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Molecular and Cellular Biology, September 2006, p. 6664-6674, Vol. 26, No. 17
0270-7306/06/$08.00+0     doi:10.1128/MCB.00138-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

New Role for Serum Response Factor in Postnatal Skeletal Muscle Growth and Regeneration via the Interleukin 4 and Insulin-Like Growth Factor 1 Pathways{dagger}

Claude Charvet,1,4,5,6 Christophe Houbron,2,4,5,6,{ddagger} Ara Parlakian,7,{ddagger} Julien Giordani,1,4,5,6 Charlotte Lahoute,1,4,5,6 Anne Bertrand,1,4,5,6 Athanassia Sotiropoulos,8 Laure Renou,1,4,5,6 Alain Schmitt,3,4,5,6 Judith Melki,9 Zhenlin Li,7 Dominique Daegelen,1,4,5,6* and David Tuil1,4,5,6*

Département de Génétique et Développement,1 Plate-Forme de Recombinaison Homologue,2 Plate-Forme de Microscopie Electronique, Institut Cochin, Paris F-75014, France,3 INSERM, U567, Paris F-75014, France,4 CNRS, UMR 8104, Paris F-75014, France,5 Université Paris 5, Faculté de Médecine René Descartes, UM 3, Paris F-75014, France,6 CNRS, UMR 7079, BP256, Université Paris 6, 7 quai St.-Bernard, 75005 Paris, France,7 INSERM, U344, Université René Descartes Paris 5, Faculté Necker, 156 rue de Vaugirard, 75015 Paris, France,8 Laboratoire de Neurogénétique Moléculaire, INSERM, Université d'Evry, E0223, Genopole, 2 rue Gaston Crémieux, 91057 Evry, France9

Received 24 January 2006/ Returned for modification 17 March 2006/ Accepted 7 June 2006

Serum response factor (SRF) is a crucial transcriptional factor for muscle-specific gene expression. We investigated SRF function in adult skeletal muscles, using mice with a postmitotic myofiber-targeted disruption of the SRF gene. Mutant mice displayed severe skeletal muscle mass reductions due to a postnatal muscle growth defect resulting in highly hypotrophic adult myofibers. SRF-depleted myofibers also failed to regenerate following injury. Muscles lacking SRF had very low levels of muscle creatine kinase and skeletal alpha-actin (SKA) transcripts and displayed other alterations to the gene expression program, indicating an overall immaturity of mutant muscles. This loss of SKA expression, together with a decrease in beta-tropomyosin expression, contributed to myofiber growth defects, as suggested by the extensive sarcomere disorganization found in mutant muscles. However, we observed a downregulation of interleukin 4 (IL-4) and insulin-like growth factor 1 (IGF-1) expression in mutant myofibers which could also account for their defective growth and regeneration. Indeed, our demonstration of SRF binding to interleukin 4 and IGF-1 promoters in vivo suggests a new crucial role for SRF in pathways involved in muscle growth and regeneration.

* Corresponding author. Mailing address: Institut Cochin, Faculté de Médecine Cochin Port Royal, 24 rue du Faubourg Saint Jacques, 75014 Paris, France. Phone: 331-44-41-24-71. Fax: 331-44-41-24-21. E-mail for Dominique Daegelen: daegelen{at}cochin.inserm.fr. E-mail for David Tuil: tuil{at}cochin.inserm.fr.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} C.H. and A.P. contributed equally to this work.

Molecular and Cellular Biology, September 2006, p. 6664-6674, Vol. 26, No. 17
0270-7306/06/$08.00+0     doi:10.1128/MCB.00138-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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