The Ras Antagonist, Farnesylthiosalicylic Acid (FTS), Decreases Fibrosis and Improves Muscle Strength in dy2J/dy2J Mouse Model of Muscular Dystrophy

• Published in: PloS one Vol. 6; no. 3; p. e18049
• Main Authors: Nevo, Yoram, Aga-Mizrachi, Shlomit, Elmakayes, Edva, Yanay, Nurit, Ettinger, Keren, Elbaz, Moran, Brunschwig, Zivia, Dadush, Oshrat, Elad-Sfadia, Galit, Haklai, Roni, Kloog, Yoel, Chapman, Joab, Reif, Shimon
• Format: Journal Article
• Language: English
• Published: San Francisco Public Library of Science 22.03.2011
• Subjects: Acids; Animal models; Autoimmune diseases; Biology; Chronic conditions; Cirrhosis; Collagen; Congenital diseases; Dystrophy; Fibrosis; Gelatinase A; Gelatinase B; Grip strength; GTP-binding protein; Guanosine; Histopathology; Inflammation; Inhibition; Laboratory animals; Life sciences; Liver; Liver cirrhosis; Medicine; Mice; Muscle strength; Muscular dystrophy; Musculoskeletal system; Mutation; Nephritis; Neuritis; Pathogenesis; Pediatrics; Phosphorylation; Proteins; Ras protein; Rodents; Signal transduction; Systemic lupus erythematosus; Veterinary Science; Jerusalem Israel; Israel
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0018049

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 dy2J/dy2J mouse model of merosin deficient congenital muscular dystrophy. The dy2J/dy2J 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 dy2J/dy2J 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 dy2J/dy2J mouse model of congenital muscular dystrophy.