Molecular mechanism of sphingosine-1-phosphate action in Duchenne muscular dystrophy

Diem Hang Nguyen-Tran, Nitai C. Hait, Henrik Sperber, Junlin Qi, Karin Fischer, Nick Ieronimakis, Mario Pantoja, Aislinn Hays, Jeremy Allegood, Morayma Reyes Gil, Sarah Spiegel, Hannele Ruohola-Baker

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Duchenne muscular dystrophy (DMD) is a lethal muscle-wasting disease. Studies in Drosophila showed that genetic increase of the levels of the bioactive sphingolipid sphingosine-1-phosphate (S1P) or delivery of 2-acetyl-5-tetrahydroxybutyl imidazole (THI), an S1P lyase inhibitor, suppresses dystrophic muscle degeneration. In the dystrophic mouse (mdx), upregulation of S1P by THI increases regeneration and muscle force. S1P can act as a ligand for S1P receptors and as a histone deacetylase (HDAC) inhibitor. Because Drosophila has no identified S1P receptors and DMD correlates with increased HDAC2 levels, we tested whether S1P action in muscle involves HDAC inhibition. Here we show that beneficial effects of THI treatment in mdx mice correlate with significantly increased nuclear S1P, decreased HDAC activity and increased acetylation of specific histone residues. Importantly, the HDAC2 target microRNA genes miR-29 and miR-1 are significantly upregulated, correlating with the downregulation of the miR-29 target Col1a1 in the diaphragm of THItreated mdx mice. Further gene expression analysis revealed a significant THI-dependent decrease in inflammatory genes and increase in metabolic genes. Accordingly, S1P levels and functional mitochondrial activity are increased after THI treatment of differentiating C2C12 cells. S1P increases the capacity of the muscle cell to use fatty acids as an energy source, suggesting that THI treatment could be beneficial for the maintenance of energy metabolism in mdx muscles.

Original languageEnglish (US)
Pages (from-to)41-54
Number of pages14
JournalDMM Disease Models and Mechanisms
Volume7
Issue number1
DOIs
StatePublished - Jan 2014
Externally publishedYes

Fingerprint

Duchenne Muscular Dystrophy
Muscle
Inbred mdx Mouse
Muscles
Lysosphingolipid Receptors
Histone Deacetylases
Genes
Drosophila
Wasting Syndrome
Acetylation
Sphingolipids
Histone Deacetylase Inhibitors
Diaphragms
Diaphragm
sphingosine 1-phosphate
MicroRNAs
Gene expression
Histones
Muscle Cells
Energy Metabolism

Keywords

  • Dys
  • Dystrophin
  • HDAC
  • Mdx
  • S1P
  • THI

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine (miscellaneous)
  • Immunology and Microbiology (miscellaneous)
  • Neuroscience (miscellaneous)

Cite this

Nguyen-Tran, D. H., Hait, N. C., Sperber, H., Qi, J., Fischer, K., Ieronimakis, N., ... Ruohola-Baker, H. (2014). Molecular mechanism of sphingosine-1-phosphate action in Duchenne muscular dystrophy. DMM Disease Models and Mechanisms, 7(1), 41-54. https://doi.org/10.1242/dmm.013631

Molecular mechanism of sphingosine-1-phosphate action in Duchenne muscular dystrophy. / Nguyen-Tran, Diem Hang; Hait, Nitai C.; Sperber, Henrik; Qi, Junlin; Fischer, Karin; Ieronimakis, Nick; Pantoja, Mario; Hays, Aislinn; Allegood, Jeremy; Reyes Gil, Morayma; Spiegel, Sarah; Ruohola-Baker, Hannele.

In: DMM Disease Models and Mechanisms, Vol. 7, No. 1, 01.2014, p. 41-54.

Research output: Contribution to journalArticle

Nguyen-Tran, DH, Hait, NC, Sperber, H, Qi, J, Fischer, K, Ieronimakis, N, Pantoja, M, Hays, A, Allegood, J, Reyes Gil, M, Spiegel, S & Ruohola-Baker, H 2014, 'Molecular mechanism of sphingosine-1-phosphate action in Duchenne muscular dystrophy', DMM Disease Models and Mechanisms, vol. 7, no. 1, pp. 41-54. https://doi.org/10.1242/dmm.013631
Nguyen-Tran, Diem Hang ; Hait, Nitai C. ; Sperber, Henrik ; Qi, Junlin ; Fischer, Karin ; Ieronimakis, Nick ; Pantoja, Mario ; Hays, Aislinn ; Allegood, Jeremy ; Reyes Gil, Morayma ; Spiegel, Sarah ; Ruohola-Baker, Hannele. / Molecular mechanism of sphingosine-1-phosphate action in Duchenne muscular dystrophy. In: DMM Disease Models and Mechanisms. 2014 ; Vol. 7, No. 1. pp. 41-54.
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