Loss of dystrophin expression in skeletal muscle is associated with senescence of macrophages and endothelial cells Journal Articles uri icon

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  • Cellular senescence is the irreversible arrest of normally dividing cells and is driven by cell cycle inhibitory proteins such as p16, p21, and p53. When cells enter senescence, they secrete a host of proinflammatory factors known as the senescence-associated secretory phenotype, which has deleterious effects on surrounding cells and tissues. Little is known of the role of senescence in Duchenne muscular dystrophy (DMD), the fatal X-linked neuromuscular disorder typified by chronic inflammation, extracellular matrix remodeling, and a progressive loss in muscle mass and function. Here, we demonstrate using C57- mdx (8-wk-old) and D2- mdx (4-wk-old and 8-wk-old) mice, two mouse models of DMD, that cells displaying canonical markers of senescence are found within the skeletal muscle. Eight-week-old D2- mdx mice, which display severe muscle pathology, had greater numbers of senescent cells associated with areas of inflammation, which were mostly Cdkn1a-positive macrophages, whereas in C57- mdx muscle, senescent populations were endothelial cells and macrophages localized to newly regenerated myofibers. Interestingly, this pattern was similar to cardiotoxin (CTX)-injured wild-type (WT) muscle, which experienced a transient senescent response. Dystrophic muscle demonstrated significant upregulations in senescence pathway genes [ Cdkn1a (p21), Cdkn2a (p16INK4A), and Trp53 (p53)], which correlated with the quantity of senescence-associated β-galactosidase (SA-β-Gal)-positive cells. These results highlight an underexplored role for cellular senescence in murine dystrophic muscle.


  • Young, Laura V
  • Morrison, William
  • Campbell, Craig
  • Moore, Emma C
  • Arsenault, Michel G
  • Dial, Athan G
  • Ng, Sean
  • Bellissimo, Catherine A
  • Perry, Christopher GR
  • Ljubicic, Vladimir
  • Johnston, Adam P

publication date

  • July 1, 2021

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