Metabolic adaptations in skeletal muscle overexpressing GLUT4: effects on muscle and physical activity

To understand the long-term metabolic and functional, consequences of incre ased GLUT4 con tent, intracellular substrate utilization was investigated i n isolated muscles of transgenic mice overexpressing GLUT4 selectively in f ast-twitch skeletal muscles. Rates of glycolysis, glycogen synthesis, gluco se oxidation, and free fatty acid (FFA) oxidation as well as glycogen conte nt were assessed in isolated EDL (fast-twitch) and soleus (slow-twitch) mus cles from female and male MLC-GLUT4 transgenic and control mice. In male ML C-GLUT4 EDL, increased glucose influx predominantly led to increased glycol ysis. In contrast, in female MLC-GLUT4 EDL increased glycogen synthesis was observed. In both sexes, GLUT4 overexpression resulted in decreased exogen ous FFA oxidation rates. The decreased rate of FFA oxidation in male MLC-GL UT4 EDL was associated with increased lipid con tent in liver, but not in m uscle or at the whole body level. To determine how changes in substrate met abolism and insulin action may influence energy balance in an environment t hat encouraged physical activity, we measured voluntary training activity, body weight, and food consumption of MLC-GLUT4 and control mice in cages eq uipped with training wheels. We observed a small decrease in body weight of MLC-GLUT4 mice that was paradoxically accompanied by a 45% increase in foo d consumption. The results were explained by a marked fourfold increase in voluntary wheel exercise. The changes in substrate metabolism and physical activity in MLC-GLUT4 mice were not associated with dramatic changes in ske letal muscle morphology. Collectively, results of this study demonstrate th e feasibility of altering muscle substrate utilization by overexpression of GLUT4. The results also suggest that as a potential treatment for type II diabetes mellitus, increased skeletal muscle GLUT4 expression may provide b enefits in addition to improvement of insulin action.