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J. Biol. Chem., Vol. 278, Issue 42, 40557-40564, October 17, 2003

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Differential Regulation of the Muscle-specific GLUT4 Enhancer in Regenerating and Adult Skeletal Muscle^*

Horacio Moreno   ||, Antonio L. Serrano ¶ ||, Tomàs Santalucía ** , Anna Gumà , Carles Cantó , Nigel J. Brand **, Manuel Palacín , Stefano Schiaffino ||  and Antonio Zorzano  ||||

From the Parc Científic de Barcelona and Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Avda. Diagonal 645, E-08028 Barcelona, Spain, ^||Department of Biomedical Sciences, Consiglio Nazionale delle Ricerche Institute of Neurosciences, University of Padova, 35121 Padova, Italy, Venetian Institute of Molecular Medicine, 35129 Padova, Italy, and ^**Department of Cardiothoracic Surgery, National Heart and Lung Institute, Imperial College London, Dovehouse Street, London SW3 6LY, United Kingdom

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.

Received for publication, June 23, 2003 , and in revised form, July 28, 2003.

^* This work was supported by research grants from the Dirección General de Investigación Científica y Técnica (PM98/0197), Ministerio de Ciencia y Tecnología (SAF2002-02125), Instituto de Salud Carlos III (G03/028, G03/212, C03/08), Fundació la Marató de TV3 (300720), Fondo de Investigaciones Sanitarias (00-2101), Generalitat de Catalunya (SGR01-118), and COST B17 Action. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipient of a fellowship from Fondo de Investigaciones Sanitarias.

^¶ Both authors contributed equally to this study.

Current address: Kennedy Institute of Rheumatology, Imperial College London, 1 Aspenlea Rd., London W6 8LH, United Kingdom.

^|||| To whom correspondence should be addressed. Tel.: 34-93-4021519; Fax: 34-93-4021559; E-mail: azorzano{at}porthos.bio.ub.es

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