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Download fileThe Exercise-induced Improvement in Insulin-stimulated Glucose Uptake by Rat Skeletal Muscle Is Absent in Male AS160-Knockout Rats, Partially Restored by Muscle Expression of Phosphomutated AS160, and Fully Restored by Muscle Expression of Wildtype AS160
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posted on 2021-11-09, 17:16 authored by Amy Zheng, Edward B. Arias, Haiyan Wang, Seong Eun Kwak, Xiufang Pan, Dongsheng Duan, Gregory D. CarteeOne exercise session can elevate insulin-stimulated glucose uptake
(ISGU) in skeletal muscle, but the mechanisms remain elusive. Circumstantial evidence
suggests a role for Akt substrate of 160 kDa (AS160 or TBC1D4). We used genetic
approaches to rigorously test this idea. The initial experiment evaluated
AS160’s role for the postexercise increase in ISGU using muscles from male wildtype
(WT) and AS160-knockout (AS160-KO) rats. The next experiment used AS160-KO rats
with an adeno-associated virus (AAV) approach to determine if rescuing muscle AS160
deficiency could restore exercise’s ability to improve ISGU. The third
experiment tested if eliminating the muscle GLUT4 deficit in AS160-KO rats via
AAV-delivered GLUT4 would enable postexercise enhancement of ISGU. The final
experiment employed AS160-KO rats and AAV-delivery of AS160 mutated to prevent
phosphorylation of Ser588, Thr642, and Ser704 to evaluate their role in
postexercise ISGU. We discovered: 1) AS160 expression was essential for
postexercise increase in ISGU; 2) rescuing muscle AS160 expression of AS160-KO
rats restored postexercise enhancement of ISGU; 3) restoring GLUT4 expression
in AS160-KO muscle did not rescue the postexercise increase in ISGU; and 4) although
AS160 phosphorylation on 3 key sites was not required for postexercise
elevation in ISGU, it was essential for the full-exercise effect.