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Late in life, mdx mice develop a muscular dystrophy close to DMD dystrophinopathy. We suggest that the study of the effects of ageing in mdx mice would give clues to better understand the pathophysiology of DMD.

SUMMARY:In Duchenne muscular dystrophy patients, the pathological hallmark of the disease, namely, the chronic accumulation of sclerotic scar tissue in the interstitial space of skeletal muscle is attributed to manifestation of secondary pathological processes. Such anomalous generation of matrix protein is thought to be driven by the continuous degeneration and regeneration of muscle both in Duchenne Muscular Dystrophy and in the mdx mouse homolog. We examined mdx and the control strain C57bl/10 mice over a range of ages with respect to the amounts of collagen present in muscles and other organs, finding that the mdx have significantly higher collagen content at later time points in their kidney and lung as well as their muscles. Surprisingly, when we bred the mdx mice on the nu/nu background, the time course of fibrogenesis was modified depending on the tissue and the collagen content was significantly different in age-matched mice. Transplantation of normal thymic tissue into the mdx-nu/nu mice replenished their T-cells and concomitantly altered the collagen content in their tissues to levels comparable with those in immunocompetent mdx mice. This suggests that T-cells play a role in the onset of the fibrotic events that undermines the ability of dystrophic muscle to regenerate. (Lab Invest 2000, 80:881-891). D uchenne muscular dystrophy (DMD) was originally described as a myosclerosis (Duchenne, 1868), in recognition of the conspicuous deposition of collagenous scar tissue within the muscles. Fibrosis entails the excessive and inappropriate deposition of collagenous extracellular matrix. It is a central feature of many chronic diseases because it tends to disrupt and destroy the function of tissue, irrespective of the organ involved, be it kidney, heart, skin or skeletal muscle and is a major cause of suffering and death. It has also been suggested that this connective tissue proliferation may be important in the pathogenesis of the disease (Ionasecu and Ionasecu, 1982). Certainly, in primary myopathies such as Duchenne and congenital muscular dystrophies, striking increases in the levels of matrix proteins are a major histopathological feature (Stephens et al, 1982). In skeletal muscle, in addition to its obvious impact on the mechanical function of the tissue, progressive fibrosis may have widespread effects on a variety of mechanisms, which are crucial to the proper function of this tissue. Thus, the mechanisms of vascular and extravascular perfusion, which are critical for the supply of nutrients and removal of waste products in this metabolically active tissue, are likely to be compromised by the accumulation of dense, sclerotic scar tissue in the interfibre spaces. It has also been suggested that this scar tissue may itself assume a pathogenic role and contribute to the disease progression by interfering with effective muscle regeneration and re-innervation (Lipton, 1979).Experimental investigation of dystrophinopathies has been rendered possible by the advent of authentic animal models of DMD, of whic...

The mdx mouse, a genetic homologue of human Duchenne muscular dystrophy (DMD), has been attributed with a greater regenerative capacity of its skeletal muscles. Here, we have tested the hypothesis that muscles of mdx mice regenerate better than those of nondystrophic animals. We studied muscle regeneration resulting from a denervation-devascularization injury (DD) of extensor digitorum longus muscle (EDL) at 3 weeks and 2 months in mdx and wild-type (C57BL/10) mice. Histological and morphometrical studies of muscle regeneration were made from 3 to 180 days later. When DD was performed in 3-week-old C57BL/10 mice, the percentages of nonperipheral nuclei in regenerated fibers decreased progressively over 3 months. This decrease did not occur in animals where DDs were performed at 2 months, suggesting that two different populations of muscle precursor cells are mobilized in muscle regeneration in mice at these two ages. Moreover, mdx EDL muscle regenerated similarly to the controls for up to 60 postoperative days, as shown by distribution of mean diameters and percentage of nonperipheral nuclei of muscle fibers. After 60 postoperative days, necrosis/regeneration characteristics of mdx muscles recurred, suggesting that mdx-regenerated muscle fibers remain susceptible to degeneration.

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