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.
Highlights
Merosin deficient congenital muscular dystrophy (MDC1A, OMIM # 607855) is the most common form of the congenital muscular dystrophies
Treatment of wild type C57BL/6J (WT) mice with Farnesythiosalicylic acid (FTS) caused an increase in Ras expression which was by far much lower than the increase observed in the dy2J/dy2J mice (206.76629.37)
We found that Ras-GTP levels were higher in dy2J/dy2J compared to the levels in WT mice
Summary
Merosin deficient congenital muscular dystrophy (MDC1A, OMIM # 607855) is the most common form of the congenital muscular dystrophies. It is an autosomal recessive disorder caused by mutations in the LAMA2 gene, localized to chromosome 6q22– q23. Most children affected with this disorder have severe clinical symptoms. They do not achieve independent ambulation and die in childhood or early adulthood [1,2]. Comparable to merosin deficient congenital muscular dystrophy children, dy2J/dy2J mice demonstrate a peripheral neuropathy in addition to the muscular dystrophy [7,8,9]
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