Attenuated muscle regeneration is a key factor in dysferlin-deficient muscular dystrophy
Attenuated muscle regeneration is a key factor in dysferlin-deficient muscular dystrophy
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DOI：
10.1093/hmg/ddp121
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发表时间：
2009-06-01
影响因子：
3.5
通讯作者：
Bushby, Kate
中科院分区：
文献类型：
--
作者：
Chiu, Yen-Hui;Hornsey, Mark A.;Bushby, Kate
骨骼肌需要高效、活跃的膜修复系统来克服频繁收缩的严酷考验。 Dysferlin 是该系统的一个组成部分，缺乏 Dysferlin 会导致肌营养不良（dysferlin 病），其特征是成人发病的肌肉无力、高血清肌酸激酶水平和明显的炎症浸润。我们观察到 Dysferlin 病患者的活检显示出过量的未成熟纤维，因此研究了 Dysferlin 在肌肉再生中的作用。利用notexin诱导的肌肉损伤，我们发现，在患有肌肉萎缩症的小鼠模型中，再生减弱，坏死纤维的清除延迟，炎症阶段延长，功能恢复延迟。卫星细胞激活和成肌细胞融合似乎正常，但在 Dysferlin 缺陷小鼠的再生和针刺受伤肌肉中早期中性粒细胞的募集有所减少。原代小鼠铁蛋白病成肌细胞培养物显示刺激后细胞因子释放减少，表明趋化分子的分泌受损。我们建议扩展肌肉膜修复模型，其中除了将补片修复囊泡与肌膜融合外，dysferlin 还参与趋化剂的释放。中性粒细胞募集减少导致铁蛋白病的再生周期不完整，与膜修复缺陷相结合，最终引发营养不良病理。这项研究揭示了一种影响肌肉再生和维持的新病理机制，并强调中性粒细胞反应的增强是这些疾病的潜在治疗途径。
Skeletal muscle requires an efficient and active membrane repair system to overcome the rigours of frequent contraction. Dysferlin is a component of that system and absence of dysferlin causes muscular dystrophy (dysferlinopathy) characterized by adult onset muscle weakness, high serum creatine kinase levels and a prominent inflammatory infiltrate. We have observed that dysferlinopathy patient biopsies show an excess of immature fibres and therefore investigated the role of dysferlin in muscle regeneration. Using notexin-induced muscle damage, we have shown that regeneration is attenuated in a mouse model of dysferlinopathy, with delayed removal of necrotic fibres, an extended inflammatory phase and delayed functional recovery. Satellite cell activation and myoblast fusion appear normal, but there is a reduction in early neutrophil recruitment in regenerating and also needle wounded muscle in dysferlin-deficient mice. Primary mouse dysferlinopathy myoblast cultures show reduced cytokine release upon stimulation, indicating that the secretion of chemotactic molecules is impaired. We suggest an extension to the muscle membrane repair model, where in addition to fusing patch repair vesicles with the sarcolemma dysferlin is also involved in the release of chemotactic agents. Reduced neutrophil recruitment results in incomplete cycles of regeneration in dysferlinopathy which combines with the membrane repair deficit to ultimately trigger dystrophic pathology. This study reveals a novel pathomechanism affecting muscle regeneration and maintenance in dysferlinopathy and highlights enhancement of the neutrophil response as a potential therapeutic avenue in these disorders.