Animal models of muscular dystrophy--what can they teach us?

Abstract

The discovery and characterization of the X-linked gene which is defective in Duchenne muscular dystrophy (DMD) and of its protein product, dystrophin, has led to the identification of biochemical homologues of this disease in the mouse, the dog and the cat. All three animal models resemble DMD in that they lack dystrophin and that their skeletal muscle fibres undergo spontaneous necrosis and regeneration. In the dog and man, the degenerative and fibrotic aspects predominate, leading to a progressive loss of muscle structure and function, and to severe clinical disability. By contrast, in the mouse and the cat there is little fibrosis and the regenerative process seems to overcompensate, producing a true muscle hypertrophy and little or no clinical deficit. This interspecies variation in pathological response limits the usefulness of these animals as models for therapeutic testing, calling into question the strength of linkage between a given biochemical lesion and a particular pattern of pathology. However, these differences do give a valuable perspective to the pathology of the dystrophin-deficiency diseases, permitting identification of the immediate and secondary consequences of the lack of dystrophin. Moreover, the dystrophic mouse and dog are readily bred as colonies, thus providing consistent material for investigating the function of dystrophin and for testing methods of replacing its function or compensating for the absence of this function in the muscles of DMD patients. The fact that a lack of dystrophin is compatible, in some species, with only minor muscle dysfunction, raises hopes for an effective therapy in man.