Human Molecular Genetics Advance Access originally published online on September 9, 2008
Human Molecular Genetics 2008 17(24):3897-3908; doi:10.1093/hmg/ddn292
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Published by Oxford University Press 2008
Suppression of autophagy in skeletal muscle uncovers the accumulation of ubiquitinated proteins and their potential role in muscle damage in Pompe disease
1 Arthritis and Rheumatism Branch 2 Light Imaging Section, Office of Science and Technology, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA 3 The Department of Physiology and Cell Biology, Tokyo Medical and Dental University, Tokyo, Japan
* To whom correspondence should be addressed at: 50 South Drive, Bld. 50/1345, NIAMS, NIH, Bethesda, MD 20892-1820, USA. Tel: +1 3014961474; Fax: +1 3014358017; Email: rabenn{at}arb.niams.nih.gov
Received July 16, 2008; Accepted September 8, 2008
The role of autophagy, a catabolic lysosome-dependent pathway, has recently been recognized in a variety of disorders, including Pompe disease, the genetic deficiency of the glycogen-degrading lysosomal enzyme acid-alpha glucosidase. Accumulation of lysosomal glycogen, presumably transported from the cytoplasm by the autophagic pathway, occurs in multiple tissues, but pathology is most severe in skeletal and cardiac muscle. Skeletal muscle pathology also involves massive autophagic buildup in the core of myofibers. To determine if glycogen reaches the lysosome via autophagy and to ascertain whether autophagic buildup in Pompe disease is a consequence of induction of autophagy and/or reduced turnover due to defective fusion with lysosomes, we generated muscle-specific autophagy-deficient Pompe mice. We have demonstrated that autophagy is not required for glycogen transport to lysosomes in skeletal muscle. We have also found that Pompe disease involves induction of autophagy but manifests as a functional deficiency of autophagy because of impaired autophagosomal–lysosomal fusion. As a result, autophagic substrates, including potentially toxic aggregate-prone ubiquitinated proteins, accumulate in Pompe myofibers and may cause profound muscle damage.