One exercise session can increase subsequent insulin-stimulated glucose uptake (ISGU) by healthy skeletal muscle, and recently published research linked this outcome to exercise-induced elevation in γ3-AMPK activity which leads to greater phosphorylation of Akt substrate of 160 kDa (pAS160) on an AMPK-phosphomotif (Ser704), which in turn favors greater insulin-stimulated pAS160 on a key Akt-phosphomotif (Thr642) that regulates ISGU. Studying healthy muscle is important, but a more urgent need is to understand the mechanisms for enhanced ISGU in insulin resistant muscle. Our primary goal was to determine if exercise, which increases ISGU, also increases γ3-AMPK activity and pAS160 on key regulatory sites at 3-hours post-exercise (3hPEX) in insulin resistant muscle. Rats fed a high fat diet (HFD; 2 week) known to cause muscle insulin resistance performed acute swim exercise (2 h) or remained sedentary (SED). Other chow-fed (low fat diet, LFD; 2 week) SED rats served as healthy controls. Isolated epitrochlearis muscles from 3hPEX rats (and SED controls) were used for ISGU, pAS160 and γ1- and γ3-AMPK isoform-specific activity. ISGU was lower in HFD SED muscles compared to LFD SED, but this decrement was eliminated in the HFD 3hPEX group. The γ3-AMPK activity, but not γ1-AMPK activity, was elevated in HFD 3hPEX muscles versus both SED controls. In addition, insulin-stimulated pAS160 on Thr642 and Ser704 in HFD 3hPEX muscles was elevated above HFD SED controls and equal to values in LFD SED muscles. These novel results demonstrated, for the first time in an insulin-resistant model, that the post-exercise increase in ISGU was accompanied by enhanced pAS160Ser704 and γ3-AMPK activation. Our working hypothesis is that these key signaling events are necessary for acute exercise to restore the ISGU of insulin resistant muscles to values equal to normal LFD SED controls.


M.W. Pataky: None. E.B. Arias: None. X. Zheng: None. H. Wang: None. G.D. Cartee: None.


National Institute of Diabetes and Digestive and Kidney Diseases

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