Reduced necrosis of dystrophic muscle by depletion of host neutrophils, or blocking TNFalpha function with Etanercept in mdx mice.
Necrosis of skeletal muscle fibres in the lethal childhood myopathy Duchenne Muscular Dystrophy results from deficiency of the cell membrane associated protein, dystrophin. We test the hypothesis in dystrophin-deficient mice, that the initial sarcolemmal breakdown resulting from dystrophin deficiency is exacerbated by inflammatory cells, specifically neutrophils, and that cytokines, specifically Tumour Necrosis Factor alpha (TNFalpha), contribute to myofibre necrosis. Antibody depletion of host neutrophils resulted in a delayed and significantly reduced amount of skeletal muscle breakdown in young dystrophic mdx mice. A more striking and prolonged protective effect was seen after pharmacological blockade of TNFalpha bioactivity using Etanercept. The extent of exercise induced myofibre necrosis in adult mdx mice after voluntarily wheel exercise was also reduced after Etanercept administration. These data show a clear role for neutrophils and TNFalpha in necrosis of dystrophic mdx muscle in vivo. Etanercept is a highly specific anti-inflammatory drug, widely used clinically, and potential application to muscular dystrophies is suggested by this reduced breakdown of mdx skeletal muscle.
Hodgetts
Stuart
S
School of Anatomy and Human Biology, The University of Western Australia, 35 Stirling Highway, Crawley, Western Australia 6009, Australia.
Radley
Hannah
H
Davies
Marilyn
M
Grounds
Miranda D
MD
D000818:Animals; D000906:Antibodies / Q000276:immunology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D016189:Dystrophin / Q000172:deficiency; D000068800:Etanercept; D005260:Female; D007074:Immunoglobulin G / Q000494:pharmacology* / Q000627:therapeutic use; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D007249:Inflammation / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control; D051379:Mice; D018101:Mice, Inbred mdx; D018482:Muscle, Skeletal / Q000187:drug effects / Q000276:immunology* / Q000503:physiopathology; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy / Q000276:immunology* / Q000503:physiopathology; D009336:Necrosis / Q000188:drug therapy / Q000503:physiopathology* / Q000517:prevention & control; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology*; D010805:Physical Conditioning, Animal / Q000009:adverse effects; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000906:Antibodies; D016189:Dystrophin; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000068800:Etanercept