title: The Ras antagonist, farnesylthiosalicylic acid (FTS), decreases fibrosis and improves muscle strength in dy/dy mouse model of muscular dystrophy.
abstract: The Ras superfamily of guanosine-triphosphate (GTP)-binding proteins regulates a diverse spectrum of intracellular processes involved in inflammation and fibrosis. Farnesythiosalicylic acid (FTS) is a unique and potent Ras inhibitor which decreased inflammation and fibrosis in experimentally induced liver cirrhosis and ameliorated inflammatory processes in systemic lupus erythematosus, neuritis and nephritis animal models. FTS effect on Ras expression and activity, muscle strength and fibrosis was evaluated in the dy(2J)/dy(2J) mouse model of merosin deficient congenital muscular dystrophy. The dy(2J)/dy(2J) mice had significantly increased RAS expression and activity compared with the wild type mice. FTS treatment significantly decreased RAS expression and activity. In addition, phosphorylation of ERK, a Ras downstream protein, was significantly decreased following FTS treatment in the dy(2J)/dy(2J) mice. Clinically, FTS treated mice showed significant improvement in hind limb muscle strength measured by electronic grip strength meter. Significant reduction of fibrosis was demonstrated in the treated group by quantitative Sirius Red staining and lower muscle collagen content. FTS effect was associated with significantly inhibition of both MMP-2 and MMP-9 activities. We conclude that active RAS inhibition by FTS was associated with attenuated fibrosis and improved muscle strength in the dy(2J)/dy(2J) mouse model of congenital muscular dystrophy.
authors: Pediatric Neuromuscular Laboratory and the Neuropediatric Unit, Hadassah Hebrew University Hospital, Jerusalem, Israel. nevo@hadassah.org.il
authors: Yoram
authors: Y
authors: Nevo
authors: Shlomit
authors: S
authors: Aga-Mizrachi
authors: Edva
authors: E
authors: Elmakayes
authors: Nurit
authors: N
authors: Yanay
authors: Keren
authors: K
authors: Ettinger
authors: Moran
authors: M
authors: Elbaz
authors: Zivia
authors: Z
authors: Brunschwig
authors: Oshrat
authors: O
authors: Dadush
authors: Galit
authors: G
authors: Elad-Sfadia
authors: Roni
authors: R
authors: Haklai
authors: Yoel
authors: Y
authors: Kloog
authors: Joab
authors: J
authors: Chapman
authors: Shimon
authors: S
authors: Reif
mesh_terms: D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D017931:DNA Primers; D004195:Disease Models, Animal; D005204:Farnesol / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D005355:Fibrosis / Q000517:prevention & control*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D053580:Muscle Strength / Q000187:drug effects*; D009136:Muscular Dystrophies / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D012459:Salicylates / Q000494:pharmacology / Q000627:therapeutic use*; D018631:ras Proteins / Q000037:antagonists & inhibitors*
chemical_list: D017931:DNA Primers; D012459:Salicylates; C093323:farnesylthiosalicylic acid; D005204:Farnesol; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D018631:ras Proteins