Inactivation of glycogen synthase kinase 3β (GSK-3β) enhances mitochondrial biogenesis during myogenesis

Biochim Biophys Acta Mol Basis Dis. 2018 Sep;1864(9 Pt B):2913-2926. doi: 10.1016/j.bbadis.2018.06.002. Epub 2018 Jun 6.


Background: Mitochondrial biogenesis is crucial for myogenic differentiation and regeneration of skeletal muscle tissue and is tightly controlled by the peroxisome proliferator-activated receptor-γ co-activator 1 (PGC-1) signaling network. In the present study, we hypothesized that inactivation of glycogen synthase kinase (GSK)-3β, previously suggested to interfere with PGC-1 in non-muscle cells, potentiates PGC-1 signaling and the development of mitochondrial biogenesis during myogenesis, ultimately resulting in an enhanced myotube oxidative capacity.

Methods: GSK-3β was inactivated genetically or pharmacologically during myogenic differentiation of C2C12 muscle cells. In addition, m. gastrocnemius tissue was collected from wild-type and muscle-specific GSK-3β knock-out (KO) mice at different time-points during the reloading/regeneration phase following a 14-day hind-limb suspension period. Subsequently, expression levels of constituents of the PGC-1 signaling network as well as key parameters of mitochondrial oxidative metabolism were investigated.

Results: In vitro, both knock-down as well as pharmacological inhibition of GSK-3β not only increased expression levels of important constituents of the PGC-1 signaling network, but also potentiated myogenic differentiation-associated increases in mitochondrial respiration, mitochondrial DNA copy number, oxidative phosphorylation (OXPHOS) protein abundance and the activity of key enzymes involved in the Krebs cycle and fatty acid β-oxidation. In addition, GSK-3β KO animals showed augmented reloading-induced increases in skeletal muscle gene expression of constituents of the PGC-1 signaling network as well as sub-units of OXPHOS complexes compared to wild-type animals.

Conclusion: Inactivation of GSK-3β stimulates activation of PGC-1 signaling and mitochondrial biogenesis during myogenic differentiation and reloading of the skeletal musculature.

Keywords: GSK-3β; Myogenesis; Myogenic differentiation; PGC-1 and mitochondrial biogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / physiology
  • Cell Line
  • Disease Models, Animal
  • Female
  • Glycogen Synthase Kinase 3 beta / antagonists & inhibitors
  • Glycogen Synthase Kinase 3 beta / genetics
  • Glycogen Synthase Kinase 3 beta / physiology*
  • Hindlimb Suspension / adverse effects
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscle Development / physiology*
  • Muscle, Skeletal / cytology
  • Muscle, Skeletal / physiology*
  • Muscular Atrophy / etiology
  • Muscular Atrophy / pathology
  • Myoblasts / cytology
  • Myoblasts / physiology
  • Organelle Biogenesis*
  • Oxidative Phosphorylation / drug effects
  • Pyridines / pharmacology
  • Pyrimidines / pharmacology
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Transcription Factors / metabolism


  • Chir 99021
  • Pyridines
  • Pyrimidines
  • Transcription Factors
  • peroxisome-proliferator-activated receptor-gamma coactivator-1
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse