Pflügers Archiv

, Volume 445, Issue 3, pp 437–443

Blockades of mitogen-activated protein kinase and calcineurin both change fibre-type markers in skeletal muscle culture

  • James Higginson
  • Henning Wackerhage
  • Niall Woods
  • Peter Schjerling
  • Aivaras Ratkevicius
  • Niels Grunnet
  • Bjørn Quistorff
Skeletal Muscle

Abstract.

Activation of either the calcineurin or the extracellular signal-regulated kinase (ERK1/2) pathway increases the percentage of slow fibres in vivo suggesting that both pathways can regulate fibre phenotypes in skeletal muscle. We investigated the effect of calcineurin blockade with cyclosporin A and mitogen-activated protein kinase kinase (MEK1/2) blockade with U0126 upon myosin heavy chain (MHC) isoform mRNA levels and activities of metabolic enzymes after 1 day, 3 days and 7 days of treatment in primary cultures of spontaneously twitching rat skeletal muscle. U0126 treatment significantly decreased MHC Iβ mRNA levels and significantly increased MHC IIX, MHC IIB, embryonal MHC and perinatal MHC mRNA levels when compared to control. In addition, U0126 treatment significantly increased lactate dehydrogenase, creatine kinase, hexokinase, malate dehydrogenase and β-hydroxyacyl-CoA dehydrogenase activities above control values while a significant reduction in the percentage of pyruvate dehydrogenase in the active form was also observed. Calcineurin blockade significantly decreased both MHC Iβ and embryonal mRNA levels below control and significantly increased MHC IIX mRNA levels. Significant increases in the activities of both lactate dehydrogenase and creatine kinase above control values were also seen following cyclosporin A treatment. In conclusion, the results suggest that calcineurin upregulates slow-fibre genes and suppresses fast-fibre genes. Similarly, the ERK1/2 pathway upregulates slow-fibre MHC and suppresses fast-fibre MHC isoforms. However, the effect on enzyme activities is not fibre-type specific. The effect of U0126 on the percentage of pyruvate dehydrogenase in the active form suggests that the ERK1/2 pathway may also be involved in regulation of the phosphorylation state of this enzyme.

Cyclosporin A ERK1/2 MAPK NFAT U0126 

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Copyright information

© Springer-Verlag 2002

Authors and Affiliations

  • James Higginson
    • 1
  • Henning Wackerhage
    • 1
  • Niall Woods
    • 1
  • Peter Schjerling
    • 2
  • Aivaras Ratkevicius
    • 3
  • Niels Grunnet
    • 3
  • Bjørn Quistorff
    • 3
  1. 1.Muscle Research Group, Department of Biological Sciences, University of Central Lancashire, Preston PR1 2HE, UK
  2. 2.Copenhagen Muscle Research Centre, Rigshospitalet, Denmark
  3. 3.Department of Medical Biochemistry and Genetics, University of Copenhagen, Denmark

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