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

Abstract

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.

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This work was funded by grants from the Association Française contre les Myopathies (AFM) and by the European 6th Framework Programme Network of Excellence MYORES. C. Charvet held a BDI graduate fellowship from the Centre National de la Recherche Scientifique and an AFM fellowship.

The NFATc2 cDNA probe was kindly provided by G. Pavlath (Emory University, Atlanta, Georgia). We thank E. Souil from the Tissue Morphology Technology Facility and F. Letourneur from the Genome and Sequencing Facility (Cochin Institute Paris 5 University) for their assistance. We also thank D. Couton and D. Bellanger for valuable technical help, H. Gilgenkrantz for critically reading the manuscript, and Region Ile de France for contributing to the Cochin Institute animal care facility.