Dysfunction of endocytic and autophagic pathways in a lysosomal storage disease

Authors

  • Tokiko Fukuda MD, PhD,

    1. Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD
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  • Lindsay Ewan BA,

    1. Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD
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  • Martina Bauer BA,

    1. Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD
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  • Robert J. Mattaliano PhD,

    1. Cell and Protein Therapeutics R&D, Genzyme Corporation, Framingham, MA
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  • Kristien Zaal PhD,

    1. Light Imaging Section, Office of Science and Technology, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD
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  • Evelyn Ralston PhD,

    1. Light Imaging Section, Office of Science and Technology, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD
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  • Paul H. Plotz MD,

    1. Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD
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  • Nina Raben MD, PhD

    Corresponding author
    1. Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD
    • 9000 Rockville Pike, Clinical Center Building 10/9N244, NIH, NIAMS, Bethesda, MD 20892-1820
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Abstract

Objective

To understand the mechanisms of skeletal muscle destruction and resistance to enzyme replacement therapy in Pompe disease, a deficiency of lysosomal acid α-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. Ann Neurol 2006

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