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Am J Physiol Cell Physiol ; 321(1): C94-C103, 2021 07 01.
Article in English | MEDLINE | ID: mdl-33979211

ABSTRACT

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 ß-galactosidase (SA-ß-Gal)-positive cells. These results highlight an underexplored role for cellular senescence in murine dystrophic muscle.


Subject(s)
Cellular Senescence/genetics , Cyclin-Dependent Kinase Inhibitor p21/genetics , Endothelial Cells/metabolism , Macrophages/metabolism , Muscle, Skeletal/metabolism , Muscular Dystrophy, Animal/genetics , Animals , Cyclin-Dependent Kinase Inhibitor p16/genetics , Cyclin-Dependent Kinase Inhibitor p16/metabolism , Cyclin-Dependent Kinase Inhibitor p21/metabolism , Disease Models, Animal , Dystrophin/deficiency , Dystrophin/genetics , Endothelial Cells/pathology , Gene Expression Regulation , Humans , Macrophages/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Inbred mdx , Muscle, Skeletal/pathology , Muscular Dystrophy, Animal/metabolism , Muscular Dystrophy, Animal/pathology , Muscular Dystrophy, Duchenne/genetics , Muscular Dystrophy, Duchenne/metabolism , Muscular Dystrophy, Duchenne/pathology , Myofibrils/metabolism , Myofibrils/pathology , Signal Transduction , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , beta-Galactosidase/genetics , beta-Galactosidase/metabolism
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