Skip to main content

Glucocorticoid treatment alleviates dystrophic myofiber pathology by activation of the calcineurin/NF-AT pathway.

Publication ,  Journal Article
St-Pierre, SJG; Chakkalakal, JV; Kolodziejczyk, SM; Knudson, JC; Jasmin, BJ; Megeney, LA
Published in: FASEB J
December 2004

Duchenne muscular dystrophy (DMD) is a progressive and ultimately fatal skeletal muscle disease. Currently, the most effective therapy is the administration of a subclass of glucocorticoids, most notably deflazacort. Although deflazacort treatment can attenuate DMD progression, extend ambulation, and maintain muscle strength, the mechanism of its action remains unknown. Prior observations have shown that activation of a JNK1-mediated signal transduction cascade contributes to the progression of the DMD phenotype, in part by phosphorylation and inhibition of a calcineurin sensitive NF-ATc1 transcription factor. Here, we observed that deflazacort treatment restored myocyte viability in muscle cells with constitutive activation of JNK1 and in dystrophic mdx mice. However, deflazacort treatment did not alter JNK1 activity itself, but rather led to an increase in the activity of the calcineurin phosphatase and an up-regulation of NF-ATc1-dependent gene expression. The prophylactic effect of deflazacort treatment was associated with increased expression of NF-ATc1 target genes such as the dystrophin homologue utrophin. Moreover, the muscle sparing effects of deflazacort were completely abolished when used in conjunction with the calcineurin inhibitor cyclosporine. Collectively, these results show that deflazacort attenuates loss of dystrophic myofiber integrity by up-regulating the activity of the phosphatase calcineurin, which in turn negates JNK1 inhibition of NF-ATc1-mediated phosphorylation and nuclear exclusion of NF-ATc1.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

FASEB J

DOI

EISSN

1530-6860

Publication Date

December 2004

Volume

18

Issue

15

Start / End Page

1937 / 1939

Location

United States

Related Subject Headings

  • Utrophin
  • Transcriptional Activation
  • Transcription Factors
  • Signal Transduction
  • Pregnenediones
  • Nuclear Proteins
  • NFATC Transcription Factors
  • Muscular Dystrophy, Duchenne
  • Muscle, Skeletal
  • Muscle Fibers, Skeletal
 

Citation

APA
Chicago
ICMJE
MLA
NLM
St-Pierre, S. J. G., Chakkalakal, J. V., Kolodziejczyk, S. M., Knudson, J. C., Jasmin, B. J., & Megeney, L. A. (2004). Glucocorticoid treatment alleviates dystrophic myofiber pathology by activation of the calcineurin/NF-AT pathway. FASEB J, 18(15), 1937–1939. https://doi.org/10.1096/fj.04-1859fje
St-Pierre, Simon J. G., Joe V. Chakkalakal, Steven M. Kolodziejczyk, Jennifer C. Knudson, Bernard J. Jasmin, and Lynn A. Megeney. “Glucocorticoid treatment alleviates dystrophic myofiber pathology by activation of the calcineurin/NF-AT pathway.FASEB J 18, no. 15 (December 2004): 1937–39. https://doi.org/10.1096/fj.04-1859fje.
St-Pierre SJG, Chakkalakal JV, Kolodziejczyk SM, Knudson JC, Jasmin BJ, Megeney LA. Glucocorticoid treatment alleviates dystrophic myofiber pathology by activation of the calcineurin/NF-AT pathway. FASEB J. 2004 Dec;18(15):1937–9.
St-Pierre, Simon J. G., et al. “Glucocorticoid treatment alleviates dystrophic myofiber pathology by activation of the calcineurin/NF-AT pathway.FASEB J, vol. 18, no. 15, Dec. 2004, pp. 1937–39. Pubmed, doi:10.1096/fj.04-1859fje.
St-Pierre SJG, Chakkalakal JV, Kolodziejczyk SM, Knudson JC, Jasmin BJ, Megeney LA. Glucocorticoid treatment alleviates dystrophic myofiber pathology by activation of the calcineurin/NF-AT pathway. FASEB J. 2004 Dec;18(15):1937–1939.

Published In

FASEB J

DOI

EISSN

1530-6860

Publication Date

December 2004

Volume

18

Issue

15

Start / End Page

1937 / 1939

Location

United States

Related Subject Headings

  • Utrophin
  • Transcriptional Activation
  • Transcription Factors
  • Signal Transduction
  • Pregnenediones
  • Nuclear Proteins
  • NFATC Transcription Factors
  • Muscular Dystrophy, Duchenne
  • Muscle, Skeletal
  • Muscle Fibers, Skeletal