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首页> 外文期刊>Skeletal Muscle >Angiotensin II type 1 receptor antagonists alleviate muscle pathology in the mouse model for laminin-α2-deficient congenital muscular dystrophy (MDC1A)
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Angiotensin II type 1 receptor antagonists alleviate muscle pathology in the mouse model for laminin-α2-deficient congenital muscular dystrophy (MDC1A)

机译：血管紧张素II 1型受体拮抗剂可缓解小鼠模型中层粘连蛋白-α2缺陷型先天性肌营养不良（MDC1A）的肌肉病理

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Background Laminin-α2-deficient congenital muscular dystrophy (MDC1A) is a severe muscle-wasting disease for which no curative treatment is available. Antagonists of the angiotensin II receptor type 1 (AT1), including the anti-hypertensive drug losartan, have been shown to block also the profibrotic action of transforming growth factor (TGF)-β and thereby ameliorate disease progression in mouse models of Marfan syndrome. Because fibrosis and failure of muscle regeneration are the main reasons for the severe disease course of MDC1A, we tested whether L-158809, an analog derivative of losartan, could ameliorate the dystrophy in dyW/dyW mice, the best-characterized model of MDC1A. Methods L-158809 was given in food to dyW/dyW mice at the age of 3?weeks, and the mice were analyzed at the age of 6 to 7?weeks. We examined the effect of L-158809 on muscle histology and on muscle regeneration after injury as well as the locomotor activity and muscle strength of the mice. Results We found that TGF-β signaling in the muscles of the dyW/dyW mice was strongly increased, and that L-158809 treatment suppressed this signaling. Consequently, L-158809 reduced fibrosis and inflammation in skeletal muscle of dyW/dyW mice, and largely restored muscle regeneration after toxin-induced injury. Mice showed improvement in their locomotor activity and grip strength, and their body weight was significantly increased. Conclusion These data provide evidence that AT1 antagonists ameliorate several hallmarks of MDC1A in dyW/dyW mice, the best-characterized mouse model for this disease. Because AT1 antagonists are well tolerated in humans and widely used in clinical practice, these results suggest that losartan may offer a potential future treatment of patients with MDC1A.
机译：背景层粘连蛋白-α2缺陷型先天性肌营养不良症（MDC1A）是一种严重的肌肉萎缩性疾病，目前尚无治疗方法。血管紧张素II受体1型（AT1）的拮抗剂，包括抗高血压药氯沙坦，已被证明也可以阻断转化生长因子（TGF）-β的纤维化作用，从而改善马凡氏综合征小鼠模型的疾病进展。由于纤维化和肌肉再生失败是MDC1A严重病程的主要原因，因此我们测试了氯沙坦的类似衍生物L-158809是否可以减轻dyW / dyW小鼠（最典型的MDC1A模型）的营养不良。方法在3-4周龄的dyW / dyW小鼠中，以食物形式给予L-158809，并对6至7周龄的小鼠进行分析。我们检查了L-158809对肌肉组织学和损伤后肌肉再生以及小鼠的自发活动和肌肉强度的影响。结果我们发现dyW / dyW小鼠的肌肉中的TGF-β信号强烈增加，并且L-158809处理抑制了该信号。因此，L-158809减少了dyW / dyW小鼠骨骼肌的纤维化和炎症，并在毒素诱导的损伤后很大程度上恢复了肌肉再生。小鼠表现出自发活动和握力的改善，并且体重显着增加。结论这些数据提供了证据，表明dyW / dyW小鼠中AT1拮抗剂改善了MDC1A的几个特征，dyW / dyW小鼠是该疾病最典型的小鼠模型。由于AT1拮抗剂在人类中具有良好的耐受性，并且在临床实践中得到广泛使用，因此这些结果表明，氯沙坦可能为MDC1A患者提供潜在的未来治疗方法。

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