Regulation of Pgc1a expression by a Gsk3b-Tfeb signaling axis in skeletal muscle (WP4763)

Mus musculus

In (skeletal) muscle cells, PGC-1 signaling controls mitochondrial biogenesis and oxidative substrate metabolism. PGC-1 signaling disturbance in skeletal muscle is linked to several chronic diseases. This pathway depicts the mechanism in which inhibition of GSK-3β increases Pgc-1α abundance, through dephosphorylation of Tfeb [ Theeuwes et al, 2019]. This reaction allows Tfeb to translocate to the nucleus, where it stimulates the transcription of the PPARGC1A gene to the Pgc-1α protein. Phosphorylation of Tfeb leads to binding with members of the 14-3-3 protein family, which disables transport into the nucleus. If the dephosphorylation of Tfeb through Gsk-3β is a direct or indirect reaction is as of yet unknown.


Denise Slenter and Alex Pico


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Mus musculus



Pathway Ontology

peroxisome proliferator-activated receptor signaling pathway

Cell Type Ontology

skeletal muscle fiber


Label Type Compact URI Comment
CHIR99021 Metabolite pubchem.compound:9956119
PPARGC1A promotor GeneProduct ncbigene:19017 (Human Entrez Gene: 10891)
14-3-3 protein family Protein interpro:IPR000308
Gsk-3β Protein uniprot:Q9WV60 AKA glycogen synthase kinase (GSK)-3β (Human Uniprot: P49841)
Tfeb Protein uniprot:Q9R210 transcription factor EB (TFEB)
Tfeb Protein uniprot:Q9R210 transcription factor EB (TFEB)
Pgc-1α Protein uniprot:O70343 (Human Uniprot: Q9UBK2)
Tfeb Protein uniprot:Q9R210 transcription factor EB (TFEB) (Human Uniprot: P19484)
Tfeb Protein uniprot:Q9R210 transcription factor EB (TFEB)


  1. Selective glycogen synthase kinase 3 inhibitors potentiate insulin activation of glucose transport and utilization in vitro and in vivo. Ring DB, Johnson KW, Henriksen EJ, Nuss JM, Goff D, Kinnick TR, et al. Diabetes. 2003 Mar;52(3):588–95. PubMed Europe PMC Scholia
  2. Glycogen synthase kinase-3 (GSK3) inhibition induces prosurvival autophagic signals in human pancreatic cancer cells. Marchand B, Arsenault D, Raymond-Fleury A, Boisvert FM, Boucher MJ. J Biol Chem. 2015 Feb 27;290(9):5592–605. PubMed Europe PMC Scholia
  3. Protein kinase C controls lysosome biogenesis independently of mTORC1. Li Y, Xu M, Ding X, Yan C, Song Z, Chen L, et al. Nat Cell Biol. 2016 Oct;18(10):1065–77. PubMed Europe PMC Scholia
  4. YWHA/14-3-3 proteins recognize phosphorylated TFEB by a noncanonical mode for controlling TFEB cytoplasmic localization. Xu Y, Ren J, He X, Chen H, Wei T, Feng W. Autophagy. 2019 Jun;15(6):1017–30. PubMed Europe PMC Scholia
  5. Regulation of PGC-1α expression by a GSK-3β-TFEB signaling axis in skeletal muscle. Theeuwes WF, Gosker HR, Schols AMWJ, Langen RCJ, Remels AHV. Biochim Biophys Acta Mol Cell Res. 2020 Feb;1867(2):118610. PubMed Europe PMC Scholia