Reduced necrosis of dystrophic muscle by depletion of host neutrophils, or blocking TNFalpha function with Etanercept in mdx mice

Neuromuscul Disord. 2006 Oct;16(9-10):591-602. doi: 10.1016/j.nmd.2006.06.011. Epub 2006 Aug 28.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / immunology
  • Disease Models, Animal
  • Down-Regulation / drug effects
  • Down-Regulation / immunology
  • Dystrophin / deficiency
  • Etanercept
  • Female
  • Immunoglobulin G / pharmacology*
  • Immunoglobulin G / therapeutic use
  • Immunosuppressive Agents / pharmacology
  • Immunosuppressive Agents / therapeutic use
  • Inflammation / drug therapy
  • Inflammation / physiopathology
  • Inflammation / prevention & control
  • Mice
  • Mice, Inbred mdx
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / immunology*
  • Muscle, Skeletal / physiopathology
  • Muscular Dystrophy, Duchenne / drug therapy
  • Muscular Dystrophy, Duchenne / immunology*
  • Muscular Dystrophy, Duchenne / physiopathology
  • Necrosis / drug therapy
  • Necrosis / physiopathology*
  • Necrosis / prevention & control
  • Neutrophils / drug effects
  • Neutrophils / immunology*
  • Physical Conditioning, Animal / adverse effects
  • Receptors, Tumor Necrosis Factor / therapeutic use
  • Treatment Outcome
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Antibodies
  • Dystrophin
  • Immunoglobulin G
  • Immunosuppressive Agents
  • Receptors, Tumor Necrosis Factor
  • Tumor Necrosis Factor-alpha
  • Etanercept