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