Dysferlin, annexin A1, and mitsugumin 53 are upregulated in muscular dystrophy and localize to longitudinal tubules of the T-system with stretch

Leigh B. Waddell, Frances A. Lemckert, Xi F. Zheng, Jenny Tran, Frances J. Evesson, Joanne M. Hawkes, Angela Lek, Neil E. Street, Peihui Lin, Nigel F. Clarke, Andrew P. Landstrom, Michael J. Ackerman, Noah Weisleder, Jianjie Ma, Kathryn N. North, Sandra T. Cooper

Research output: Contribution to journalArticle

54 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)302-313
Number of pages12
JournalJournal of Neuropathology and Experimental Neurology
Volume70
Issue number4
DOIs
StatePublished - Apr 1 2011

Keywords

  • Annexin A1
  • Dysferlin
  • MG53
  • Membrane repair
  • Muscular dystrophy
  • Skeletal muscle

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Neurology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Fingerprint Dive into the research topics of 'Dysferlin, annexin A1, and mitsugumin 53 are upregulated in muscular dystrophy and localize to longitudinal tubules of the T-system with stretch'. Together they form a unique fingerprint.

  • Cite this

    Waddell, L. B., Lemckert, F. A., Zheng, X. F., Tran, J., Evesson, F. J., Hawkes, J. M., Lek, A., Street, N. E., Lin, P., Clarke, N. F., Landstrom, A. P., Ackerman, M. J., Weisleder, N., Ma, J., North, K. N., & Cooper, S. T. (2011). Dysferlin, annexin A1, and mitsugumin 53 are upregulated in muscular dystrophy and localize to longitudinal tubules of the T-system with stretch. Journal of Neuropathology and Experimental Neurology, 70(4), 302-313. https://doi.org/10.1097/NEN.0b013e31821350b0