title: Enhanced Muscular Dystrophy from Loss of Dysferlin Is Accompanied by Impaired Annexin A6 Translocation after Sarcolemmal Disruption.
abstract: Dysferlin is a membrane-associated protein implicated in membrane resealing; loss of dysferlin leads to muscular dystrophy. We examined the same loss-of-function Dysf mutation in two different mouse strains, 129T2/SvEmsJ (Dysf(129)) and C57BL/6J (Dysf(B6)). Although there are many genetic differences between these two strains, we focused on polymorphisms in Anxa6 because these variants were previously associated with modifying a pathologically distinct form of muscular dystrophy and increased the production of a truncated annexin A6 protein. Dysferlin deficiency in the C57BL/6J background was associated with increased Evan's Blue dye uptake into muscle and increased serum creatine kinase compared to the 129T2/SvEmsJ background. In the C57BL/6J background, dysferlin loss was associated with enhanced pathologic severity, characterized by decreased mean fiber cross-sectional area, increased internalized nuclei, and increased fibrosis, compared to that in Dysf(129) mice. Macrophage infiltrate was also increased in Dysf(B6) muscle. High-resolution imaging of live myofibers demonstrated that fibers from Dysf(B6) mice displayed reduced translocation of full-length annexin A6 to the site of laser-induced sarcolemmal disruption compared to Dysf(129) myofibers, and impaired translocation of annexin A6 associated with impaired resealing of the sarcolemma. These results provide one mechanism by which the C57BL/6J background intensifies dysferlinopathy, giving rise to a more severe form of muscular dystrophy in the Dysf(B6) mouse model through increased membrane leak and inflammation.
authors.affiliation: Center for Genetic Medicine, Northwestern University, Chicago, Illinois. Electronic address: alexis.demonbreun@northwestern.edu.
authors.forename: Alexis R
authors.initials: AR
authors.lastname: Demonbreun
authors.affiliation: Center for Genetic Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Madison V
authors.initials: MV
authors.lastname: Allen
authors.affiliation: Center for Genetic Medicine, Northwestern University, Chicago, Illinois.
authors.forename: James L
authors.initials: JL
authors.lastname: Warner
authors.affiliation: Center for Genetic Medicine, Northwestern University, Chicago, Illinois.
authors.forename: David Y
authors.initials: DY
authors.lastname: Barefield
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, Illinois.
authors.forename: Swathi
authors.initials: S
authors.lastname: Krishnan
authors.affiliation: Department of Pathology, The University of Chicago, Chicago, Illinois.
authors.forename: Kaitlin E
authors.initials: KE
authors.lastname: Swanson
authors.affiliation: Center for Genetic Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Judy U
authors.initials: JU
authors.lastname: Earley
authors.affiliation: Center for Genetic Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: McNally
mesh_terms: D000818:Animals; D017317:Annexin A6 / Q000235:genetics / Q000378:metabolism*; D000073939:Dysferlin; D015151:Immunoblotting; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009137:Muscular Dystrophy, Animal / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D021381:Protein Transport; D012508:Sarcolemma / Q000378:metabolism
chemical_list: D017317:Annexin A6; C497505:Dysf protein, mouse; D000073939:Dysferlin; D008565:Membrane Proteins