Sphingosine 1-phosphate mediated suppression of dystrophic muscle wasting in Drosophila and mice. Mario Pantoja¹, Karin A. Fischer¹, Nicholas Ieronimakis², Timothy L. Dosey¹, Junlin Qi¹, Aislinn Hayes², Morayma Reyes^2,3, Hannele Ruohola-Baker¹. 1) Dept Biochem, Univ Washington, Seattle, WA; 2) Dept Pathology; 3) Dept Labortory Medicine.

   Presently, there is no effective treatment for the lethal muscle wasting disease Duchenne Muscular Dystrophy (DMD). Using Drosophila, we show that reduction of wunen, a lipid phosphate phosphatase 3, that inactivates the bioactive lipid Sphingosine-1-Phosphate (S1P), suppresses dystrophic muscle defects as assayed by myofibril integrity and movement. Furthermore, increasing S1P levels by reducing S1P lyase, Sply, or by upregulating lace, a serine palmitoyl-CoA transferase, also leads to suppression of dystrophic muscle degeneration. Importantly, suppression of dystrophic defects by S1P upregulation is evolutionarily conserved as we show that treatment of dystrophic mdx mice with the small molecule 2-acetyl-4(5)-tetrahydroxybutyl imidazole (THI), which elevates S1P levels systemically, significantly increases muscle fiber size and specific force while reducing DMD pathology of fibrosis and fat deposition. Moreover, delivery of THI to adult dystrophic flies phenocopies the genetic suppression observed with Sply reduction and shows that elevation of S1P in adult animals is sufficient to suppress muscle wasting. We further evaluate increased S1P signaling in dystrophic animals by treating flies with the S1P agonist, FTY720, and show that this drug significantly suppresses muscle degeneration. Furthermore, we will discuss dissecting the mode of action of S1P mediated suppression in both flies and mice as well as the use of Drosophila as a drug discovery tool for Duchenne Muscular Dystrophy.