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)-3 beta potently increased Pgc-1 alpha abundance and oxidative metabolism in skeletal muscle cells. The current study aims to unravel the molecular mechanism driving the increase in Pgc-1 alpha mediated by GSK-3 beta inactivation.
Methods: GSK-3 beta was inactivated genetically or pharmacologically in C2C12 myotubes and the requirement of transcription factors known to be involved in Pgc-1 alpha transcription for increases in Pgc-1 alpha abundance mediated by inactivation of GSK-3 beta was examined.
Results: Enhanced PGC-1 alpha promoter activation after GSK-3 beta inhibition suggested a transcriptionally-controlled mechanism. While myocyte enhancer factor (MEF)2 transcriptional activity was unaltered, GSK-3 beta inactivation increased the abundance and activity of the transcription factors estrogen-related receptor (ERR)alpha and ERR gamma. Pharmacological inhibition or knock-down of ERR alpha and ERR gamma however failed to prevent increases in Pgc-1 alpha mRNA mediated by GSK-3 beta inactivation. Interestingly, GSK-3 beta 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-1 alpha gene expression, PGC-1 alpha promoter activity and PGC-1 alpha protein abundance induced by GSK-3 beta inactivation. Furthermore, mutation of a specific TFEB binding site on the PGC-1 alpha promoter blocked promoter activation upon inhibition of GSK-3 beta.
Conclusions: In skeletal muscle, GSK-3 beta inactivation causes dephosphorylation and nuclear translocation of TFEB resulting in TFEB-dependent induction of Pgc-1 alpha expression.
|Number of pages||11|
|Journal||Biochimica et Biophysica Acta-Molecular Cell Research|
|Publication status||Published - Feb 2020|
- GSK-3 beta
- PGC-1 alpha
- Mitochondrial biogenesis
- Skeletal muscle
- GLYCOGEN-SYNTHASE KINASE-3
- MITOCHONDRIAL BIOGENESIS
- INVERSE AGONIST