Enhanced Muscular Dystrophy from Loss of Dysferlin Is Accompanied by Impaired Annexin A6 Translocation after Sarcolemmal Disruption

Am J Pathol. 2016 Jun;186(6):1610-22. doi: 10.1016/j.ajpath.2016.02.005. Epub 2016 Apr 9.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Annexin A6 / genetics
  • Annexin A6 / metabolism*
  • Dysferlin
  • Immunoblotting
  • Membrane Proteins / deficiency*
  • Membrane Proteins / genetics
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Muscular Dystrophy, Animal / genetics*
  • Muscular Dystrophy, Animal / metabolism
  • Muscular Dystrophy, Animal / pathology*
  • Polymerase Chain Reaction
  • Polymorphism, Single Nucleotide
  • Protein Transport
  • Sarcolemma / metabolism

Substances

  • Annexin A6
  • Dysf protein, mouse
  • Dysferlin
  • Membrane Proteins