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

https://doi.org/10.1016/j.bbamcr.2019.118610Get rights and content
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Highlights

  • Inactivation of GSK-3β increases PGC-1α abundance and promoter activation.

  • Inactivation of GSK-3β increases TFEB nuclear translocation.

  • Increased PGC-1α expression upon GSK-3β inhibition requires TFEB.

  • GSK-3 inhibition enhances PGC-1α promoter activity dependent on a TFEB binding site.

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.

Abbreviations

COPD
chronic obstructive pulmonary disease
PGC-1
peroxisome proliferator-activated receptor γ co-activator 1
GSK-3
glycogen synthase kinase-3
CHIR
CHIR99021
MEF
myocyte enhancer factor
ERR
estrogen-related receptor
MITF
microphthalmia-associated transcription factor
TFE3
transcription factor binding to IGHM enhancer3
TFEB
transcription factor EB
CLEAR
coordinated lysosomal expression and regulation
Perm1
PGC-1 and ERR-induced regulator in muscle
mTOR
mammalian target of rapamycin
OXPHOS
oxidative phosphorylation
Akt
protein kinase B

Keywords

GSK-3β
PGC-1α
TFEB
Mitochondrial biogenesis
Skeletal muscle

Cited by (0)

1

Authors contributed equally.