EXERCISE IN TRANSGENIC MICE OVEREXPRESSING GLUT4 GLUCOSE TRANSPORTERS- EFFECTS ON SUBSTRATE METABOLISM AND GLYCOGEN REGULATION

We assessed the effects of GLUT4 glucose transporter expression on sub strate metabolism and glycogen regulation during exercise. Transgenic mice overexpressing human (h)GLUT4 in muscle and fat (TG) and their wi ld-type littermates (WT) were studied by indirect calorimetry at rest and during acute treadmill exercise (30 minutes) and recovery (30 minu tes). The rate of carbon dioxide production ((V) over dot co(2)) incre ased to a greater degree in TG during exercise, whereas resting (V) ov er dot co(2), resting oxygen production ((V) over dot o(2)), and exerc ise-induced increments in (V) over dot o(2) were similar in TG and WT. As a result, the respiratory quotient (RO) was increased by .03 to .0 5 in TG during exercise, due to greater consumption of carbohydrate (u p to similar to 64% more) and less consumption of lipid (up to similar to 40% less) compared with WT,without differences in overall energy e xpenditure. These differences in substrate metabolism were observed de spite relative hypoglycemia and elevated free fatty acids (FFAs) in TG that persisted throughout resting, exercise, and recovery periods. To further assess substrate availability, glycogen content and glycogen synthase activity were measured in skeletal muscle and liver. At rest, muscle glycogen content was 50% higher and glycogen synthase I was 40 % lower in TG compared with WT. During exercise and recovery, muscle g lycogen was more profoundly depleted in TG than in WT, and glycogen sy nthase I increased to levels observed in WT, with no change in total g lycogen synthase. In the liver, glycogen content and total glycogen sy nthase were similar in TG and WT under resting conditions, while glyco gen synthase I was reduced by 48%. Exercise and recovery induced a mor e profound depletion of liver glycogen (76% v 30%) and greater increme nts in both I-form and total glycogen synthase in TG, In conclusion, ( 1) TG overexpressing GLUT4 exhibit greater muscle glycogen content at rest than WT; (2) during exercise, TG metabolize more carbohydrate, ma de possible by increased glycogenolysis in muscle and liver, and this predominates as a fuel source despite hypoglycemia and increased avail ability of FFA; (3) increased carbohydrate metabolism is linked to a d ecrease in lipid metabolism such that there is no change in overall en ergy expenditure; and (4) glycogen synthase I activity is inversely pr oportional to tissue glycogen content despite differences in circulati ng glucose, insulin, and FFA concentrations, indicating that glycogen content has an overriding regulatory influence on glycogen synthase. C opyright (C) 1997 by W.B. Saunders Company.