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Originally published In Press as doi:10.1074/jbc.M008100200 on March 16, 2001

J. Biol. Chem., Vol. 276, Issue 21, 18257-18264, May 25, 2001
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A Novel Role of Neuregulin in Skeletal Muscle
NEUREGULIN STIMULATES GLUCOSE UPTAKE, GLUCOSE TRANSPORTER TRANSLOCATION, AND TRANSPORTER EXPRESSION IN MUSCLE CELLS*

Elisabeth SuárezDagger , Daniel Bach, Joan Cadefau§, Manuel Palacín, Antonio Zorzano, and Anna Gumà

From the Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, and the § Unitat de Bioquímica i Biologia Molecular, Departament de Ciències Fisiològiques I, Facultat de Medicina, Universitat de Barcelona, E-08028 Barcelona, Spain

Neuregulins regulate the expression of acetylcholine receptor genes and induce development of the neuromuscular junction in muscle. In studying whether neuregulins regulate glucose uptake in muscle, we analyzed the effect of a recombinant neuregulin, rheregulin-beta 1-(177-244) (HRG), on L6E9 muscle cells, which express the neuregulin receptors ErbB2 and ErbB3. L6E9 responded acutely to HRG by a time- and concentration-dependent stimulation of 2-deoxyglucose uptake. HRG-induced stimulation of glucose transport was additive to the effect of insulin. The acute stimulation of the glucose transport induced by HRG was a consequence of the translocation of GLUT4, GLUT1, and GLUT3 glucose carriers to the cell surface. The effect of HRG on glucose transport was dependent on phosphatidylinositol 3-kinase activity. HRG also stimulated glucose transport in the incubated soleus muscle and was additive to the effect of insulin. Chronic exposure of L6E9 cells to HRG potentiated myogenic differentiation, and under these conditions, glucose transport was also stimulated. The activation of glucose transport after chronic HRG exposure was due to enhanced cell content of GLUT1 and GLUT3 and to increased abundance of these carriers at the plasma membrane. However, under these conditions, GLUT4 expression was markedly down-regulated. Muscle denervation is associated with GLUT1 induction and GLUT4 repression. In this connection, muscle denervation caused a marked increase in the content of ErbB2 and ErbB3 receptors, which occurred in the absence of alterations in neuregulin mRNA levels. This fact suggests that neuregulins regulate glucose transporter expression in denervated muscle. We conclude that neuregulins regulate glucose uptake in L6E9 muscle cells by mechanisms involving the recruitment of glucose transporters to the cell surface and modulation of their expression. Neuregulins may also participate in the adaptations in glucose transport that take place in the muscle fiber after denervation.

* This work was supported by research grants from the Dirección General de Investigación Científica y Técnica (PM98/0197), the Generalitat de Catalunya (1999SGR00039), the Fondo de Investigaciones Sanitarias (00/2101), and the Fundació Marató de TV3 (991110).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger Recipient of a pre-doctoral fellowship from the Universitat de Barcelona, Spain.

To whom correspondence may be addressed: Dept. Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Avda. Diagonal, 645, E-08028 Barcelona, Spain. Tel.: 34-93-402-1519; Fax: 34-93-402-1559; E-mail: azorzano@porthos.bio.ub.es or aguma@ porthos.bio.ub.es.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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