THE EFFECTS OF WORTMANNIN ON RAT SKELETAL-MUSCLE - DISSOCIATION OF SIGNALING PATHWAYS FOR INSULIN-ACTIVATED AND CONTRACTION-ACTIVATED HEXOSE-TRANSPORT

Both the anabolic hormone insulin and contractile activity stimulate t he uptake of glucose into mammalian skeletal muscle, In this study, we examined the role of phosphatidylinositol 3-kinase (PI 3-kinase), a p utative mediator of insulin actions, in the stimulation of hexose upta ke in response to hormone and contraction, Phosphatidylinositol 3,4-bi sphosphate and phosphatidylinositol 3,4,5-triphosphate accumulate in s keletal muscle exposed to insulin but not hypoxia, which mimics stimul ation of the contractile-dependent pathway of hexose transport activat ion, The fungal metabolite wortmannin, an inhibitor of PI 3-kinase, co mpletely blocks the appearance of 3'-phospholipids in response to insu lin, Moreover, wortmannin entirely prevented the increase in hexose up take in muscle exposed to insulin but was without effect on muscle sti mulated by repetitive contraction or hypoxia, These results support th e view that PI 3-kinase is involved in the signaling pathways mediatin g insulin-responsive glucose transport in skeletal muscle but is not r equired for stimulation by hypoxia or contraction, Furthermore, these data indicate that there exist at least two signaling pathways leading to activation of glucose transport in skeletal muscle with differenti al sensitivities to wortmannin.