Why short stature is beneficial in Duchenne muscular dystrophy.

INTRODUCTION: Duchenne muscular dystrophy (DMD) is caused by a genetic defect resulting in absent dystrophin, yet children are able to walk when small and young but lose this ability as they grow. The mdx mouse has absent dystrophin yet does not exhibit significant disability. METHODS: Allometric modeling of linearly increasing load per muscle fiber and stress on the sarcolemma with growth and exponential decline associated with loss of muscle fibers correlated with case studies and animal models of DMD. RESULTS: Smaller species or breeds are predictably less affected than large as follows: mdx mice < small golden retriever muscular dystrophy (GRMD) dogs < large GRMD dogs < humans. Case reports of combined growth hormone and dystrophin deficiency show a relatively benign course of disease. CONCLUSIONS: Future therapeutic trials in DMD might include specific growth inhibitors in combination with standard of care treatments to delay the clinical onset and reduce the severity of disease and disability.

Comparative study of the kidneys from dystrophic mice

The Duchenne Muscular Dystrophy (DMD) is a recessive genetic disease linked to chromosome X. Thisdisease is characterized by an absence or dysfunction in the expression of dystrophin. Experimental modelsmdxare widely used for the development of research addressing the DMD. The objective of this research is tocontribute to a detailed study of possible renal morphological changes resulting from DMD. We used five pairsof kidneys frommdxmice and five from normal mice, which were subjected to measurement, light microscopy,and scanning electron microscopy. The morphological findings of kidneys frommdxmice are within thepatterns described in animal studies with severe dehydration, which exhibit signs of diffuse hemorrhage inthe cortical and medullary area, while the glomeruli in the cortical region showed a decrease in urinary space,located between the Bowman’s capsule and the inner cell mass of the glomeruli. However, future experimentswith animals in different ages can assist in the proving of the morphological changes found here.

Truncated dystrophins can influence neuromuscular synapse structure.

Duchenne muscular dystrophy (DMD) is characterized by muscle degeneration and structural defects in the neuromuscular synapse that are caused by mutations in dystrophin. Whether aberrant neuromuscular synapse structure is an indirect consequence of muscle degeneration or a direct result of loss of dystrophin function is not known. Rational design of truncated dystrophins has enabled the design of expression cassettes highly effective at preventing muscle degeneration in mouse models of DMD using gene therapy. Here we examined the functional capacity of a minidystrophin (minidysGFP) and a microdystrophin (microdystrophin(DeltaR4-R23)) transgene on the maturation and maintenance of neuromuscular junctions (NMJ) in mdx mice. We found that minidysGFP prevents fragmentation and the loss of postsynaptic folds at the NMJ. In contrast, microdystrophin (DeltaR4-R23) was unable to prevent synapse fragmentation in the limb muscles despite preventing muscle degeneration, although fragmentation was observed to temporally correlate with the formation of ringed fibers. Surprisingly, microdystrophin(DeltaR4-R23) increased the length of synaptic folds in the diaphragm muscles of mdx mice independent of muscle degeneration or the formation of ringed fibers. We also demonstrate that the number and depth of synaptic folds influences the density of voltage-gated sodium channels at the neuromuscular synapse in mdx, microdystrophin(DeltaR4-R23)/mdx and mdx:utrophin double knockout mice. Together, these data suggest that maintenance of the neuromuscular synapse is governed through its lateral association with the muscle cytoskeleton, and that dystrophin has a direct role in promoting the maturation of synaptic folds to allow more sodium channels into the junction.

A combined metabolomic and proteomic investigation of the effects of a failure to express dystrophin in the mouse heart.

Muscle degeneration in the heart of 1-9 month-old mdx mice (a model for Duchenne muscular dystrophy) has been monitored using metabolomic and proteomic approaches. In both data sets, a pronounced aging trend was detected in control and mdx mice, and this trend was separate from the disease process. In addition, the characteristic increase in taurine associated with dystrophic tissue is correlated with proteins associated with oxidative phosphorylation and mitochondrial metabolism.

Covert persistence of mdx mouse myopathy is revealed by acute and chronic effects of irradiation.

To compare muscle fiber loss in young and old mdx mice, we have blocked regeneration in one leg with a high dose (18 Gy) of X-rays administered at two ages; 16 days, just prior to the onset of the myopathy, and 15 weeks, when the myopathy is considered to be quiescent. Mice were examined 4 days after irradiation to look for acute effects, or after 6 weeks to look for cumulative effects. Tibial length, muscle weight, muscle fiber size, fiber number and histological changes were recorded. Signs of acute damage to muscle fibers, leakage of Procion Orange dye into fibers and loss of creatine kinase from the fibers were also examined. Irradiation caused no acute or chronic damage to muscle fibers; on the contrary, in the youngest mdx mice, irradiation delayed the onset of the disease. However, in mdx but not in normal mice, there was a loss of muscle mass and fiber number in irradiated by comparison with the non-irradiated contra-lateral muscles. This loss, attributed to fiber necrosis in the absence of regeneration, was as great in animals irradiated at 15 weeks as in those irradiated at 16 days. Such persistence of muscle fiber necrosis contradicts the standard view of the mdx mouse and establishes it as a closer model of Duchenne muscular dystrophy than is generally appreciated.

Dystrophin and beta-dystroglycan in photoreceptor terminals from normal and mdx3Cv mouse retinae.

Mutations in the dystrophin gene cause muscular dystrophy as well as cognitive impairments, including an abnormal dark-adapted electroretinogram. To investigate the basis for the ocular phenotype, we analysed dystrophin and the dystrophin-associated protein beta-dystroglycan in retinae from mdx3Cv mice. This strain has a mutation in the dystrophin gene and abnormalities in the electroretinogram which are similar to those of muscular dystrophy patients. Despite an overall reduction of all dystrophin isoforms and of beta-dystroglycan in retinal tissue from mutant mice, we observed no apparent change in the histotypic layering of the retina, or in the ultrastructure of several specific cell types, including rods and cones. In retinae from wild type and mdx3Cv mice, dystrophin and beta-dystroglycan were concentrated in small extensions of rod and cone photoreceptor terminals protruding into the outer plexiform layer. Beta-dystroglycan but not dystrophin was also clustered around the inner limiting membrane and the capillary basal laminae. While the labelling pattern around the basal laminae was not altered in the mutant mice, we found that the area as well as the intensity of the dystrophin and beta-dystroglycan immunoreactivity associated with the terminals of rod photoreceptors were severely reduced. The same parameters were much less affected in cone terminals. These results show, that dystrophin and beta-dystroglycan are differentially distributed in the retina, and that a severe reduction of dystrophin has no gross effect on retinal structure, but could influence intraretinal signalling at the level of the photoreceptor terminals. Moreover, the mutation in mdx3Cv mice has a selective effect on rods, providing an explanation for the altered electroretinogram.