title: Abnormal prostaglandin E2 production blocks myogenic differentiation in myotonic dystrophy.
abstract: The congenital form of myotonic dystrophy type 1 (DM1) is the most severe type of the disease associated with CTG expansions over 1500 repeats and delayed muscle maturation. The mechanistic basis of the congenital form of DM1 is mostly unknown. Here, we show that muscle satellite cells bearing large CTG expansions (>3000) secrete a soluble factor that inhibits the fusion of normal myoblasts in culture. We identified this factor as prostaglandin E2 (PGE(2)). In these DM1 cells, PGE(2) production is increased through up-regulation of cyclooxygenase 2 (Cox-2), mPGES-1 and prostaglandin EP2/EP4 receptors. Elevated levels of PGE(2) inhibit myogenic differentiation by decreasing the intracellular levels of calcium. Exogenous addition of acetylsalicylic acid, an inhibitor of Cox enzymes, abolishes PGE(2) abnormal secretion and restores the differentiation of DM1 muscle cells. These data indicate that the delay in muscle maturation observed in congenital DM1 may result, at least in part, from an altered autocrine mechanism. Inhibitors of prostaglandin synthesis may thus offer a powerful method to restore the differentiation of DM1 muscle cells.
authors: Neuroscience Research Unit, Laval University, CHUQ, Pavillon CHUL, Ste-Foy, Quebec, Canada G1V 4G2.
authors: Daniel
authors: D
authors: Beaulieu
authors: Philippe
authors: P
authors: Thebault
authors: Richard
authors: R
authors: Pelletier
authors: Pierre
authors: P
authors: Chapdelaine
authors: Mark
authors: M
authors: Tarnopolsky
authors: Denis
authors: D
authors: Furling
authors: Jack
authors: J
authors: Puymirat
mesh_terms: D001241:Aspirin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D009223:Myotonic Dystrophy / Q000235:genetics / Q000378:metabolism*; D032496:Satellite Cells, Skeletal Muscle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D019680:Trinucleotide Repeat Expansion; D015854:Up-Regulation
chemical_list: D016861:Cyclooxygenase Inhibitors; D015232:Dinoprostone; D001241:Aspirin; D002118:Calcium