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Glycogen synthase kinase 3 suppresses myogenic differentiation through negative regulation of NFATc3

Jos L J van der Velden1, Annemie M W J Schols1, Jodil Willems1

  • 1Department of Respiratory Medicine, Nutrition and Toxicology Research Institute Maastricht, Maastricht University, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands.

The Journal of Biological Chemistry
|November 6, 2007
PubMed

Insights

Inhibiting GSK-3beta promotes muscle growth by enhancing myogenic differentiation via NFATc3. This finding offers a potential strategy for treating skeletal muscle atrophy.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Physiology

Background:

  • Skeletal muscle atrophy is a debilitating condition linked to chronic diseases.
  • Stimulating muscle growth presents a therapeutic avenue for combating atrophy.
  • Glycogen synthase kinase 3beta (GSK-3beta) negatively regulates skeletal muscle growth.

Purpose of the Study:

  • To investigate if inhibiting GSK-3beta stimulates myogenic differentiation.
  • To determine if GSK-3beta's effect on differentiation is mediated by the transcription factor NFAT.
  • To explore GSK-3beta inhibition as a therapeutic strategy for muscle atrophy.

Main Methods:

  • Utilized mouse embryonic fibroblasts and C2C12 myoblasts.
  • Assessed myotube formation and muscle-specific gene expression.
  • Investigated nuclear translocation and promoter transactivation of NFATc3.
  • Employed GSK-3beta deficiency, reintroduction of wild-type and mutant GSK-3beta, calcineurin blockade, and NFATc3 deficiency models.

Main Results:

  • GSK-3beta deficiency enhanced myotube formation and muscle gene expression.
  • Inhibition of GSK-3beta restored differentiation after calcineurin blockade, indicating NFAT involvement.
  • GSK-3beta deficiency led to increased NFATc3 nuclear translocation and activity.
  • NFATc3 deficiency attenuated the muscle gene expression stimulated by GSK-3beta inhibition.

Conclusions:

  • GSK-3beta negatively regulates myogenic differentiation through an NFATc3-dependent transcriptional mechanism.
  • Inhibiting GSK-3beta shows promise for preventing or treating skeletal muscle atrophy.

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