587-P: AS160 Expression, but Not AS160 Serine-588, Threonine-642, and Serine-704 Phosphorylation, Is Essential for Elevated Insulin-Stimulated Glucose Uptake by Skeletal Muscle from Female Rats after Acute Exercise

Abstract

One exercise bout can substantially enhance subsequent insulin-stimulated glucose uptake (ISGU) in skeletal muscle. Evidence suggests that the insulin signaling protein Akt Substrate of 160 kDa (AS160; also known as TBC1D4) may be involved in this outcome. Supporting this idea, we recently reported that in male rats, AS160 expression was essential for increased postexercise-ISGU (PEX-ISGU). Furthermore, AS160 phosphorylation on Ser588, Thr642, and Ser704 was required for a portion (~45%) of the elevated PEX-ISGU. We now use the same approach to test AS160’s role in elevated PEX-ISGU in female rats. The initial experiment tested if AS160 is essential for exercise effects on ISGU by studying wildtype (WT) and AS160-kockout (AS160-KO) rats. The next experiment used AS160-KO rats together with an adeno-associated virus (AAV) approach to determine if AAV-delivery of WT-AS160 could restore the exercise benefit on ISGU. The final experiment employed AS160-KO rats and AAV-delivery of either WT-AS160 or AS160 mutated to prevent phosphorylation of key sites (Ser588, Thr642, and Ser704) to evaluate the requirement of phosphorylation on these sites for improved PEX-ISGU. The results from the first two experiments using female rats were very similar to our earlier findings with male rats: 1) AS160 expression was essential for increase PEX-ISGU; and 2) restoring muscle AS160 expression of AS160-KO rats rescued exercise’s ability to improve ISGU. However, in contrast to the results in male rats, preventing AS160 phosphorylation on Ser588, Thr642, and Ser704 did not diminish the magnitude of elevated PEX-ISGU in female rats. Future research will be required to elucidate the mechanisms underlying the sexual dimorphism with regard to the role of AS160 phosphorylation in elevated PEX-ISGU. Disclosure H.Wang: None. A.Zheng: None. E.B.Arias: None. S.Kwak: None. X.Pan: None. Y.Yue: None. D.Duan: None. G.D.Cartee: None. Funding National Institutes of Health (R01DK071771)