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

J. Higginson, Henning Wackerhage, N. M. Woods, J. Schjerling, Aivaras Ratkevicius, N. Grunnet, B. Quistorff

Research output: Contribution to journalArticle

31 Citations (Scopus)

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 Ibeta 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 beta-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 Ibeta 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.

Original languageEnglish
Pages (from-to)437-443
Number of pages6
JournalPflugers Archiv : European Journal of Physiology
Volume445
Issue number3
DOIs
Publication statusPublished - Dec 2002

Keywords

  • cyclosporin A
  • ERKI/2
  • MAPK
  • NFAT
  • U0126
  • GENE-EXPRESSION
  • FIBER-TYPE
  • SIGNAL-TRANSDUCTION
  • ENZYME-ACTIVITY
  • MYOSIN
  • TRANSCRIPTION
  • HYPERTROPHY
  • PATHWAYS
  • EXERCISE
  • CALCIUM

Cite this

Blockades of mitogen-activated protein kinase and calcineurin both change fibre-type markers in skeletal muscle culture. / Higginson, J.; Wackerhage, Henning; Woods, N. M.; Schjerling, J.; Ratkevicius, Aivaras; Grunnet, N.; Quistorff, B.

In: Pflugers Archiv : European Journal of Physiology, Vol. 445, No. 3, 12.2002, p. 437-443.

Research output: Contribution to journalArticle

Higginson, J, Wackerhage, H, Woods, NM, Schjerling, J, Ratkevicius, A, Grunnet, N & Quistorff, B 2002, 'Blockades of mitogen-activated protein kinase and calcineurin both change fibre-type markers in skeletal muscle culture', Pflugers Archiv : European Journal of Physiology, vol. 445, no. 3, pp. 437-443. https://doi.org/10.1007/s00424-002-0939-1
Higginson, J. ; Wackerhage, Henning ; Woods, N. M. ; Schjerling, J. ; Ratkevicius, Aivaras ; Grunnet, N. ; Quistorff, B. / Blockades of mitogen-activated protein kinase and calcineurin both change fibre-type markers in skeletal muscle culture. In: Pflugers Archiv : European Journal of Physiology. 2002 ; Vol. 445, No. 3. pp. 437-443.
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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 Ibeta 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 beta-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 Ibeta 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.",
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T1 - Blockades of mitogen-activated protein kinase and calcineurin both change fibre-type markers in skeletal muscle culture

AU - Higginson, J.

AU - Wackerhage, Henning

AU - Woods, N. M.

AU - Schjerling, J.

AU - Ratkevicius, Aivaras

AU - Grunnet, N.

AU - Quistorff, B.

PY - 2002/12

Y1 - 2002/12

N2 - 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 Ibeta 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 beta-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 Ibeta 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.

AB - 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 Ibeta 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 beta-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 Ibeta 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.

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KW - ERKI/2

KW - MAPK

KW - NFAT

KW - U0126

KW - GENE-EXPRESSION

KW - FIBER-TYPE

KW - SIGNAL-TRANSDUCTION

KW - ENZYME-ACTIVITY

KW - MYOSIN

KW - TRANSCRIPTION

KW - HYPERTROPHY

KW - PATHWAYS

KW - EXERCISE

KW - CALCIUM

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DO - 10.1007/s00424-002-0939-1

M3 - Article

VL - 445

SP - 437

EP - 443

JO - Pflugers Archiv : European Journal of Physiology

JF - Pflugers Archiv : European Journal of Physiology

SN - 0031-6768

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ER -