Regulation of PGC-1α expression by a GSK-3β-TFEB signaling axis in skeletal muscle

Biochim Biophys Acta Mol Cell Res. 2020 Feb;1867(2):118610. doi: 10.1016/j.bbamcr.2019.118610. Epub 2019 Nov 16.

Abstract

Objective: In muscle cells, the peroxisome proliferator-activated receptor γ 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)-3β potently increased Pgc-1α abundance and oxidative metabolism in skeletal muscle cells. The current study aims to unravel the molecular mechanism driving the increase in Pgc-1α mediated by GSK-3β inactivation.

Methods: GSK-3β was inactivated genetically or pharmacologically in C2C12 myotubes and the requirement of transcription factors known to be involved in Pgc-1α transcription for increases in Pgc-1α abundance mediated by inactivation of GSK-3β was examined.

Results: Enhanced PGC-1α promoter activation after GSK-3β inhibition suggested a transcriptionally-controlled mechanism. While myocyte enhancer factor (MEF)2 transcriptional activity was unaltered, GSK-3β inactivation increased the abundance and activity of the transcription factors estrogen-related receptor (ERR)α and ERRγ. Pharmacological inhibition or knock-down of ERRα and ERRγ however failed to prevent increases in Pgc-1α mRNA mediated by GSK-3β inactivation. Interestingly, GSK-3β 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-1α gene expression, PGC-1α promoter activity and PGC-1α protein abundance induced by GSK-3β inactivation. Furthermore, mutation of a specific TFEB binding site on the PGC-1α promoter blocked promoter activation upon inhibition of GSK-3β.

Conclusions: In skeletal muscle, GSK-3β inactivation causes dephosphorylation and nuclear translocation of TFEB resulting in TFEB-dependent induction of Pgc-1α expression.

Keywords: GSK-3β; Mitochondrial biogenesis; PGC-1α; Skeletal muscle; TFEB.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / antagonists & inhibitors
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism*
  • Binding Sites
  • Cell Line
  • Cell Nucleus / metabolism
  • Glycogen Synthase Kinase 3 beta / antagonists & inhibitors
  • Glycogen Synthase Kinase 3 beta / genetics
  • Glycogen Synthase Kinase 3 beta / metabolism*
  • MEF2 Transcription Factors / genetics
  • MEF2 Transcription Factors / metabolism
  • Mice
  • Muscle, Skeletal / cytology
  • Muscle, Skeletal / metabolism
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / genetics
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism*
  • Phosphorylation
  • Promoter Regions, Genetic
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Receptors, Estrogen / antagonists & inhibitors
  • Receptors, Estrogen / genetics
  • Receptors, Estrogen / metabolism
  • Signal Transduction
  • Transcriptional Activation
  • Up-Regulation

Substances

  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • ERRalpha estrogen-related receptor
  • Esrrg protein, mouse
  • MEF2 Transcription Factors
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • RNA, Small Interfering
  • Receptors, Estrogen
  • Tcfeb protein, mouse
  • Glycogen Synthase Kinase 3 beta