title: α-Lipoic acid up-regulates expression of peroxisome proliferator-activated receptor β in skeletal muscle: involvement of the JNK signaling pathway.
abstract: We hypothesized that α-lipoic acid (α-LA) might interact with the transcriptional control of peroxisome proliferator-activated receptor (PPAR)β in skeletal muscle. Molecular mechanisms were investigated using differentiated C2C12 myotubes treated with α-LA and/or PPARβ agonist GW0742. In vivo studies with 3-mo-old C57Bl6 mice were realized: voluntary wheel running (VWR) training (7 wk), and a 6 wk diet containing (or not) α-LA (0.25% wt/wt). This last condition was combined with (or not) 1 bout of treadmill exercise (18 m/min for 1 h). Using a reporter assay, we demonstrate that α-LA is not an agonist of PPARβ but regulates PPARβ target gene expression through an active PPARβ pathway. GW0742-induced pyruvate dehydrogenase kinase 4 mRNA is potentiated by α-LA. In C2C12, α-LA lowers the activation of the JNK signaling pathway and increases PPARβ mRNA and protein levels (2-fold) to the same extent as with the JNK inhibitor SP600125. Similarly to VWR training effect, PPARβ expression increases (2-fold) in vastus lateralis of animals fed an α-LA-enriched diet. However, α-LA treatment does not further stimulate the adaptive up-regulation of PPARβ observed in response to 1 bout of exercise. We have identified a novel mechanism of regulation of PPARβ expression/action in skeletal muscle with potential physiologic application through the action of α-LA, involving the JNK pathway.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 1065, Mediterranean Center of Molecular Medicine (C3M), Nice, France; and University of Nice-Sophia Antipolis, Nice, France anne-sophie.rousseau@unice.fr.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Rousseau
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 1065, Mediterranean Center of Molecular Medicine (C3M), Nice, France; and University of Nice-Sophia Antipolis, Nice, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Sibille
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 1065, Mediterranean Center of Molecular Medicine (C3M), Nice, France; and University of Nice-Sophia Antipolis, Nice, France.
authors.forename: Joseph
authors.initials: J
authors.lastname: Murdaca
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 1065, Mediterranean Center of Molecular Medicine (C3M), Nice, France; and University of Nice-Sophia Antipolis, Nice, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Mothe-Satney
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 1065, Mediterranean Center of Molecular Medicine (C3M), Nice, France; and University of Nice-Sophia Antipolis, Nice, France.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Grimaldi
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 1065, Mediterranean Center of Molecular Medicine (C3M), Nice, France; and University of Nice-Sophia Antipolis, Nice, France.
authors.forename: Jaap G
authors.initials: JG
authors.lastname: Neels
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation / Q000187:drug effects*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D048068:PPAR-beta / Q000378:metabolism*; D010805:Physical Conditioning, Animal / Q000379:methods; D011494:Protein Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D008063:Thioctic Acid / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D048068:PPAR-beta; D012333:RNA, Messenger; D008063:Thioctic Acid; D011494:Protein Kinases; C403287:pyruvate dehydrogenase kinase 4
keywords: C2C12; antioxidant; exercise; mice; stress kinases