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

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.Ras超家族（Ras superfamily）的鸟苷三磷酸（guanosine triphosphate, GTP）结合蛋白可调控参与炎症与纤维化进程的多种胞内生物学过程。法尼基硫代水杨酸（Farnesythiosalicylic acid, FTS）是一种独特且强效的Ras抑制剂，可在实验诱导的肝硬化模型中减轻炎症与纤维化，并在系统性红斑狼疮、神经炎及肾炎的动物模型中改善炎症病理进程。本研究在层粘连蛋白缺陷型先天性肌营养不良的dy2J/dy2J小鼠模型中，评估了FTS对Ras表达与活性、肌肉力量及纤维化的影响。与野生型小鼠相比，dy2J/dy2J小鼠的RAS表达与活性显著升高。FTS处理可显著降低RAS的表达与活性。此外，在经FTS处理的dy2J/dy2J小鼠体内，Ras下游蛋白细胞外调节蛋白激酶（Extracellular signal-regulated kinase, ERK）的磷酸化水平显著下降。临床功能评估结果显示，经电子握力计检测，FTS处理组小鼠的后肢肌肉力量得到显著改善。定量天狼星红染色及肌肉胶原含量检测均证实，处理组小鼠的纤维化程度显著降低。FTS的相关效应与基质金属蛋白酶-2（Matrix Metalloproteinase-2, MMP-2）和基质金属蛋白酶-9（Matrix Metalloproteinase-9, MMP-9）的活性显著受抑密切相关。综上，在dy2J/dy2J先天性肌营养不良小鼠模型中，通过FTS实现的RAS活性抑制可减轻纤维化程度并改善肌肉力量。