Exercise promotes glucose clearance by increasing skeletal muscle Glut4 (glucose transporter 4)-mediated glucose uptake. Importantly, exercise upregulates muscle Glut4 expression in an insulin-independent manner under conditions of insulin resistance, such as with type 2 diabetes. However, the insulin-independent mechanism responsible for rescued muscle Glut4 expression is poorly understood. In this study, we use voluntary wheel running (VWR) in mice to test the prevailing hypothesis that insulin-independent upregulation of skeletal muscle Glut4 protein expression with exercise is through increased Glut4 transcription. We demonstrated that four weeks of VWR exercise in obese mice rescued high fat diet (HFD)-induced decreased muscle Glut4 protein, and improved both fasting plasma insulin and hepatic triglyceride (TAG) levels, but did not rescue muscle Glut4 mRNA. Persistent reduction in Glut4 mRNA suggested a post-transcriptional mechanism regulated insulin-independent muscle Glut4 protein expression in response to exercise in lean and obese mice. Reduction of Glut4 protein in sedentary animals upon treatment with rapamycin revealed mTORC1-dependent Glut4 regulation. However, no difference in Glut4 protein expression was observed in VWR-exercised mice treated with either rapamycin or Torin 1, indicating that exercise-dependent regulation on Glut4 was mTOR-independent. Our novel findings provide new insight on mechanisms responsible for exercise-dependent regulation of Glut4 in muscle.
- Received March 4, 2016.
- Accepted July 5, 2016.
- © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.