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 Wild-Type AS160

Author:

Zheng Amy1,Arias Edward B.1,Wang Haiyan1,Kwak Seong Eun1,Pan Xiufang2,Duan Dongsheng2345,Cartee Gregory D.167ORCID

Affiliation:

1. Muscle Biology Laboratory, School of Kinesiology, University of Michigan, Ann Arbor, MI

2. Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia, MO

3. Department of Biomedical Sciences, College of Veterinary Medicine, University of Missouri, Columbia, MO

4. Department of Neurology, School of Medicine, University of Missouri, Columbia, MO

5. Department of Biomedical, Biological & Chemical Engineering, College of Engineering, University of Missouri, Columbia, MO

6. Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI

7. Institute of Gerontology, University of Michigan, Ann Arbor, MI

Abstract

One 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 the role of AS160 in postexercise increase in ISGU using muscles from male wild-type (WT) and AS160-knockout (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 the ability of exercise 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 used 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 the following: 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 three key sites was not required for postexercise elevation in ISGU, it was essential for the full exercise effect.

Publisher

American Diabetes Association

Subject

Endocrinology, Diabetes and Metabolism,Internal Medicine

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