Mutual interference of myotonia and muscular dystrophy in the mouse: A study on ADR-MDX double mutants

For Duchenne muscular dystrophy (DMD, dystrophin deficiency) and Thomsen/Be cker myotonia (muscular chloride channel deficiency) genetically homologous mouse models are available, the dystrophin-deficient MDX mouse and the myo tonic ADR mouse. Whereas the latter shows more severe symptoms than human m yotonia patients, the MDX mouse, in contrast to DMD patients, is only mildl y affected. We have introduced, by appropriate breeding, the defect leading to myotonia (Clc1 null mutation, ndr allele) into MDX mice, thus creating ADR-MDX double mutants. The expectation was that, due to mechanical stress during myotonic cramps, the ADR status should symptomatically aggravate the muscle fibre necrosis caused by the dystrophin deficiency. The overall sym ptoms of the double mutants were dominated by myotonia. Weight reduction an d premature death rate were higher in ADR-MDX than in ADR mice. Sarcolemmal ruptures as indicated by influx into muscle fibres of serum globulins and injected Evans blue were found with great inter-individual variation in MDX and in ADR-MDX muscles. Affected fibres were found mainly in large groups in MDX but single or in small clusters in ADR-MDX leg muscles. The symptoms of myotonia (aftercontractions, shift towards oxidative fibres) were less pronounced in ADR-MDX than in ADR muscles. Conversely, numbers of damaged f ibres as well as the percentage of central nuclei (an indicator of fibre re generation) were significantly lower in ADR-MDX than in MDX skeletal muscle s. Thus it appears that, at the level of the muscle fibre, myotonia and mus cular dystrophy attenuate each other. (C) 1998 Elsevier Science B.V. All ri ghts reserved.