Dysfunction of endocytic and autophagic pathways in a lysosomal storage disease

Ann Neurol. 2006 Apr;59(4):700-8. doi: 10.1002/ana.20807.


Objective: To understand the mechanisms of skeletal muscle destruction and resistance to enzyme replacement therapy in Pompe disease, a deficiency of lysosomal acid alpha-glucosidase (GAA), in which glycogen accumulates in lysosomes primarily in cardiac and skeletal muscles.

Methods: We have analyzed compartments of the lysosomal degradative pathway in GAA-deficient myoblasts and single type I and type II muscle fibers isolated from wild-type, untreated, and enzyme replacement therapy-treated GAA knock-out mice.

Results: Studies in myoblasts from GAA knock-out mice showed a dramatic expansion of vesicles of the endocytic/autophagic pathways, decreased vesicular movement in overcrowded cells, and an acidification defect in a subset of late endosomes/lysosomes. Analysis by confocal microscopy of isolated muscle fibers demonstrated that the consequences of the lysosomal glycogen accumulation are strikingly different in type I and II muscle fibers. Only type II fibers, which are the most resistant to therapy, contain large regions of autophagic buildup that span the entire length of the fibers.

Interpretation: The vastly increased autophagic buildup may be responsible for skeletal muscle damage and prevent efficient trafficking of replacement enzyme to lysosomes.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Intramural

MeSH terms

  • Age Factors
  • Animals
  • Autophagy / physiology*
  • Blotting, Western / methods
  • Cells, Cultured
  • Disease Models, Animal
  • Endocytosis / physiology*
  • Fluorescent Antibody Technique / methods
  • Glucan 1,4-alpha-Glucosidase / deficiency
  • Green Fluorescent Proteins / metabolism
  • In Vitro Techniques
  • Lysosomal Storage Diseases / genetics
  • Lysosomal Storage Diseases / metabolism
  • Lysosomal Storage Diseases / physiopathology*
  • Lysosomal-Associated Membrane Protein 1 / metabolism
  • Mice
  • Mice, Knockout
  • Microscopy, Electron, Transmission / methods
  • Muscle Fibers, Skeletal / metabolism
  • Muscle Fibers, Skeletal / ultrastructure
  • Myoblasts / metabolism
  • Myoblasts / ultrastructure
  • Time Factors
  • Transfection / methods
  • Transport Vesicles / metabolism
  • Transport Vesicles / ultrastructure
  • Tubulin / metabolism


  • Lysosomal-Associated Membrane Protein 1
  • Tubulin
  • Green Fluorescent Proteins
  • Glucan 1,4-alpha-Glucosidase