New role for serum response factor in postnatal skeletal muscle growth and regeneration via the interleukin 4 and insulin-like growth factor 1 pathways.
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.
Charvet
Claude
C
Institut Cochin, Faculté de Médecine Cochin Port Royal, 24 rue du Faubourg Saint Jacques, 75014 Paris, France.
Houbron
Christophe
C
Parlakian
Ara
A
Giordani
Julien
J
Lahoute
Charlotte
C
Bertrand
Anne
A
Sotiropoulos
Athanassia
A
Renou
Laure
L
Schmitt
Alain
A
Melki
Judith
J
Li
Zhenlin
Z
Daegelen
Dominique
D
Tuil
David
D
D000818:Animals; D000831:Animals, Newborn; D001483:Base Sequence; D002467:Cell Nucleus / Q000378:metabolism; D048429:Cell Size; D005786:Gene Expression Regulation; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D019426:Integrases / Q000235:genetics; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000166:cytology / Q000254:growth & development* / Q000502:physiology* / Q000648:ultrastructure; D009929:Organ Size; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012038:Regeneration; D012518:Sarcomeres / Q000473:pathology / Q000648:ultrastructure; D026362:Serum Response Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D012333:RNA, Messenger; D026362:Serum Response Factor; D015847:Interleukin-4; D007334:Insulin-Like Growth Factor I; C045073:Cre recombinase; D019426:Integrases