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J Biol Chem, Vol. 273, Issue 33, 20910-20915, August 14, 1998
Restoration of Hypoxia-stimulated Glucose Uptake in
GLUT4-deficient Muscles by Muscle-specific GLUT4 Transgenic
Complementation
Juleen R.
Zierath ,
Tsu-Shuen
Tsao§,
Antine E.
Stenbit§,
Jeffrey W.
Ryder ,
Dana
Galuska , and
Maureen
J.
Charron§
From the Department of Clinical Physiology,
Karolinska Hospital, S-171 76, Stockholm, Sweden and the
§ Department of Biochemistry, Albert Einstein College of
Medicine, Bronx, New York 10461-1602
To investigate whether GLUT4 is
required for exercise/hypoxia-induced glucose uptake, we assessed
glucose uptake under hypoxia and normoxia in extensor digitorum longus
(EDL) and soleus muscles from GLUT4-deficient mice. In EDL and soleus
from wild type control mice, hypoxia increased 2-deoxyglucose uptake
2-3-fold. Conversely, hypoxia did not alter 2-deoxyglucose uptake in
either EDL or soleus from either male or female GLUT4-null mice. Next
we introduced the fast-twitch skeletal muscle-specific MLC-GLUT4
transgene into GLUT4-null mice to determine whether changes in the
metabolic milieu accounted for the lack of hypoxia-mediated glucose
transport. Transgenic complementation of GLUT4 in EDL was sufficient to
restore hypoxia-mediated glucose uptake. Soleus muscles from
MLC-GLUT4-null mice were transgene-negative, and hypoxia-stimulated
2-deoxyglucose uptake was not restored. Although ablation of GLUT4 in
EDL did not affect normoxic glycogen levels, restoration of GLUT4 to
EDL led to an increase in glycogen under hypoxic conditions. Male GLUT4-null soleus displayed reduced normoxic glycogen stores, but
female null soleus contained significantly more glycogen under normoxia
and hypoxia. Reduced normoxic levels of ATP and phosphocreatine were
measured in male GLUT4-null soleus but not in EDL. However, transgenic
complementation of GLUT4 prevented the decrease in hypoxic ATP and
phosphocreatine levels noted in male GLUT4-null and control EDL. In
conclusion, we have demonstrated that GLUT4 plays an essential role in
the regulation of muscle glucose uptake in response to hypoxia. Because
hypoxia is a useful model for exercise, our results suggest that
stimulation of glucose transport in response to exercise in skeletal
muscle is totally dependent upon GLUT4. Furthermore, the compensatory
glucose transport system that exists in GLUT4-null soleus muscle is not
sensitive to hypoxia/muscle contraction.
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.

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