Portal to the Penn Neuroscience Community

Home

MINS Members

MINS News

Weekly Events

MINS Colloquium Schedule

History

Community Outreach Programs

Neuroscience Graduate Group
Other Educational Activities

Society for Neuroscience

Classified Ads

 MINS Members

Alan M. Kelly, B.V.Sc, M.R.C.VS, Ph.D.

RESEARCH INTERESTS

RESEARCH TECHNIQUES

RESEARCH SUMMARY

Although the mdx mouse is a genetic homologue of Duchenne muscular dystrophy (DMD) in man, murine limb muscle is reported to exhibit resistance to the pathological consequences of dystrophin deficiency. This apparent species difference has limited the utility of the mdx mouse in studies of the pathogenesis and therapy of muscular dystrophy. We have shown that the respiratory muscles of the mdx mouse undergo progressive degeneration and fibrosis. These dystrophic changes are most advanced in the diaphragm where they are correlated with profound alterations in the muscle's physiological properties. These changes are evident by 3 months of age; by 18 months, the collagen density in the mdx diaphragm is greater than seven times that of controls and the muscle has shortened by 35%. By this stage, isometric strength per unit cross sectional area has dropped by 80%. This is correlated with the elimination of type IIx and a 50% increase in the proportion of slow fibers in the diaphragm. The evolution of the dystrophic process in the respiratory muscles suggests that the work of breathing is an important factor. Significantly, respiratory failure is the leading cause of mortality associated with DMD. These findings have relevance to the physiologic role of dystrophin, the membrane protein that is deficient in dystrophic muscle. The function of dystrophin is not known. In view of our findings, we have proposed that contraction-induced injury leads to fiber disruption in dystrophic muscle. To test this postulate, we have designed a simple functional assay involving the uptake of the fluorescent dye, Procoin Orange (MW630) in stimulated muscle in vitro. Our results suggest that dystrophin deficiency shifts the normal balance between injury and repair in muscle towards the former by lowering the threshold for contraction induced damage. Ultimate degeneration of dystrophin-deficient muscle would therefore appear to result from the cumulative effects of heightened membrane fragility with eventual overloading of muscle regenerative capacity.

KEY WORDS: