Department of Histology, Microbiology & Medical Biotechnology, University of Padova, Padova, Italy.
Nat Med. 2010 Nov;16(11):1313-20. doi: 10.1038/nm.2247. Epub 2010 Oct 31.
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.
自噬对于细胞成分的更新至关重要，通过自噬溶酶体途径清除受损的细胞器对于组织稳态至关重要。这个降解系统的缺陷在各种疾病中起作用，但在肌肉萎缩症中对自噬知之甚少。我们之前发现，与胶原 VI 缺乏相关的肌肉萎缩症表现出功能失调的线粒体和自发的细胞凋亡，导致肌纤维变性。在这里，我们证明这种异常细胞器的持续存在和细胞凋亡是由自噬缺陷引起的。胶原 VI 敲除（Col6a1(-/-)）小鼠的骨骼肌自噬通量受损，与饥饿后自噬体诱导减少、beclin-1 和 BCL-2/腺病毒 E1B 相互作用蛋白-3（Bnip3）的诱导减少以及自噬体缺乏相匹配。通过遗传、饮食和药理学方法强制激活自噬可恢复肌纤维的存活，并改善 Col6a1(-/-) 小鼠的肌肉萎缩表型。此外，Bethlem 肌肉病或 Ullrich 先天性肌肉萎缩症患者的肌肉活检显示 beclin-1 和 Bnip3 的蛋白含量减少。这些发现表明，一些先天性肌肉萎缩症中自噬机制的缺陷激活是致病的。
