Cell proliferation in denervated muscle: time course, distribution and relation to disuse

The effects of denervation on skeletal muscle fibers have been intensively investigated, but the effects on other cell types within muscle tissue are not well understood. In the present experiments, cell proliferation was analyzed in mouse extensor digitorum longus muscles denervated for periods of one day to six weeks. Incorporation of tritiated thymidine into DNA increased 36 h after denervation, reached a maximum at a level twenty times control at 4 days, and returned towards control values by 7 days. Incorporation first increased in the endplate area, but 12 h later involved the entire muscle. Six weeks after denervation, muscles labeled at 4 days had lost 90% of the total label. Muscle disuse, produced by tetrodotoxin block of the nerve for up to 4 days, did not result in a proliferative response. Thus, cell proliferation after denervation is not a response to simple disuse, but rather to a nerve- or muscle-related mitogen. Since the response is mostly distributed throughout the entire muscle, the mitogen probably emanates from muscle fibers.