Dysferlinopathies are a non-lethal group of late-onset muscular dystrophies. Here, we evaluated the fusion ability of primary myoblasts from young dysf-/- mice and the muscle histopathology prior to, and during early stages of disease onset. The ability of primary myoblasts of 5-week-old dysf-/- mice to form large myotubes was delayed compared to their wild-type counterparts, as evaluated by scanning electron microscopy. However, their fusion activity, as reflected by the presence of actin filaments connecting several cells, was enhanced by the antifibrotic drug halofuginone. Early dystrophic signs were already apparent in 4-week-old dysf-/- mice; their collagen level was double that in wild-type mice and continued to rise until 5 months of age. Continuous treatment with halofuginone from 4 weeks to 5 months of age reduced muscle fibrosis in a phosphorylated-Smad3 inhibition-related manner. Halofuginone also enhanced myofiber hypertrophy, reduced the percentage of centrally nucleated myofibers, and increased muscle performance. Together, the data suggest an inhibitory effect of halofuginone on the muscle histopathology at very early stages of dysferlinopathy, and enhancement of muscle performance. These results offer new opportunities for early pharmaceutical treatment in dysferlinopathies with favorable outcomes at later stages of life.

中文翻译：

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卤夫酮改善年轻dysf小鼠的早期病理症状

Dysferlinopathies 是一组非致命性的迟发性肌营养不良症。在这里，我们评估了来自年轻dysf-/-小鼠的原代成肌细胞的融合能力以及疾病发作之前和早期阶段的肌肉组织病理学。通过扫描电子显微镜评估，与野生型对应物相比，5 周龄的dysf-/- 小鼠的原代成肌细胞形成大肌管的能力被延迟。然而，它们的融合活性，如连接几个细胞的肌动蛋白丝的存在所反映的，被抗纤维化药物卤夫酮增强。在 4 周龄的dysf-/- 小鼠中，早期的营养不良症状已经很明显；它们的胶原蛋白水平是野生型小鼠的两倍，并且持续上升直到 5 个月大。从 4 周到 5 个月，用卤夫酮连续治疗以磷酸化 Smad3 抑制相关的方式减少肌肉纤维化。Halofuginone 还增强了肌纤维肥大，降低了中心成核肌纤维的百分比，并提高了肌肉性能。总之，这些数据表明卤夫酮在dysferlinopathy 的非常早期阶段对肌肉组织病理学具有抑制作用，并能增强肌肉性能。这些结果为dysferlinopathies的早期药物治疗提供了新的机会，并在生命后期取得了良好的结果。数据表明卤夫酮在dysferlinopathy 的非常早期阶段对肌肉组织病理学具有抑制作用，并增强肌肉性能。这些结果为dysferlinopathies的早期药物治疗提供了新的机会，并在生命后期取得了良好的结果。数据表明卤夫酮在dysferlinopathy 的非常早期阶段对肌肉组织病理学具有抑制作用，并增强肌肉性能。这些结果为dysferlinopathies的早期药物治疗提供了新的机会，并在生命后期取得了良好的结果。