title: Dysferlin, annexin A1, and mitsugumin 53 are upregulated in muscular dystrophy and localize to longitudinal tubules of the T-system with stretch.
abstract: Mutations in dysferlin cause an inherited muscular dystrophy because of defective membrane repair. Three interacting partners of dysferlin are also implicated in membrane resealing: caveolin-3 (in limb girdle muscular dystrophy type 1C), annexin A1, and the newly identified protein mitsugumin 53 (MG53). Mitsugumin 53 accumulates at sites of membrane damage, and MG53-knockout mice display a progressive muscular dystrophy. This study explored the expression and localization of MG53 in human skeletal muscle, how membrane repair proteins are modulated in various forms of muscular dystrophy, and whether MG53 is a primary cause of human muscle disease. Mitsugumin 53 showed variable sarcolemmal and/or cytoplasmic immunolabeling in control human muscle and elevated levels in dystrophic patients. No pathogenic MG53 mutations were identified in 50 muscular dystrophy patients, suggesting that MG53 is unlikely to be a common cause of muscular dystrophy in Australia. Western blot analysis confirmed upregulation of MG53, as well as of dysferlin, annexin A1, and caveolin-3 to different degrees, in different muscular dystrophies. Importantly, MG53, annexin A1, and dysferlin localize to the t-tubule network and show enriched labeling at longitudinal tubules of the t-system in overstretch. Our results suggest that longitudinal tubules of the t-system may represent sites of physiological membrane damage targeted by this membrane repair complex.
authors.affiliation: Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Discipline of Paediatrics and Child Health, University of Sydney, Sydney, Australia.
authors.forename: Leigh B
authors.initials: LB
authors.lastname: Waddell
authors.forename: Frances A
authors.initials: FA
authors.lastname: Lemckert
authors.forename: Xi F
authors.initials: XF
authors.lastname: Zheng
authors.forename: Jenny
authors.initials: J
authors.lastname: Tran
authors.forename: Frances J
authors.initials: FJ
authors.lastname: Evesson
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Hawkes
authors.forename: Angela
authors.initials: A
authors.lastname: Lek
authors.forename: Neil E
authors.initials: NE
authors.lastname: Street
authors.forename: Peihui
authors.initials: P
authors.lastname: Lin
authors.forename: Nigel F
authors.initials: NF
authors.lastname: Clarke
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Landstrom
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ackerman
authors.forename: Noah
authors.initials: N
authors.lastname: Weisleder
authors.forename: Jianjie
authors.initials: J
authors.lastname: Ma
authors.forename: Kathryn N
authors.initials: KN
authors.lastname: North
authors.forename: Sandra T
authors.initials: ST
authors.lastname: Cooper
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D017305:Annexin A1 / Q000378:metabolism*; D001706:Biopsy; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D003593:Cytoplasm / Q000378:metabolism; D004247:DNA / Q000235:genetics; D000073939:Dysferlin; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D008565:Membrane Proteins / Q000378:metabolism*; D018613:Microscopy, Confocal; D008870:Microtubules / Q000378:metabolism*; D008875:Middle Aged; D009124:Muscle Proteins / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*; D049288:Muscular Dystrophies, Limb-Girdle / Q000378:metabolism*; D010812:Physical Stimulation; D012508:Sarcolemma / Q000378:metabolism; D000070584:Tripartite Motif Proteins; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D017305:Annexin A1; D002352:Carrier Proteins; C114839:DYSF protein, human; D000073939:Dysferlin; D008565:Membrane Proteins; D009124:Muscle Proteins; C558399:TRIM72 protein, human; D000070584:Tripartite Motif Proteins; D004247:DNA