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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Change history
02 March 2011
In the version of this article initially published, the affiliation of two of the authors was incorrectly listed. The Institute of Medical Genetics-National Research Council, Bologna, Italy should have been listed as the Institute of Molecular Genetics, National Research Council, c/o Rizzoli Orthopaedic Institute, Bologna, Italy. The error has been corrected in the HTML and PDF versions of the article.
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Acknowledgements
We thank N. Bergamin for her involvement in the initial study, P. Braghetta for help with mouse manipulations, E. Rizzo and S. Castagnaro for histology, S. Cogliati for assistance with mitochondria isolation and F. Gualandi for muscle biopsies. We are grateful to N. Heintz (Rockefeller University) for supplying the beclin-1–EGFP expression construct and E. Kominami (Juntendo University School of Medicine) for the YFP-LC3 construct. This work was supported by the Telethon Foundation (GGP08107 and TCP04009), the Italian Ministry of University and Research, Association Francaise contre les Myopathies and the EU (BIO-NMD and MYOAGE).
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P.G. performed biochemical analyses, autophagy assays, mouse treatments, analysis and interpretation of data, and contributed to manuscript preparation. L.C. carried out RNA analysis, muscle transfections, molecular biology, analysis and interpretation of data, and contributed to manuscript preparation. P.S. performed electron microscopy. M.C. performed TUNEL and histology. A.A. performed tetramethylrhodamine methyl ester (TMRM) analysis. E.B. carried out muscle transfections and mitochondria isolation. B.B. analyzed muscle mechanics. A.U. performed TUNEL analysis. T.T. genotyped and maintained mice. L.M., P. Bernardi and N.M.M. were involved in data analysis. P. Bonaldo and M.S. designed the study, analyzed data and wrote the paper. All authors discussed the results and commented on the manuscript.
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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 (2010). https://doi.org/10.1038/nm.2247
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DOI: https://doi.org/10.1038/nm.2247
