Ultra-structural time-course study in the C. elegans model for Duchenne muscular dystrophy highlights a crucial role for sarcomere-anchoring structures and sarcolemma integrity in the earliest steps of the muscle degeneration process
Ultra-structural time-course study in the C. elegans model for Duchenne muscular dystrophy highlights a crucial role for sarcomere-anchoring structures and sarcolemma integrity in the earliest steps of the muscle degeneration process
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DOI：
10.1093/hmg/ddv353
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发表时间：
2015-11-15
影响因子：
3.5
通讯作者：
Gieseler, Kathrin
中科院分区：
文献类型：
--
作者：
Brouilly, Nicolas;Lecroisey, Claire;Gieseler, Kathrin
杜氏肌营养不良症（DMD）是一种遗传性疾病，其特征是由于肌营养不良蛋白基因突变导致的进行性肌肉变性。尽管在治愈性治疗的设计方面取得了很大进展，但目前大多数患者接受类固醇分子的姑息治疗，如泼尼松或地夫可特，这些类固醇分子被认为通过其免疫抑制特性起作用。这些分子只是稍微减缓疾病的进展，并导致严重的副作用。仍然需要进行基础研究，以揭示可作为治疗靶点的疾病所涉及的机制。通过研究秀丽隐杆线虫DMD模型，我们在这里表明，抗肌萎缩蛋白依赖性肌肉变性可能是细胞自主的，并影响最参与运动的肌肉细胞。我们证明，肌肉退化是依赖于运动和生产力。通过电子显微镜进行的详尽研究首次建立了肌肉变性整个过程中发生的亚细胞事件的年表。这个年表强调了肌营养不良蛋白在稳定肌节锚定结构和肌膜中的关键作用。我们的研究结果表明，在肌肉变性过程开始时观察到的肌节锚定结构和肌膜完整性的破坏，触发了导致肌细胞死亡的亚细胞后果。DMD患者肌肉活检的超微结构分析表明，C。elegans是人类发病机制的模型。最后，我们发现泼尼松治疗后肌膜完整性的丧失大大减少，表明这种分子在质膜稳定中的作用。
Duchenne muscular dystrophy (DMD) is a genetic disease characterized by progressive muscle degeneration due to mutations in the dystrophin gene. In spite of great advances in the design of curative treatments, most patients currently receive palliative therapies with steroid molecules such as prednisone or deflazacort thought to act through their immunosuppressive properties. These molecules only slightly slow down the progression of the disease and lead to severe side effects. Fundamental research is still needed to reveal the mechanisms involved in the disease that could be exploited as therapeutic targets. By studying a Caenorhabditis elegans model for DMD, we show here that dystrophin-dependent muscle degeneration is likely to be cell autonomous and affects the muscle cells the most involved in locomotion. We demonstrate that muscle degeneration is dependent on exercise and force production. Exhaustive studies by electron microscopy allowed establishing for the first time the chronology of subcellular events occurring during the entire process of muscle degeneration. This chronology highlighted the crucial role for dystrophin in stabilizing sarcomeric anchoring structures and the sarcolemma. Our results suggest that the disruption of sarcomeric anchoring structures and sarcolemma integrity, observed at the onset of the muscle degeneration process, triggers subcellular consequences that lead to muscle cell death. An ultra-structural analysis of muscle biopsies from DMD patients suggested that the chronology of subcellular events established in C. elegans models the pathogenesis in human. Finally, we found that the loss of sarcolemma integrity was greatly reduced after prednisone treatment suggesting a role for this molecule in plasma membrane stabilization.