Metabolic stress and altered glucose transport - Activation of AMP-activated protein kinase as a unifying coupling mechanism

5' AMP-activated protein kinase (AMPK) can be activated in response to cell ular fuel depletion and leads to switching off ATP-consuming pathways and s witching on ATP-regenerating pathways in many cell types. We have hypothesi zed that AMPK is a central mediator of insulin-independent glucose transpor t, which enables fuel-depleted muscle cells to take up glucose for ATP rege neration under conditions of metabolic stress. To test this hypothesis, rat epitrochlearis muscles were isolated and incubated in vitro under several conditions that evoke metabolic stress accompanied by intracellular fuel de pletion, Rates of glucose transport in the isolated muscles were increased by all of these conditions, including contraction (5-fold above basal), hyp oxia (8-fold), 2,4-dinotrophenol (11-fold), rotenone (7-fold), and hyperosm olarity (8-fold). All of these stimuli simultaneously increased both alpha 1 and alpha 2 isoform-specific AMPK activity. There was close correlation b etween alpha 1 (r(2) = 0.72) and alpha 2 (r(2) = 0.67) AMPK activities and the rate of glucose transport, irrespective of the metabolic stress used, a ll of which compromised muscle fuel status as judged by ATP, phosphocreatin e, and glycogen content, 5-Aminoimidazole-4-carboxamide ribonucleoside, a p harmacological AMPK activator that is metabolized to an AMP-mimetic ZMP, al so increased both glucose transport and AMPK activity but did not change fu el status, Insulin stimulated glucose transport by 6.5-fold above basal but did not affect AMPK activity, These results suggest that the activation of AMPK may be a common mechanism leading to insulin-independent glucose tran sport in skeletal muscle under conditions of metabolic stress.