Genetic elevation of Sphingosine 1-phosphate suppresses dystrophic muscle phenotypes in Drosophila

Abstract

SUMMARYDuchenne 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.

Targeting the sphingosine-1-phosphate axis in cancer, inflammation and beyond

“…Studies in Drosophila melanogaster have shown that genetic elevation of S1P (caused by the deletion of S1P lyase) suppresses dystrophic muscle phenotypes 61 . Because there are no known S1PR homologues in D. melanogaster , it was suggested that localized intracellular S1P elevation directly promotes the suppression of muscle wasting in fruitflies 61 .…”

“…Because there are no known S1PR homologues in D. melanogaster , it was suggested that localized intracellular S1P elevation directly promotes the suppression of muscle wasting in fruitflies 61 . Thus, it is possible that inhibitors of S1P lyase may provide a new therapeutic strategy for myopathies.…”

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

“…Furthermore, increasing S1P levels by oral delivery of 2-acetyl-4(5)-tetrahydroxybutyl imidazole (THI), an inhibitor of S1P lyase (which catalyzes the irreversible degradation of S1P), also leads to suppression of dystrophic muscle degeneration in flies (Pantoja et al, 2013). In mice, administration of THI is beneficial in the recovery from acute muscle injury in the mdx dystrophic model (Loh et al, 2012; Ieronimakis et al, 2013).…”

Sphingosine-1-phosphate receptor 3 influences cell cycle progression in muscle satellite cells

“…In Drosophila, perturbations in sphingosine levels lead to defects in muscle development and integrity (Herr et al, 2003), while elevation of intracellular S1P levels reduces muscle wasting in flies with dystrophic muscle (Pantoja et al, 2013). In mammals, S1P affects calcium homeostasis, cell contraction and differentiation of skeletal muscle (Donati et al, 2005; Formigli et al, 2002, 2009).…”