Autophagy is defective in collagen VI muscular dystrophies, and its reactivation rescues myofiber degeneration
Autophagy is defective in collagen VI muscular dystrophies, and its reactivation rescues myofiber degeneration
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DOI：
10.1038/nm.2247
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发表时间：
2010-11-01
期刊：
影响因子：
82.9
通讯作者：
Bonaldo, Paolo
中科院分区：
文献类型：
--
作者：
Grumati, Paolo;Coletto, Luisa;Bonaldo, Paolo
自噬对细胞成分的周转至关重要，通过自噬-溶酶体途径清除受损的细胞器对组织稳态至关重要。这种降解系统的缺陷在多种疾病中起作用，但对肌营养不良症的自噬作用知之甚少。我们之前发现，与胶原VI缺乏相关的肌肉萎缩症表现出线粒体功能障碍和自发凋亡，导致肌纤维变性。在这里，我们证明这种异常细胞器和细胞凋亡的持续存在是由缺陷的自噬引起的。胶原vi敲除（Col6a1(-/-)）小鼠的骨骼肌自噬通量受损，这与饥饿后beclin-1和BCL-2/腺病毒e1b相互作用蛋白-3 （Bnip3）的诱导降低和自噬体缺乏相匹配。通过遗传、饮食和药理学方法强制激活自噬恢复了肌纤维存活，改善了Col6a1（-/-）小鼠的营养不良表型。此外，Bethlem肌病或乌尔里希先天性肌营养不良患者的肌肉活检显示beclin-1和Bnip3蛋白含量降低。这些发现表明，自噬机制的缺陷激活在一些先天性肌营养不良症中是致病的。
Autophagy is crucial in the turnover of cell components, and clearance of damaged organelles by the autophagic-lysosomal pathway is essential for tissue homeostasis. Defects of this degradative system have a role in various diseases, but little is known about autophagy in muscular dystrophies. We have previously found that muscular dystrophies linked to collagen VI deficiency show dysfunctional mitochondria and spontaneous apoptosis, leading to myofiber degeneration. Here we demonstrate that this persistence of abnormal organelles and apoptosis are caused by defective autophagy. Skeletal muscles of collagen VI-knockout (Col6a1(-/-)) mice had impaired autophagic flux, which matched the lower induction of beclin-1 and BCL-2/adenovirus E1B-interacting protein-3 (Bnip3) and the lack of autophagosomes after starvation. Forced activation of autophagy by genetic, dietary and pharmacological approaches restored myofiber survival and ameliorated the dystrophic phenotype of Col6a1(-/-) mice. Furthermore, muscle biopsies from subjects with Bethlem myopathy or Ullrich congenital muscular dystrophy had reduced protein amounts of beclin-1 and Bnip3. These findings indicate that defective activation of the autophagic machinery is pathogenic in some congenital muscular dystrophies.