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

W. F. Theeuwes, H. R. Gosker*, R. C. J. Langen, N. A. M. Pansters, A. M. W. J. Schols, A. H. V. Remels

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

19 Citations (Web of Science)

Abstract

Background: Mitochondria] biogenesis is crucial for myogenic differentiation and regeneration of skeletal muscle tissue and is tightly controlled by the peroxisome proliferator-activated receptor-gamma co-activator 1 (PGC-1) signaling network. In the present study, we hypothesized that inactivation of glycogen synthase kinase (GSK)-3 beta, 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-3 beta 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-3 beta knockout (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-3 beta 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 beta-oxidation. In addition, GSK-3 beta 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-3 beta stimulates activation of PGC-1 signaling and mitochondrial biogenesis during myogenic differentiation and reloading of the skeletal musculature.

Original languageEnglish
Pages (from-to)2913-2926
Number of pages14
JournalBiochimica et Biophysica Acta-Molecular Basis of Disease
Volume1864
Issue number9
DOIs
Publication statusPublished - Sep 2018

Keywords

  • GSK-3 beta
  • Myogenic differentiation
  • Myogenesis
  • PGC-1 and mitochondrial biogenesis
  • PROLIFERATOR-ACTIVATED RECEPTOR
  • ADULT SKELETAL-MUSCLE
  • OBSTRUCTIVE PULMONARY-DISEASE
  • PDK4 GENE-EXPRESSION
  • ERR-ALPHA
  • OXIDATIVE CAPACITY
  • SATELLITE CELLS
  • HEART-FAILURE
  • MYOBLAST DIFFERENTIATION
  • TRANSCRIPTIONAL CONTROL

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