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

• Published in: Nature medicine Vol. 16; no. 11; pp. 1313 - 1320
• Main Authors: Urciuolo, Anna, Sabatelli, Patrizia, Tiepolo, Tania, Sandri, Marco, Coletto, Luisa, Bertaggia, Enrico, Blaauw, Bert, Grumati, Paolo, Maraldi, Nadir M, Cescon, Matilde, Bernardi, Paolo, Bonaldo, Paolo, Angelin, Alessia, Merlini, Luciano
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-11-2010; Nature Publishing Group
• Subjects: 631/80/82/39; 692/420; 692/699/1670/1669; Animals; Apoptosis; Apoptosis Regulatory Proteins - metabolism; Autophagy; Autophagy (Cytology); Beclin-1; Biomedical and Life Sciences; Biomedicine; Blotting, Western; Cancer Research; Care and treatment; Cell Nucleus - metabolism; Cellular biology; Collagen Type VI - deficiency; Collagen Type VI - metabolism; Diaphragm - pathology; Diaphragm - ultrastructure; Dystrophy; Genetic aspects; Homeostasis; Humans; In Situ Nick-End Labeling; Infectious Diseases; Medical research; Membrane Proteins - metabolism; Metabolic Diseases; Mice; Mice, Inbred C57BL; Mitochondrial Proteins - metabolism; Molecular Medicine; Muscle Fibers, Skeletal - metabolism; Muscle Fibers, Skeletal - pathology; Muscles; Muscular Dystrophies - metabolism; Muscular Dystrophies - pathology; Muscular dystrophy; Neurosciences; Phenotype; Physiological aspects; Risk factors; Rodents; Italy
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.2247

Autophagy is often believed to be elevated in disease, contributing to pathogenesis. Paolo Bonaldo and his colleagues now show that it is actually too little autophagy that occurs in some forms of muscular dystrophy, resulting in the continued presence of defective mitochondria and thus myofiber degeneration. They also show that increasing autophagy via dietary or pharmacological means can ameliorate muscle pathology in a mouse model of human muscular dystrophy.
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.