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Papers In Press, published online ahead of print July 30, 2003
Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona, Barcelona 08028
Corresponding Author: azorzano{at}bio.ub.es
We have reported a novel functional co-operation between MyoD, myocyte enhancer factor-2 (MEF2) and the thyroid hormone receptor in a muscle-specific enhancer of the rat GLUT4 gene in muscle cells. Here, we demonstrate that the muscle-specific enhancer of the GLUT4 gene operates in skeletal muscle and is muscle-fiber-dependent and innervation-independent. In normal conditions, both in soleus and in extensor digitorum longus muscles, the activity of the enhancer required the integrity of the MEF2-binding site and cancellation of the binding site of thyroid hormone receptor enhanced its activity suggesting an inhibitory role. Muscle regeneration of soleus and extensor digitorum longus muscles caused a marked induction of GLUT4 and stimulation of the enhancer activity, which was independent of innervation. During muscle regeneration, the enhancer activity was markedly inhibited by cancellation of the binding sites of MEF2, MyoD or thyroid hormone receptors. Different MEF2 isoforms expressed in skeletal muscle (MEF2A, MEF2C and MEF2D) and all members of the MyoD family had the capacity to participate in the activity of the GLUT4 enhancer as assessed by transient transfection in cultured cells. Our data indicate that the GLUT4 enhancer operates in muscle fibers and its activity contributes to the differences in GLUT4 gene expression between oxidative and glycolytic muscle fibers and to the GLUT4 up-regulation that occurs during muscle regeneration. The activity of the enhancer is maintained in adult muscle by MEF2, whereas during regeneration the operation of the enhancer depends on MEF2, myogenic transcription factors of the MyoD family and thyroid hormone receptors.
J. Biol. Chem, 10.1074/jbc.M306609200
Submitted on June 23, 2003
Revised on July 28, 2003
Accepted on July 30, 2003
Differential regulation of the muscle-specific GLUT4 enhancer in regenerating and adult skeletal muscle
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