CALCIUM STIMULATES GLUCOSE-TRANSPORT IN SKELETAL-MUSCLE BY A PATHWAY INDEPENDENT OF CONTRACTION

In this study we investigated the possibility that an increase in cytoplasmic Ca2+ concentration that is too low to cause muscle contraction can induce an increase in glucose transport activity in skeletal muscle. The compound N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7), which induces Ca2+ release from the sarcoplasmic reticulum (SR), caused a dose-dependent increase in tension in rat epitrochlearis muscles at concentrations more than approximately 200 mu-M. Although 100-mu-M W-7 did not increase muscle tension, it accelerated loss of preloaded 45Ca2+. Glucose transport activity, measured with the nonmetabolizable glucose analogue 3-O-methylglucose, increase sixfold in muscles treated for 100 min with 50-mu-M W-7 (P < 0.001) and eightfold in response to 100 mu-M W-7 (P < 0.001). The increase in glucose transport activity was completely blocked with 25-mu-M cytochalasin B. There was no decrease in ATP or creatine phosphate concentrations ([approximately P]) in muscles incubated with 50-mu-M W-7. Dantrolene (25 mu-M), which blocks Ca2+ release from the SR, blocked the effects of W-7 both on 45Ca2+ release and on glucose transport activity. 9-Aminoacridine, another inhibitor of Ca2+ release from the SR, also blocked the stimulation of hexose transport by W-7. Caffeine, a compound structurally unrelated to W-7 that also releases Ca2+ from the SR, also increased glucose transport activity. Incubation of muscles with 3 mM caffeine for 30 min, which did not cause contraction or lower [approximately P], induced a threefold increase in 3-O-methylglucose transport (P < 0.001). These results provide evidence suggesting that an increase in cytoplasmic Ca2+ too low to cause contraction or [approximately P] depletion can bring about an increase in glucose transport activity in skeletal muscle.