Peroxisome proliferator-activated receptor gamma ligands differentially modulate muscle cell differentiation and MyoD gene expression via peroxisome proliferator-activated receptor gamma -dependent and -independent pathways.
The effects of distinct classes of peroxisome proliferator-activated receptor gamma (PPARgamma) ligands on myogenesis and MyoD gene expression were examined in mouse skeletal muscle C2C12 myoblasts. Treatment of C2C12 cells with the PPARgamma ligand, 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2), repressed morphologically defined myogenesis and reduced endogenous mRNA levels of the myogenic differentiation markers MyoD, myogenin, and alpha-actin. In contrast, two synthetic PPARgamma ligands, L-805645 and ciglitazone, exhibited no effects. In transient transfection assays, 15d-PGJ2 specifically inhibited the expression of a MyoD promoter-luciferase reporter gene (MyoDLuc) in a cell type- and promoter-specific manner, indicating that 15d-PGJ2 functions in part by repressing MyoD gene transcription. The inhibition of MyoD gene expression by 15d-PGJ2 is mediated by the distal region of the MyoD gene promoter. PPARgamma on its own also inhibited MyoDLuc expression and further augmented the 15d-PGJ2 response. In contrast, L-805645 and ciglitazone did not inhibit MyoDLuc expression on their own but did so in the presence of ectopically expressed PPARgamma. Interestingly, a transdominant inhibitor of PPARgamma (hPPARgamma2Delta500) had no effect on the 15d-PGJ2-dependent repression of MyoDLuc expression but overcame L-805645/PPARgamma-dependent repression. Finally, saturating concentrations of L-805645, which did not affect myogenesis, failed to ablate 15d-PGJ2-mediated repression of the myogenic program. Thus, distinct PPARgamma ligands may repress MyoD gene expression through PPARgamma-dependent and -independent pathways, and 15d-PGJ2 can inhibit the myogenic program independent of its cognate receptor, PPARgamma.
Hunter
J G
JG
Department of Biochemistry, McMaster University, Hamilton, Ontario L8N 3Z5, Canada.
van Delft
M F
MF
Rachubinski
R A
RA
Capone
J P
JP
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D008024:Ligands; D051379:Mice; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D017570:MyoD Protein / Q000235:genetics*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism* / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism* / Q000502:physiology
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D008024:Ligands; D017570:MyoD Protein; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D015230:Prostaglandin D2