Differential regulation of the muscle-specific GLUT4 enhancer in regenerating and adult skeletal muscle

被引:34
作者
Moreno, H
Serrano, AL
Santalucía, T
Gumà, A
Cantó, C
Brand, NJ
Palacín, M
Schiaffino, S
Zorzano, A
机构
[1] Univ Barcelona, Fac Biol, Parc Cient Barcelona, E-08028 Barcelona, Spain
[2] Univ Barcelona, Fac Biol, Dept Bioquim & Biol Mol, E-08028 Barcelona, Spain
[3] Univ Padua, Dept Biomed Sci, CNR, Inst Neurosci, I-35121 Padua, Italy
[4] Venetian Inst Mol Med, I-35129 Padua, Italy
[5] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, Dept Cardiothorac Surg, London SW3 6LY, England
关键词
D O I
10.1074/jbc.M306609200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
We have reported a novel functional co-operation among 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. Under normal conditions, both in soleus and in extensor digitorum longus muscles, the activity of the enhancer required the integrity of the MEF2-binding site. Cancellation of the binding site of thyroid hormone receptor enhanced its activity, suggesting an inhibitory role. Muscle regeneration of the 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.
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页码:40557 / 40564
页数:8
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