Article

Grumati P, Coletto L, Sabatelli P et al.Autophagy is defective in collagen VI muscular dystrophies, and its reactivation rescues myofiber degeneration. Nat Med 16:1313-1320

Department of Histology, Microbiology & Medical Biotechnology, University of Padova, Padova, Italy.
Nature medicine (Impact Factor: 27.36). 10/2010; 16(11):1313-20. DOI: 10.1038/nm.2247
Source: PubMed

ABSTRACT

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.

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    • "On the other hand, should autophagy be regarded as a process for disease progression? As previous discussions, autophagy under physiological condition is important for cellular homeostasis, the appropriate induction of autophagy is benefit for the clearance of " garbage " in normal aging process and will be a potential strategy for attenuating sarcopenia and other myopathies resulted from dysfunctional autophagy (Grumati et al., 2010; Vainshtein et al., 2014). "
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    • "Increasing evidence demonstrates that skeletal muscle autophagy plays an important role in control body nutrient trafficking and metabolism, which is critical for whole-body metabolic homeostasis (Neel et al. 2013). Moreover, recent studies have found autophagy dysregulation in muscular dystrophies (Grumati et al. 2010; Pauly et al. 2012). However, it is not known whether there are defects in autophagy activity in ALS skeletal muscle. "
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    • "To investigate the effects of CsA administration in Col6a1 −/− mice under physiological conditions, we subjected animals to i.p. injection of vehicle or CsA at 5 mg/kg body weight every 12 h and analyzed muscles after 10 days of treatment (Figure 1A). This dosage of CsA was previously found to trigger a marked amelioration of the myopathic phenotype of Col6a1 −/− mice, with rescue from mitochondrial depolarization and apoptosis and reactivation of the autophagic flux in muscle fibers (Irwin et al., 2003; Grumati et al., 2010). To evaluate whether this CsA treatment triggered de novo formation of myofibers in Col6a1 −/− mice, we first analyzed the cross-sectional area of regenerating, centrally nucleated fibers in TA muscle, by dividing regenerating myofibers into four different size ranges. "
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