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J Biol Chem, Vol. 273, Issue 24, 14679-14682, June 12, 1998

COMMUNICATION
Insulin, but Not Contraction, Activates Akt/PKB in Isolated Rat Skeletal Muscle

From the Howard Hughes Medical Institute, Department of Medicine and The Cox Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6148

Insulin and muscle contraction potently stimulate glucose uptake in mammalian skeletal muscle. Studies in muscle and adipose tissue have shown that insulin induces its receptor-dependent phosphorylation of insulin receptor substrates 1 and 2, which leads to activation of polyphosphatidylinositol (PI) 3'-kinase. In contrast, muscle contraction stimulates glucose transport via a mechanism that is independent of insulin, but the two pathways may converge downstream at the level of stimulation of GLUT4 translocation. In the present study, we have examined the role of Akt, an insulin-activated serine threonine kinase that has previously been shown to increase glucose transport in adipocytes. Either insulin or in vitro muscle contraction significantly elevated glucose transport in isolated rat epitrochlearis and soleus muscles. However, Akt kinase activity was significantly stimulated by insulin and not contraction. Moreover, wortmannin, an inhibitor of PI 3'-kinase, completely blocked the insulin-stimulated increase in Akt activity and glucose transport but did not alter either of these parameters in contracting muscles. The increases in Akt activity were paralleled by a decrease in the electrophoretic mobility of Akt, indicative of phosphorylation of Akt by an upstream kinase. These changes in Akt mobility appeared to be at least partially because of phosphorylation of Akt on serine 473. A putative downstream target of Akt, p70 S6 kinase, showed similar changes in mobility in response to insulin but not contraction. These data support the view that Akt is a downstream target of PI 3'-kinase and is involved in the signaling pathways involved in insulin but not contraction stimulation of glucose transport in skeletal muscle. These data provide further evidence that two distinct pathways exist for the stimulation of glucose transport in mammalian skeletal muscle.

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