title: Genetic elevation of sphingosine 1-phosphate suppresses dystrophic muscle phenotypes in Drosophila.
abstract: Duchenne muscular dystrophy is a lethal genetic disease characterized by the loss of muscle integrity and function over time. Using Drosophila, we show that dystrophic muscle phenotypes can be significantly suppressed by a reduction of wunen, a homolog of lipid phosphate phosphatase 3, which in higher animals can dephosphorylate a range of phospholipids. Our suppression analyses include assessing the localization of Projectin protein, a titin homolog, in sarcomeres as well as muscle morphology and functional movement assays. We hypothesize that wunen-based suppression is through the elevation of the bioactive lipid Sphingosine 1-phosphate (S1P), which promotes cell proliferation and differentiation in many tissues, including muscle. We confirm the role of S1P in suppression by genetically altering S1P levels via reduction of S1P lyase (Sply) and by upregulating the serine palmitoyl-CoA transferase catalytic subunit gene lace, the first gene in the de novo sphingolipid biosynthetic pathway and find that these manipulations also reduce muscle degeneration. Furthermore, we show that reduction of spinster (which encodes a major facilitator family transporter, homologs of which in higher animals have been shown to transport S1P) can also suppress dystrophic muscle degeneration. Finally, administration to adult flies of pharmacological agents reported to elevate S1P signaling significantly suppresses dystrophic muscle phenotypes. Our data suggest that localized intracellular S1P elevation promotes the suppression of muscle wasting in flies.
authors.affiliation: Department of Biochemistry, Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98195, USA.
authors.forename: Mario
authors.initials: M
authors.lastname: Pantoja
authors.forename: Karin A
authors.initials: KA
authors.lastname: Fischer
authors.forename: Nicholas
authors.initials: N
authors.lastname: Ieronimakis
authors.forename: Morayma
authors.initials: M
authors.lastname: Reyes
authors.forename: Hannele
authors.initials: H
authors.lastname: Ruohola-Baker
mesh_terms: D000818:Animals; D015536:Down-Regulation / Q000235:genetics*; D004331:Drosophila melanogaster / Q000235:genetics*; D008246:Lysophospholipids / Q000096:biosynthesis / Q000235:genetics*; D009137:Muscular Dystrophy, Animal / Q000175:diagnosis / Q000235:genetics* / Q000517:prevention & control*; D009154:Mutation; D009210:Myofibrils / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D015398:Signal Transduction / Q000235:genetics; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics*
chemical_list: D008246:Lysophospholipids; C060506:sphingosine 1-phosphate; D013110:Sphingosine