Characterization of the glucose transporters responsible for mechanical overloadstimulated glucose uptake in mouse skeletal muscle

Abstract

Resistance exercise training is a recommended form of physical activity for people with type 2 diabetes due to its ability to increase skeletal muscle glucose uptake. Understanding how resistance training controls muscle glucose uptake may lead to new type 2 diabetes treatments. Therefore, the overall objective of this dissertation was to identity the glucose transporter(s) that mediate muscle glucose uptake in response to mechanical overload, a model of resistance exercise training in rodents. Aim 1: Determine if glucose transporter 4 (GLUT4) is necessary for \ overload-stimulated skeletal muscle glucose uptake. Overload was induced by unilateral synergist ablation in the plantaris muscles of muscle-specific GLUT4 knockout mice. After 5 days, muscle glucose uptake was assessed. Intriguingly, the loss of GLUT4 did not impair the ability of overload to stimulate muscle glucose uptake. This exciting finding demonstrated that resistance training/mechanical overload stimulates muscle glucose uptake via a novel, exercise-responsive glucose transporter. Additional key characteristics of this novel transporter were identified and included: 1) localization to the plasma membrane; 2) ability to transport D-glucose, 2-deoxy-D-glucose, D-galactose and D xylose, but not D-fructose; and 3) binds the chemical cytochalasin B. Aim 2: Determine if glucose transporter 1 (GLUT1) is necessary for overload-stimulated skeletal muscle glucose uptake. Overload was induced by unilateral synergist ablation in the plantaris muscles of muscle-specific GLUT1 knockout mice. After 5 days, muscle glucose uptake was assessed. Surprisingly, the loss of GLUT1 did not impair either basal or overload-stimulated muscle glucose uptake. These unexpected findings demonstrated that the role of GLUT1 in muscle is presently unknown. In addition, this aim identified another key characteristic of the novel exercise/mechanical overload-responsive glucose transporter. The characteristic is that it binds the chemical BAY-876. These findings are significant because they challenge the dogma that in skeletal muscle that GLUT1 is the sole regulator of glucose uptake in the basal state and that GLUT4 is the sole exercise-responsive glucose transporter. In addition, this research represents a critical first step in the development of new type 2 diabetes therapies designed to utilize similar mechanisms as resistance training to stimulate glucose uptake into muscle.