EVIDENCE FROM TRANSGENIC MICE THAT GLUCOSE-TRANSPORT IS RATE-LIMITINGFOR GLYCOGEN DEPOSITION AND GLYCOLYSIS IN SKELETAL-MUSCLE

A line of transgenic mice was constructed in which the human Glut1 glu cose transporter is overexpressed in skeletal muscle. Overexpression o f Glut1 protein was evident in epitrochlearis, extensor digitorum long us (EDL), and quadriceps muscles, and resulted in 6.6-7.4-fold elevati ons in basal glucose transport activity as measured in isolated muscle s in vitro. The elevated glucose transporter activity in the skeletal muscles of transgenic mice was associated with a 10-fold increase in g lycogen concentration in EDL and quadriceps muscles that was not due t o an increase in muscle glycogen synthase activity or a decrease in gl ycogen phosphorylase activity. The increased glucose transport activit y 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 i n total muscle free glucose in transgenic mice, indicating that hexoki nase becomes rate-limiting for glucose uptake when the rate of glucose transport is very high. These results demonstrate that the muscle gly cogen content can be dramatically elevated by increasing the muscle Gl ut1 protein level and that glucose transport is a rate-limiting step f or muscle glucose disposal in normal, resting mice.