title: Abnormal trafficking of sarcolemmal proteins in alpha-glucosidase deficiency.
abstract: The dystrophin-associated protein complex (DAP) plays an important role in the integrity and stability of the muscle membrane. Whereas much is known about the interaction between DAP members at the sarcolemmal location, intracellular DAP assembly and trafficking is still largely unknown. In alpha-glucosidase (acid maltase) deficiency (alphaGDD), accumulation of glycogen is accompanied by cytoarchitectural abnormalities impairing normal protein metabolism. In the present study, we took advantage of this fact to examine the consequences of impaired protein handling on the formation of DAP, with the aim of gaining indirect knowledge about its sarcoplasmic trafficking and a better understanding of mechanisms leading to myopathic changes found in alphaGDD. Histological examination of alphaGDD muscle confirmed a vacuolar myopathy with glycogen accumulation both in vacuoles and within the sarcoplasm. Sarcoplasmic accumulation of sarcolemmal proteins, including dystrophin and sarcoglycans, occurred around some vacuoles and within non-vacuolated fibres. Utrophin was up-regulated and found at extra-junctional sarcolemmal locations of many fibres. AlphaGDD muscle cells developed in a fashion similar to that of controls in culture. However, vacuoles were found in 2-week-old alphaGDD myotubes, and these subsequently increased in size and number. Substantial alterations in DAP handling were found, with accumulation close to the Golgi apparatus. Utrophin was not enriched in the sarcoplasm but was up-regulated along the whole sarcolemma. Our results demonstrate a close association of dystrophin and sarcoglycans during sarcoplasmic processing. Furthermore, they suggest that the myopathy found in alphaGDD is a secondary form of DAP deficiency.
authors.affiliation: Department of Neurology, Faculty of Medicine, University of Bern, Bern, Switzerland.
authors.forename: V
authors.initials: V
authors.lastname: Radojevic
authors.forename: A M
authors.initials: AM
authors.lastname: Humm
authors.forename: K M
authors.initials: KM
authors.lastname: Rösler
authors.forename: T
authors.initials: T
authors.lastname: Lauterburg
authors.forename: J-M
authors.initials: JM
authors.lastname: Burgunder
mesh_terms: D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D016189:Dystrophin / Q000378:metabolism*; D006009:Glycogen Storage Disease Type II / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology*; D021381:Protein Transport / Q000502:physiology*; D049411:Utrophin; D014617:Vacuoles / Q000473:pathology
chemical_list: D003598:Cytoskeletal Proteins; D016189:Dystrophin; D008565:Membrane Proteins; D049411:Utrophin