α‐Lipoic acid up‐regulates expression of peroxisome proliferator‐activated receptor b in skeletal muscle: involvement of the JNK signaling pathway

We hypothesized that α‐lipoic acid (α‐LA) might interact with the transcriptional control of peroxisome proliferator‐activated receptor (PPAR)b 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.—Rousseau, A.‐S., Sibille, B., Murdaca, J., Mothe‐Satney, I., Grimaldi, P. A., Neels, J. G., α‐Lipoic acid up‐regulates expression of peroxisome proliferator‐activated receptor b in skeletal muscle: involvement of the JNK signaling pathway. FASEB J. 30, 1287–1299 (2016). www.fasebj.org