM of caffeine increased the phosphorylation of AMPK and ACC and enhanced 3MG transport. Intravenous injection of caffeine (5 mg kg−1) predominantly activated AMPKα1 and increased 3MG transport without affecting energy status.Our results suggest that of the two α isoforms of AMPK, AMPKα1 is predominantly activated by caffeine via an energy-independent mechanism and that the activation of AMPKα1 increases glucose transport and ACC phosphorylation in skeletal muscle.