Evidence from transgenic mice that glucose transport is rate-limiting for glycogen deposition and glycolysis in skeletal muscle

A line of transgenic mice was constructed in which the human Glut1 glucose transporter is overexpressed in skeletal muscle. Overexpression of Glut1 protein was evident in epitrochlearis, extensor digitorum longus (EDL), and quadriceps muscles, and resulted in 6.6-7.4-fold elevations in basal glucose transport activity as measured in isolated muscles in vitro. The elevated glucose transporter activity in the skeletal muscles of transgenic mice was associated with a 10-fold increase in glycogen concentration in EDL and quadriceps muscles that was not due to an increase in muscle glycogen synthase activity or a decrease in glycogen phosphorylase activity. The increased glucose transport activity also resulted in a 2-fold increase in muscle lactate concentration, with no increase in muscle glucose 6-phosphate. Despite a slight (10%) increase in muscle hexokinase activity, there was a 4-fold increase in total muscle free glucose in transgenic mice, indicating that hexokinase becomes rate-limiting for glucose uptake when the rate of glucose transport is very high. These results demonstrate that the muscle glycogen content can be dramatically elevated by increasing the muscle Glut1 protein level and that glucose transport is a rate-limiting step for muscle glucose disposal in normal, resting mice.