The Ras Antagonist, Farnesylthiosalicylic Acid (FTS), Decreases Fibrosis and Improves Muscle Strength in dy2J/dy2J 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 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.

Losartan, a therapeutic candidate in congenital muscular dystrophy: Studies in the dy2J/dy2J Mouse

“…Quadriceps muscle biopsies were flash‐frozen in cooled isopentane and mounted in Tissue‐Teck. Ten‐micrometer tissue sections were stained with hematoxylin–eosin (H&E) for histology, and with Sirius red counterstained with fast green for collagen quantitative measurement using Ariol SL‐50 automated image analysis (Applied Imaging, San Jose, CA) as previously described 7. The mean fibrotic area was calculated from 7 regions in each biopsy.…”

“…In recent years, we found the dy 2J / dy 2J mouse a useful model to evaluate therapeutic interventions in MDC1A 5–7. This strain presents with progressive muscle fiber necrosis starting as early as 10 days of age, followed by muscle fiber loss and marked variation in fiber size 8, 9.…”

Inhibition of Ras signalling reduces neutrophil infiltration and tissue damage in severe acute pancreatitis

“…GTPases are attached to the inner side of plasma membranes where they convert inactive Ras-guanosine-diphosphate (GDP) into active Ras-guanosinetriphosphate (GTP) (Ehrhardt et al, 2002;Hancock, 2003). Farnesylthiosalisylic acid (FTS) is a synthetic derivative of carboxylic acid, resembling the farnesyl cysteine group common to all small GTPases (Nevo et al, 2011). FTS interferes with the binding of activated Ras proteins to their escort proteins and therefore inhibits Ras-plasma membrane interactions.…”

Ras Chaperones

“…These include atherosclerosis [87], ischemia/reperfusion [88], liver fibrosis [89,90], congenital muscular dystrophy [91], glomerular nephritis [92], type 1 [93,94] and type 2 diabetes [95], hypersensitivity inflammation [69], and allergic inflammation [11,96]. These include atherosclerosis [87], ischemia/reperfusion [88], liver fibrosis [89,90], congenital muscular dystrophy [91], glomerular nephritis [92], type 1 [93,94] and type 2 diabetes [95], hypersensitivity inflammation [69], and allergic inflammation [11,96].…”