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


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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    • "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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    ABSTRACT: Accumulation of abnormal protein inclusions is implicated in motor neuron degeneration in amyotrophic lateral sclerosis (ALS). Autophagy, an intracellular process targeting misfolded proteins and damaged organelles for lysosomal degradation, plays crucial roles in survival and diseased conditions. Efforts were made to understand the role of autophagy in motor neuron degeneration and to target autophagy in motor neuron for ALS treatment. However, results were quite contradictory. Possible autophagy defects in other cell types may also complicate the results. Here, we examined autophagy activity in skeletal muscle of an ALS mouse model G93A. Through overexpression of a fluorescent protein LC3-RFP, we found a basal increase in autophagosome formation in G93A muscle during disease progression when the mice were on a regular diet. As expected, an autophagy induction procedure (starvation plus colchicine) enhanced autophagy flux in skeletal muscle of normal mice. However, in response to the same autophagy induction procedure, G93A muscle showed significant reduction in the autophagy flux. Immunoblot analysis revealed that increased cleaved caspase-3 associated with apoptosis was linked to the cleavage of several key proteins involved in autophagy, including Beclin-1, which is an essential molecule connecting autophagy and apoptosis pathways. Taking together, we provide the evidence that the cytoprotective autophagy pathway is suppressed in G93A skeletal muscle and this suppression may link to the enhanced apoptosis during ALS progression. The abnormal autophagy activity in skeletal muscle likely contributes muscle degeneration and disease progression in ALS.
    01/2015; 3(1). DOI:10.14814/phy2.12271
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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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    ABSTRACT: Mutations of genes encoding for collagen VI cause various muscle diseases in humans, including Bethlem myopathy and Ullrich congenital muscular dystrophy. Collagen VI null (Col6a1 (-/-)) mice are affected by a myopathic phenotype with mitochondrial dysfunction, spontaneous apoptosis of muscle fibers, and defective autophagy. Moreover, Col6a1 (-/-) mice display impaired muscle regeneration and defective self-renewal of satellite cells after injury. Treatment with cyclosporin A (CsA) is effective in normalizing the mitochondrial, apoptotic, and autophagic defects of myofibers in Col6a1 (-/-) mice. A pilot clinical trial with CsA in Ullrich patients suggested that CsA may increase the number of regenerating myofibers. Here, we report the effects of CsA administration at 5 mg/kg body weight every 12 h in Col6a1 (-/-) mice on muscle regeneration under physiological conditions and after cardiotoxin (CdTx)-induced muscle injury. Our findings indicate that CsA influences satellite cell activity and triggers the formation of regenerating fibers in Col6a1 (-/-) mice. Data obtained on injured muscles show that under appropriate administration, regimens CsA is able to stimulate myogenesis in Col6a1 (-/-) mice by significantly increasing the number of myogenin (MyoG)-positive cells and of regenerating myofibers at the early stages of muscle regeneration. CsA is also able to ameliorate muscle regeneration of Col6a1 (-/-) mice subjected to multiple CdTx injuries, with a concurrent maintenance of the satellite cell pool. Our data show that CsA is beneficial for muscle regeneration in Col6a1 (-/-) mice.
    Frontiers in Aging Neuroscience 09/2014; 6:244. DOI:10.3389/fnagi.2014.00244 · 4.00 Impact Factor
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    • "Therefore, it is expected that pharmacological inhibition (everolimus) of mTORC1 rescued the muscular disorder resembling sarcopenia in GSK-3α KO mice (Zhou et al., 2013). Enhancement of autophagy flux (exercise, caloric restriction, etc.) would be a potential strategy attenuating sarcopenia as well as various type of muscular dystrophy with autophagy defect (Grumati et al., 2010; De Palma et al., 2012; Vainshtein et al., 2014). "
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    ABSTRACT: Recent advances in our understanding of the biology of muscle have led to new interest in the pharmacological treatment of muscle wasting. Loss of muscle mass and increased intramuscular fibrosis occur in both sarcopenia and muscular dystrophy. Several regulators (mammalian target of rapamycin, serum response factor, atrogin-1, myostatin, etc.) seem to modulate protein synthesis and degradation or transcription of muscle-specific genes during both sarcopenia and muscular dystrophy. This review provides an overview of the adaptive changes in several regulators of muscle mass in both sarcopenia and muscular dystrophy.
    Frontiers in Aging Neuroscience 08/2014; 6:230. DOI:10.3389/fnagi.2014.00230 · 4.00 Impact Factor
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