Total absence of dystrophin expression exacerbates ectopic myofiber calcification, fibrosis, and alters macrophage infiltration patterns

Abstract

Duchenne muscular dystrophy (DMD) causes severe disability and death of young men due to progressive muscle degeneration aggravated by sterile inflammation. DMD is also associated with cognitive and bone-function impairments. This complex phenotype results from the cumulative loss of a spectrum of dystrophin isoforms expressed from the largest human gene. Although there is evidence for the loss of shorter isoforms having impact in the central nervous system, their role in muscle is unclear. We found that at eight weeks, the active phase of pathology in dystrophic mice, dystrophin-null mice (mdxβgeo) presented with a mildly exacerbated phenotype but without an earlier onset, increased serum CK levels, or decreased muscle strength. However, at 12 months, mdxβgeo diaphragm strength was lower while fibrosis increased, compared to mdx. The most striking features of the dystrophin-null phenotype were increased ectopic myofiber calcification and altered macrophage infiltration patterns, particularly the close association of macrophages with calcified fibers. Ectopic calcification had the same temporal pattern of presentation and resolution in mdxβgeo and mdx muscles despite very significant intensity differences across muscle groups. Comparison of the rare dystrophin-null patients against those with mutations affecting full-length dystrophins may provide mechanistic insights for developing more effective treatments for DMD.

Description

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link.

Keywords

Duchenne muscular dystrophy, Ectopic calcium, Macrophages, mdx mouse, mdxbgeo mouse

Citation

Young, C. et al. (2019) Total absence of dystrophin expression exacerbates ectopic myofiber calcification, fibrosis, and alters macrophage infiltration patterns. The American Journal of Pathology,

Rights

Research Institute

Institute for Allied Health Sciences Research