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Muscular dystrophy is a group of more than 30 different clinical genetic disorders that are characterized by progressive skeletal muscle wasting and degeneration. Primary deficiency of specific extracellular matrix, sarcoplasmic, cytoskeletal, or nuclear membrane protein results in several secondary changes such as sarcolemmal instability, calcium influx, fiber necrosis, oxidative stress, inflammatory response, breakdown of extracellular matrix, and eventually fibrosis which leads to loss of ambulance and cardiac and respiratory failure. A number of molecular processes have now been identified which hasten disease progression in human patients and animal models of muscular dystrophy. Accumulating evidence further suggests that aberrant activation of several signaling pathways aggravate pathological cascades in dystrophic muscle. Although replacement of defective gene with wild-type is paramount to cure, management of secondary pathological changes has enormous potential to improving the quality of life and extending lifespan of muscular dystrophy patients. In this article, we have reviewed major cellular and molecular mechanisms leading to muscle wasting in muscular dystrophy. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting.
Copyright © 2013 Elsevier Ltd. All rights reserved.
Eukaryotic pre-mRNA splicing allows for a large, diverse proteome to be coded by a relatively small genome. Alternative splicing events are well regulated, but when mutations disrupt the splice sites or regulatory elements, disease can occur. Similarly, mutations can cause disease through aberrant transcript production. Enhancers, one of the splicing regulatory elements, are frequent targets of disease causing mutations. This review provides an overview of the splicing reaction and mechanisms of alternative splicing and provides examples of enhancer defects that cause disease.
Functional magnetic resonance imaging was performed on a 36-year-old woman with muscular dystrophy, intractable epilepsy, and bilateral temporo-occipital lissencephaly. We observed islands of task-specific activation in lissencephalic cortex homologous to visual association regions activated in normal subjects on the same visual confrontation naming task. This result suggests lissencephalic cortex may develop specific functional connections with other brain regions.
It has been proposed that a defect in tocopherol transport may lead to a chronic vitamin deficiency in Duchenne muscular dystrophy (DMD). To test this hypothesis, a pilot clinical trial which involved the infusion of tocopherol-laden plasma was carried out. An increased uptake of tocopherol into erythrocyte membranes during infusions failed to produce a significant reduction in plasma enzyme levels or to arrest the dystrophic process in the two children examined. Further studies to investigate treatments with increased amounts of tocopherol, in conjunction with other antioxidants, may prove a more fruitful avenue of research.
Saturation transfer electron paramagnetic resonance and the spin label 2-(3-carboxypropyl)-4,4-dimethyl-2-tridecyl-3-oxazolidinyloxyl were used to study erythrocytes from patients with Duchenne muscular dystrophy or Becker syndrome and from age-matched normal boys. There were significant differences in the spectral intensities of erythrocytes from Duchenne patients when compared to controls. Spectral intensities increased with time in the former; no such change was observed in the latter. Saturation transfer electron paramagnetic resonance spectra of erythrocytes from patients with Becker syndrome were significantly different from those from Duchenne patients but were not significantly different from normals. These observations suggest the possible usefulness of these techniques in the differential diagnosis of Duchenne muscular dystrophy. Spin label concentration spectral studies suggest that the observed spectral differences between Duchenne patients and controls were due to differential spin exchange phenomena.