Autophagy is defective in collagen VI muscular dystrophies, and its reactivation rescues myofiber degeneration

Paolo Grumati, Luisa Coletto, Patrizia Sabatelli, Matilde Cescon, Alessia Angelin, Enrico Bertaggia, Bert Blaauw, Anna Urciuolo, Tania Tiepolo, Luciano Merlini, Nadir M. Maraldi, Paolo Bernardi, Marco Sandri, Paolo Bonaldo

Research output: Contribution to journalArticlepeer-review

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 E1Bg-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.

Original languageEnglish
Pages (from-to)1313-1320
Number of pages8
JournalNature Medicine
Volume16
Issue number11
DOIs
Publication statusPublished - Nov 2010

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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