| First Author | Theeuwes WF | Year | 2020 |
| Journal | Biochim Biophys Acta Mol Cell Res | Volume | 1867 |
| Issue | 2 | Pages | 118610 |
| PubMed ID | 31738957 | Mgi Jnum | J:282955 |
| Mgi Id | MGI:6384366 | Doi | 10.1016/j.bbamcr.2019.118610 |
| Citation | Theeuwes WF, et al. (2020) Regulation of PGC-1alpha expression by a GSK-3beta-TFEB signaling axis in skeletal muscle. Biochim Biophys Acta Mol Cell Res 1867(2):118610 |
| abstractText | OBJECTIVE: In muscle cells, the peroxisome proliferator-activated receptor gamma co-activator 1 (PGC-1) signaling network, which has been shown to be disturbed in the skeletal muscle in several chronic diseases, tightly controls mitochondrial biogenesis and oxidative substrate metabolism. Previously, we showed that inactivation of glycogen synthase kinase (GSK)-3beta potently increased Pgc-1alpha abundance and oxidative metabolism in skeletal muscle cells. The current study aims to unravel the molecular mechanism driving the increase in Pgc-1alpha mediated by GSK-3beta inactivation. METHODS: GSK-3beta was inactivated genetically or pharmacologically in C2C12 myotubes and the requirement of transcription factors known to be involved in Pgc-1alpha transcription for increases in Pgc-1alpha abundance mediated by inactivation of GSK-3beta was examined. RESULTS: Enhanced PGC-1alpha promoter activation after GSK-3beta inhibition suggested a transcriptionally-controlled mechanism. While myocyte enhancer factor (MEF)2 transcriptional activity was unaltered, GSK-3beta inactivation increased the abundance and activity of the transcription factors estrogen-related receptor (ERR)alpha and ERRgamma. Pharmacological inhibition or knock-down of ERRalpha and ERRgamma however failed to prevent increases in Pgc-1alpha mRNA mediated by GSK-3beta inactivation. Interestingly, GSK-3beta inactivation activated transcription factor EB (TFEB), evidenced by decreased phosphorylation and enhanced nuclear localization of the TFEB protein. Moreover, knock-down of TFEB completely prevented increases in Pgc-1alpha gene expression, PGC-1alpha promoter activity and PGC-1alpha protein abundance induced by GSK-3beta inactivation. Furthermore, mutation of a specific TFEB binding site on the PGC-1alpha promoter blocked promoter activation upon inhibition of GSK-3beta. CONCLUSIONS: In skeletal muscle, GSK-3beta inactivation causes dephosphorylation and nuclear translocation of TFEB resulting in TFEB-dependent induction of Pgc-1alpha expression. |
