Cell proliferation in denervated muscle: identity and origin of dividing cells

DNA synthesis in skeletal muscle increases dramatically during the first week after denervation. In the present study, we have characterized the dividing cells in order to assess the specificity and significance of this response to denervation. Autoradiography of [3H]thymidine-labeled denervated muscles revealed that many classes of cells were dividing, including fibroblasts (the most numerous of the labeled cells), macrophages, vascular cells, muscle satellite cells, spindle capsule cells, perineurial cells and Schwann cells. The number of labeled satellite cells accounted for no more than 10% of the dividing cells. Labeling indices of spindle capsule, perineurial and Schwann cells reached a maximum 3 days after denervation, while those of fibroblasts and macrophages peaked at 4 days. The former group of cells, which are in close contact with nerve trunks, accounted for 28% of cell division on day 3 (but only 5% on day 4) and were apparently responding to a local influence from degenerating axons. Connective tissue cells, making up the largest class of dividing cells (80% on day 4) were found throughout the muscle and appeared to proliferate in response to changes occurring along the entire length of the muscle fibers. Macrophages involved in the response were mostly resident histiocytes, since prior labeling of blood cells showed that leukocytes did not enter the muscle in substantial number after denervation. Both muscle satellite cells and connective tissue cells are essential for the functional regeneration of muscle. Thus, on the basis of overall cytologic characterization, cell division after denervation seems to represent a limited regenerative response.