Pathogenetic mechanisms in animal models of Duchenne Muscular Dystrophy
(2003)
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- Authors
- Supervisors
- Gillis, Jean-Marie
- Abstract
- (en) Duchenne muscular dystrophy is the most frequent inherited neuromuscular disease. Its incidence is high: around 1 affected boy out 3500 male births. Genetic counselling is inefficient in case of new mutations which account for 1/3 of the cases. The disease progress so that the DMD boys are wheelchair bound in their first decade and they die in their twenties. No curative therapy is available yet. The defective gene in DMD and its encoded protein, dystrophin, have been known for more than fifteen years, but the mechanisms leading from the absence of dystrophin to the muscle cell death is still poorly understood. Dystrophin binds to the cytoskeleton via subsarcolemmal F-actin and to the extracellular matrix via dystroglycans and laminin; besides, this scaffolding is stabilized by a complex of transmembranous proteins, the function of which remains uncertain.Animals sharing similar genetic defects affecting dystrophin were discovered. CXMD dogs are the most affected, but the mdx mice are definitely the most studied model. The latter show indisputable signs of muscle dystrophy, although they look little affected in vivo despite an absence of dystrophin. The different severity of the disease between the species is a puzzling observation. To better understand the role of dystrophin, an inventory of the defects related to its absence in mdx mice is necessary. In vivo, they show altered force and endurance as well as an raised serum creatine kinase level, as observed in human DMD boys. The improper muscular function is better characterized on isolated muscles. Muscles lacking dystrophin develop less tension. The hallmark of dystrophinopathy is the inability of the affected muscle to sustain the high mechanical stress produced during "eccentric" contractions (in which the muscle is forcibly lengthened while in full contracted state). Contractions following a series of such eccentric contractions show a marked reduction of force. This is correlated with the intracellular accumulation of vital dye, normally excluded from the fibres, witnessing membrane damages. Therefore, an important role of dystrophin is thought to be related to the maintenance of the mechanical integrity of the membrane during the high strains that occur in muscle contractions. In mdx muscle, calcium accumulates with age, as in muscles from DMD boys. The precise localisation of the accumulation is unresolved. [...]
- Affiliations
Citations
Raymackers, J.-M. (2003). Pathogenetic mechanisms in animal models of Duchenne Muscular Dystrophy. https://hdl.handle.net/2078.5/129664