Evidence for apoptosis in dystrophin deficient muscular dystrophy

Duchenne's muscular dystrophy (DMD), the most common form of muscular dystrophy in children, is caused by a mutation in the gene encoding the protein dystrophin, which is normally found in muscle cells. Muscle fibers lacking dystrophin go through cycles of degeneration and regeneration due to intense stimulation by growth factors. However, despite growth factor stimulation there is gradually progressive muscle cell death. The mechanism by which the absence of dystrophin leads to cell death is not well understood. Mdx mice, a murine model of DMD, have a mutation in the dystrophin gene and display transient DMD-like muscle pathology between 2 and 8 weeks of age. Using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL), an accepted indicator of apoptosis, we demonstrated the presence of apoptotic nuclei in mdx mice but not in control wild type mice (p< .05). We showed a temporal association between apoptosis and pathologic changes in the muscle, as evidenced by central nuclei, a marker of myocyte damage. Furthermore, we used electron microscopy to demonstrate membrane blebbing, condensed chromatin in nuclei, and apoptotic bodies in dystrophin deficient muscle cells. Together, these data suggest that the loss of dystrophin activates a program that leads to muscle cell death by an apoptotic mechanism. We are presently conducting experiments to evaluate whether the intense growth factor stimulation in dystrophin deficient muscle cells may lead to the aberrant expression of genes that normally drive cellular proliferation. We hypothesize that the aberrant expression of these proliferation-associated genes may secondarily activate the apoptotic program in dystrophin deficient muscle cells.

Duke Scholars

Author Stephen Xavier Skapek Pediatrics, Transplant and Cellular Therapy