THE MUTANT mdx: INHERITED MYOPATHY IN THE MOUSE

Abstract

The mdx mutant mouse was first observed during a survey of genetic variations of pyruvate kinase in the mouse. Affected mice have high serum levels of this enzyme and although showing little disability they have widespread and severe muscle disease. Light and electron microscopy, muscle enzyme histochemistry and combined cholinesterase-silver impregnations were used for the study of affected and control animals aged 1 day to 1 year. An early ultrastructural abnormality present already at 1 day was scattered focal streaming of Z-lines. Later there was also segmental muscle fibre necrosis and regeneration. The proportion of muscle fibres showing either necrosis, regeneration or internal nuclei was assessed in several muscles, at ages ranging from 10 days to 1 year. Acute segmental necrosis and regeneration were most marked at 1 to 2 months, although they were present at all ages. The number of fibres with internal nuclei increased progressively until 3 months when 70-80% showed this abnormality. Nerve terminals were unaffected but there was a reduction in the number and depth of postsynaptic folds at motor end-plates in adult animals, confirmed by morphometric analysis. Quantitative study of L4 motor root and tibial nerve showed that fibre numbers, axonal calibres and myelin sheath thickness were normal at all ages. No qualitative abnormalities were found in the CNS or other organs. The findings strongly suggest that the mdx mutant has a primary muscle disease and that the nervous system is normal.

Expression of the glucose transporter GLUT4 in the muscular dystrophic mdx mouse

“…In accord with previous reports, the mdx mice did not show striking alterations in development [1,10], with their mean body weight even being increased compared with control mice at 6-7 months of age [30]. High activities of the muscular enzyme creatine kinase were present in the serum of mdx compared with control mice, as previously described [1,[31][32][33].…”

“…These changes were clearly dependent on the muscle studied. Indeed, the amount of GLUT4 was unchanged in the heart, which is moderately or not at all involved in the mouse syndrome [10,34]. By clearly not related to dystrophin deficiency, which occurs in all muscles, including the heart [7][8][9]35].…”

“…It seems to be more closely related to the ability of muscle to regenerate. The necrosis and regeneration of skeletal muscle in mdx mice has been well documented [10][11][12], with acute necrosis and regeneration being most marked in hindleg muscles at 1-2 months [10]. This is accompanied by increases in protein synthesis and degradation rates in hindlimb skeletal muscles [36].…”

“…Nevertheless, the evolution of the mdx-associated disease is not identical in all muscles. Necrosis and regeneration are present, although variable, in most muscles throughout the life-span of the animals [10]. By contrast, the mdx mouse diaphragm exhibits a pattern of progressive degeneration, fibrosis and severe functional deficit comparable with that of DMD limb muscle [13].…”

“…It is absent from the skeletal muscle of both DMD humans and mdx mice [6][7][8][9]. Although muscular dystrophies are characterized by muscle degeneration, a major difference between the mdx mouse and the DMD human syndromes is the successful muscle fibre regeneration that occurs in the mdx mice, which restores muscle histology and function to approximate normality [10][11][12]. This explains the lack of muscle weakness and the normal life-span of mdx mice.…”