Myonuclear apoptosis in dystrophic mdx muscle occurs by perforin-mediated cytotoxicity

J Clin Invest. 1997 Jun 1;99(11):2745-51. doi: 10.1172/JCI119464.

Abstract

Myonuclear apoptosis is an early event in the pathology of dystrophin-deficient muscular dystrophy in the mdx mouse. However, events that initiate apoptosis in muscular dystrophy are unknown, and whether elimination of apoptosis can ameliorate subsequent muscle wasting remains a major question. We have tested the hypothesis that cytotoxic T-lymphocytes initiate myonuclear apoptosis in dystrophic muscle, and examined whether perforin-mediated cytotoxicity plays a role in the pathophysiology of muscular dystrophy. Mdx mice showed muscle invasion by cytotoxic T cells and helper T cells at the onset of histologically detectable muscle fiber pathology. At this time, perforin-expressing cells were also present at elevated concentration. Mdx mice depleted of CD8(+) cells showed a significant reduction of apoptotic myonuclei concentration and a reduction in necrosis, judged by macrophage invasion of muscle fibers. Double-mutant mice, deficient in dystrophin and perforin, showed nearly complete absence of myonuclear apoptosis, and a significant reduction in the concentration of macrophages in the connective tissue surrounding muscle fibers. However, muscle fiber invasion by macrophages was not reduced significantly in double mutant mice. Thus, cytotoxic T-lymphocytes contribute significantly to apoptosis and necrosis in mdx dystrophy, and perforin-mediated killing is primarily responsible for myonuclear apoptosis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis / immunology*
  • Cytotoxicity, Immunologic*
  • Dystrophin / deficiency*
  • Dystrophin / genetics
  • Membrane Glycoproteins / immunology*
  • Mice
  • Mice, Knockout
  • Muscle, Skeletal / pathology*
  • Muscular Dystrophy, Animal / immunology
  • Muscular Dystrophy, Animal / metabolism
  • Muscular Dystrophy, Animal / pathology*
  • Perforin
  • Pore Forming Cytotoxic Proteins
  • T-Lymphocytes / immunology*

Substances

  • Dystrophin
  • Membrane Glycoproteins
  • Pore Forming Cytotoxic Proteins
  • Perforin