Suppression of autophagy in skeletal muscle uncovers the accumulation of ubiquitinated proteins and their potential role in muscle damage in Pompe disease
Open Access
- 4 September 2008
- journal article
- research article
- Published by Oxford University Press (OUP) in Human Molecular Genetics
- Vol. 17 (24), 3897-3908
- https://doi.org/10.1093/hmg/ddn292
Abstract
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.Keywords
This publication has 59 references indexed in Scilit:
- Structural Basis for Sorting Mechanism of p62 in Selective AutophagyJournal of Biological Chemistry, 2008
- Downstream of Akt: FoxO3 and mTOR in the regulation of autophagy in skeletal muscleAutophagy, 2008
- The role of autophagy in neonatal tissues: Just a response to amino acid starvation?Autophagy, 2008
- Autophagy fights disease through cellular self-digestionNature, 2008
- The Itinerary of Autophagosomes: From Peripheral Formation to Kiss‐and‐Run Fusion with LysosomesTraffic, 2008
- Homeostatic Levels of p62 Control Cytoplasmic Inclusion Body Formation in Autophagy-Deficient MiceCell, 2007
- A block of autophagy in lysosomal storage disordersHuman Molecular Genetics, 2007
- Dissection of Autophagosome Formation Using Apg5-Deficient Mouse Embryonic Stem CellsThe Journal of cell biology, 2001
- LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processingThe EMBO Journal, 2000
- Pathological features of glycogen storage disease type II highlighted in the knockout mouse modelThe Journal of Pathology, 1999