Muscular dystrophy and muscle regeneration.

An animal model of muscular dystrophy, the dystrophic (129ReJ dy/dy) mutant mouse, was used to evaluate the regenerative phenomenon in dystrophic muscle. The effect of age on "spontaneous" regeneration (i.e., regeneration in the absence of secondary trauma) was assessed by quantitative morphometric analysis and evaluation of myosatellite cell dynamics (i.e., myosatellite cell frequency, proliferative activity, and fusion capability). Spontaneous regeneration ceased by the time the mice were 8 weeks old. The findings suggested that the small "regenerating" myofibers found in older dystrophic muscle had been formed earlier in the time course of the disease and were growth-inhibited. To determine the cause of the cessation of regeneration, dystrophic muscle was subjected to the severe trauma of whole-muscle transplantation, a trauma that results in total myofiber necrosis followed by de novo myotube formation. When young dystrophic muscle (from 4- to 6-week-old dystrophic mice) was orthotopically transplanted, the time course of degeneration-regeneration was similar to that seen in age-matched normal muscle. Moreover, the regenerated dystrophic myofibers were capable of long-term survival (200 days or longer after transplantation), and they failed to show evidence of histologic changes consistent with murine dystrophy. When older dystrophic muscle (from 17-week-old dystrophic mice), muscle that failed to display spontaneous regeneration, was transplanted, it displayed remarkable regenerative capacity. It was suggested that the cessation of spontaneous regeneration in older dystrophic murine muscle is due not to exhaustion of myosatellite cell proliferative capacity, but rather to age-related loss of the mitogenic effect of dystrophy on the myosatellite cells of dystrophic muscle.