Duchenne Muscular Dystrophy (DMD) is a lethal muscle wasting disease. Studies in Drosophila showed that genetic increase of the bioactive sphingolipid sphingosine-1-phosphate (S1P) or delivery of 2-acetyl-5-tetrahydroxybutyl imidazole (THI), an S1P lyase inhibitor, suppress dystrophic muscle degeneration. In 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. Since Drosophila have 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 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 down regulation of miR-29 target, Col1a1 in the diaphragm of THI treated mdx mice. Further gene expression analysis revealed a significant THI dependent decrease in inflammation 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 muscle cell capacity to use fatty acids as energy source, suggesting that THI treatment may be beneficial for maintenance of energy metabolism of mdx muscles.
- Received July 11, 2013.
- Accepted September 24, 2013.
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