The mdx mouse diaphragm reproduces the degenerative changes of Duchenne muscular dystrophy

Abstract

Although murine X-linked muscular dystrophy (mdx) and Duchenne muscular dystrophy (DMD) are genetically homologous and both characterized by a complete absence of dystrophin, the limb muscles of adult mdx mice suffer neither the detectable weakness nor the progressive degeneration that are features of DMD. Here we show that the mdx mouse diaphragm exhibits a pattern of degeneration, fibrosis and severe functional deficit comparable to that of DMD limb muscle, although adult mice show no overt respiratory impairment. Progressive functional changes include reductions in strength (to 13.5% of control by two years of age), elasticity, twitch speed and fibre length. The collagen density rises to at least seven times that of control diaphragm and ten times that of mdx hind-limb muscle. By 1.5 years of age, similar but less severe histological changes emerge in the accessory muscles of respiration. On the basis of these findings, we propose that dystrophin deficiency alters the threshold for work-induced injury. Our data provide a quantitative framework for studying the pathogenesis of dystrophy and extend the application of the mdx mouse as an animal model.

Down‐regulation of mitochondrial mRNAs in the mdx mouse model for Duchenne muscular dystrophy

“…Variations in the expression of mitochondrial genes were thus reported to be 2-to 4-fold during myogenic differentiation [30], and 1.5-to g-fold in more extreme situations such as mitochondrial myopathies [15] and cancer cells [28]. In addition, the general trend in mdx and DMD muscles of a shift towards oxidative slow-type muscle fibers [3,18,20,25], richer in mitochondrial DNA and RNA [31], partially reduces the decrease in the overall mitochondrial RNA content here. (ii) The second element is under-expression of the encoded proteins.…”

“…Dystrophin transcripts are normally expressed in a tissue specific manner (for a review see [13]) and the impact of dystrophin deficiency is only particularly severe in the diaphragm of the aging mdx mouse [25]. Moreover .…”

“…Regeneration and recovery are evident by 5 to 6 weeks and muscle fibers are somehow protected from further definitive necrosis. One exception concerns the diaphragm which shows a characteristic DMD histological pattern of necrosis and connective tissue proliferation in the aging mdx mouse [25].…”

Retroviral‐mediated transfer of a dystrophin minigene into mdx mouse myoblasts in vitro

“…: mouse is an animal model ot" DMD, lacking dystrophin expression in all but a very small percentage of myofibres [1,3] due to a point mutation in the mouse homologue ot" the DMD gone [4]. Although severe dystrophic changes are observed in the muscles of the diaphragm [5], the mdx mouse does not show the progressive degeneration of limb muscles characteristic of the human disease. Instead, a high level of myofibre regeneration in the limbs seems to effectively restore muscle integrity and function [6].…”

Anisomycin Activates Utrophin Upregulation Through a p38 Signaling Pathway

“…Although the mouse phenotype is milder than human DMD, there is a reduction in lifespan, thought to be due to respiratory or cardiac failure 11. In fact, the diaphragm is abnormal in both structure and function, making it a natural tissue to assess when testing DMD therapies 12, 13…”