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 histo−chemistry and combined cholinesterase−silver impregnations were used for the study of affected and control animals aged 1day 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 post-synaptic 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.