Inactivation of glycogen synthase kinase-3β (GSK-3β) enhances skeletal muscle oxidative metabolism

Biochim Biophys Acta Mol Basis Dis. 2017 Dec;1863(12):3075-3086. doi: 10.1016/j.bbadis.2017.09.018. Epub 2017 Sep 22.

Abstract

Background: Aberrant skeletal muscle mitochondrial oxidative metabolism is a debilitating feature of chronic diseases such as chronic obstructive pulmonary disease, type 2 diabetes and chronic heart failure. Evidence in non-muscle cells suggests that glycogen synthase kinase-3β (GSK-3β) represses mitochondrial biogenesis and inhibits PPAR-γ co-activator 1 (PGC-1), a master regulator of cellular oxidative metabolism. The role of GSK-3β in the regulation of skeletal muscle oxidative metabolism is unknown.

Aims: We hypothesized that inactivation of GSK-3β stimulates muscle oxidative metabolism by activating PGC-1 signaling and explored if GSK-3β inactivation could protect against physical inactivity-induced alterations in skeletal muscle oxidative metabolism.

Methods: GSK-3β was modulated genetically and pharmacologically in C2C12 myotubes in vitro and in skeletal muscle in vivo. Wild-type and muscle-specific GSK-3β knock-out (KO) mice were subjected to hind limb suspension for 14days. Key constituents of oxidative metabolism and PGC-1 signaling were investigated.

Results: In vitro, knock-down of GSK-3β increased mitochondrial DNA copy number, protein and mRNA abundance of oxidative phosphorylation (OXPHOS) complexes and activity of oxidative metabolic enzymes but also enhanced protein and mRNA abundance of key PGC-1 signaling constituents. Similarly, pharmacological inhibition of GSK-3β increased transcript and protein abundance of key constituents and regulators of mitochondrial energy metabolism. Furthermore, GSK-3β KO animals were protected against unloading-induced decrements in expression levels of these constituents.

Conclusion: Inactivation of GSK-3β up-regulates skeletal muscle mitochondrial metabolism and increases expression levels of PGC-1 signaling constituents. In vivo, GSK-3β KO protects against inactivity-induced reductions in muscle metabolic gene expression.

Keywords: GSK-3β; Hind limb suspension; Mitochondrial biogenesis; Mitochondrial metabolism; PGC-1α; Skeletal muscle.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cell Respiration / physiology
  • Enzyme Activation
  • Gene Expression Profiling
  • Gene Knockdown Techniques
  • Glycogen Synthase Kinase 3 beta / genetics*
  • Glycogen Synthase Kinase 3 beta / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • Muscle Fibers, Skeletal / metabolism
  • Muscle, Skeletal / enzymology
  • Muscle, Skeletal / metabolism*
  • Oxidative Phosphorylation
  • Signal Transduction
  • Transcription Factors / metabolism
  • Up-Regulation

Substances

  • Transcription Factors
  • peroxisome-proliferator-activated receptor-gamma coactivator-1
  • Glycogen Synthase Kinase 3 beta