Effects of epinephrine and cyclic AMP phosphodiesterase inhibitors on the glycogen synthetic pathway and glucose content in skeletal muscle

The actions on carbohydrate metabolism of epinephrine and the cyclic AMP phosphodiesterase inhibitors, theophylline and SQ 20009, were studied using rat hemidiaphragms incubated in vitro. The inhibition of glucose uptake produced by epinephrine was almost equal to the decrease in the incorporation of [ 14C]glucosc into glycogen, while incorporation into lactate of 14C from labeled glucose was not influenced by the hormone. Although epinephrine decreased total tissue glycogen, it had relatively little effect on the removal of radioactive glucose incorporated into glycogen during a preincubation in the absence of hormone when the tissue was subsequently incubated with nonradioactive glucose. This indicates that the decrease in the net incorporation of [ 14C]glucose into glycogen produced by the hormone in vitro is caused predominantly by an inhibition of glycogen synthesis and cannot be accounted for by an increase in the turnover rate of glycogen. Theophylline and SQ 20009 produced a dose-dependent inhibition of glucose uptake and glycogen synthesis, similar to that of epinephrine. Incubation of hemidiaphragms with epinephrine or cyclic AMP phosphodiesterase inhibitors in the presence of glucose led to an increased intracellular accumulation of glucose. Possible explanations for this phenomenon are discussed. The uptake of the nonmetabolizable sugar. 3- O-methylgucose, by skeletal muscle was not affected by epinephrine, indicating that the hormone influences only the uptake of the natural substrate, glucose, which can be incorporated into glycogen. The alterations in muscle metabolism described here were associated with increases in the tissue content of cyclic AMP and it was concluded that an important action of epinephrine in resting muscle is a cyclic AMP-mediated inhibition of the glucose-to-glycogen synthetic pathway.