MYONUCLEAR APOPTOSIS IN DYSTROPHIC MDX MUSCLE OCCURS BY PERFORIN-MEDIATED CYTOTOXICITY

Myonuclear apoptosis is an early event in the pathology of dystrophin- deficient muscular dystrophy in the mdx mouse, However, events that in itiate apoptosis in muscular dystrophy are unknown, and whether elimin ation of apoptosis can ameliorate subsequent muscle wasting remains a major question. We have tested the hypothesis that cytotoxic T-lymphoc ytes initiate myonuclear apoptosis in dystrophic muscle, and examined whether perforin-mediated cytotoxicity plays a role in the pathophysio logy of muscular dystrophy, Mdx mice showed muscle invasion by cytotox ic T cells and helper T cells at the onset of histologically detectabl e muscle fiber pathology. At this time, perforin-expressing cells were also present at elevated concentration. Mdx mice depleted of CD8(+) c ells showed a significant reduction of apoptotic myonuclei concentrati on and a reduction in necrosis, judged by macrophage invasion of muscl e fibers. Double-mutant mice, deficient in dystrophin and perforin, sh owed nearly complete absence of myonuclear apoptosis, and a significan t reduction in the concentration of macrophages in the connective tiss ue surrounding muscle fibers. However, muscle fiber invasion by macrop hages was not reduced significantly in double mutant mice. Thus, cytot oxic T-lymphocytes contribute significantly to apoptosis and necrosis in mdx dystrophy, and perforin-mediated killing is primarily responsib le for myonuclear apoptosis.