title: Deconstructing Pompe disease by analyzing single muscle fibers: to see a world in a grain of sand...
abstract: Autophagy is a major pathway for delivery of proteins and organelles to lysosomes where they are degraded and recycled. We have previously shown excessive autophagy in a mouse model of Pompe disease (glycogen storage disease type II), a devastating myopathy caused by a deficiency of the glycogen-degrading lysosomal enzyme acid alpha-glucosidase. The autophagic buildup constituted a major pathological component in skeletal muscle and interfered with delivery of the therapeutic enzyme. To assess the role of autophagy in the pathogenesis of the human disease, we have analyzed vesicles of the lysosomal-degradative pathway in isolated single muscle fibers from Pompe patients. Human myofibers showed abundant autophagosome formation and areas of autophagic buildup of a wide range of sizes. In patients, as in the mouse model, the enormous autophagic buildup causes greater skeletal muscle damage than the enlarged, glycogenfilled lysosomes outside the autophagic regions. Clearing or preventing autophagic buildup seems, therefore, a necessary target of Pompe disease therapy.
authors.affiliation: Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland 20892-1820, USA. rabenn@arb.niams.nih.gov
authors.forename: Nina
authors.initials: N
authors.lastname: Raben
authors.forename: Shoichi
authors.initials: S
authors.lastname: Takikita
authors.forename: Maria G
authors.initials: MG
authors.lastname: Pittis
authors.forename: Bruno
authors.initials: B
authors.lastname: Bembi
authors.forename: Suely K N
authors.initials: SK
authors.lastname: Marie
authors.forename: Ashley
authors.initials: A
authors.lastname: Roberts
authors.forename: Laura
authors.initials: L
authors.lastname: Page
authors.forename: Priya S
authors.initials: PS
authors.lastname: Kishnani
authors.forename: Benedikt G H
authors.initials: BG
authors.lastname: Schoser
authors.forename: Yin-Hsiu
authors.initials: YH
authors.lastname: Chien
authors.forename: Evelyn
authors.initials: E
authors.lastname: Ralston
authors.forename: Kanneboyina
authors.initials: K
authors.lastname: Nagaraju
authors.forename: Paul H
authors.initials: PH
authors.lastname: Plotz
mesh_terms: D000293:Adolescent; D000328:Adult; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D015415:Biomarkers / Q000378:metabolism; D002461:Cell Line, Transformed; D002472:Cell Transformation, Viral; D002648:Child; D006009:Glycogen Storage Disease Type II / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006579:Heterozygote; D006651:Histocytochemistry; D006801:Humans; D052119:Lysosomal-Associated Membrane Protein 2; D051907:Lysosomal Membrane Proteins / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D018613:Microscopy, Confocal; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008875:Middle Aged; D018485:Muscle Fibers, Skeletal / Q000378:metabolism* / Q000473:pathology; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D032446:Myoblasts / Q000378:metabolism
chemical_list: D015415:Biomarkers; C497811:LAMP2 protein, human; D052119:Lysosomal-Associated Membrane Protein 2; D051907:Lysosomal Membrane Proteins; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins