Exercise-induced muscle glucose uptake in mice with graded, muscle-specific GLUT-4 deletion

Kirsten F Howlett,Sofianos Andrikopoulos,Mark Hargreaves,Joseph Proietto

doi:10.1002/phy2.65

Abstract

To investigate the importance of the glucose transporter GLUT-4 for muscle glucose uptake during exercise, transgenic mice with skeletal muscle GLUT-4 expression approximately 30–60% of normal (CON) and approximately 5–10% of normal (KO) were generated using the Cre/Lox system and compared with wild-type (WT) mice during approximately 40 min of treadmill running (KO: 37.7 ± 1.3 min; WT: 40 min; CON: 40 min, P = 0.18). In WT and CON animals, exercise resulted in an overall increase in muscle glucose uptake. More specifically, glucose uptake was increased in red gastrocnemius of WT mice and in the soleus and red gastrocnemius of CON mice. In contrast, the exercise-induced increase in muscle glucose uptake in all muscles was completely abolished in KO mice. Muscle glucose uptake increased during exercise in both red and white quadriceps of WT mice, while the small increases in CON mice were not statistically significant. In KO mice, there was no change at all in quadriceps muscle glucose uptake. No differences in muscle glycogen use during exercise were observed between any of the groups. However, there was a significant increase in plasma glucose levels after exercise in KO mice. The results of this study demonstrated that a reduction in skeletal muscle GLUT-4 expression to approximately 10% of normal levels completely abolished the exercise-induced increase in muscle glucose uptake.

Highlights

During exercise, skeletal muscle glucose uptake increases up to 40–50 times the basal level, depending upon the exercise intensity and duration (James et al 1985; Katz et al 1986)
Sarcolemmal glucose transport during muscle contractions is facilitated by the glucose transporter isoform (GLUT-4), which is translocated from intracellular sites to the plasma membrane and t-tubules in response to contractile/exercise stimuli (Douen et al 1990; Kristiansen et al 1996; Roy and Marette 1996)
The results of this study demonstrate that a approximately 90% reduction in skeletal muscle GLUT-4 completely abolished muscle glucose uptake during exercise; animals with a reduction in muscle GLUT-4 protein expression of 60–70% maintained their ability to increase glucose uptake during exercise

Summary

Introduction

Skeletal muscle glucose uptake increases up to 40–50 times the basal level, depending upon the exercise intensity and duration (James et al 1985; Katz et al 1986). It has been demonstrated that skeletal muscle 2-deoxyglucose uptake during muscle contractions is directly related to muscle GLUT-4 protein content (Henriksen et al 1990), and that overexpression of GLUT-4 increases muscle glucose transport activity during tetanic, electrical stimulation (Hansen et al 1995). Recent studies suggest that GLUT4-mediated muscle glucose transport does not limit exercise-stimulated muscle glucose uptake, only doing so when glucose phosphorylation capacity is enhanced by overexpression of hexokinase (Fueger et al 2004). GLUT-4-deficient mice demonstrated increased muscle fatigability during electrical stimulation (Gorselink et al 2002), which could have been due to either reduced muscle glucose uptake during contractile activity and/or the lower prestimulation muscle glycogen levels in GLUT-4-deficient mice (Gorselink et al 2002)

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