We used a rat model of weight lifting to examine the serial biochemical and morphological changes following muscle fiber hyperplasia during 14 days of exercise. [3H]thymidine and [14C]leucine labeling were used to determine the serial changes in cellular mitotic activity and the level of amino acid uptake and myosin synthesis. Morphological changes were assessed with light and transmission electron microscopy, whereas proliferation of cells was evaluated immunohistochemically with 5-bromo-2'-deoxyuridine (BrdU). The intensity of the exercise and degree of muscle damage were monitored by serum creatine kinase (CK) activity. Damaged fibers were sparsely distributed, and a significant CK leakage was observed 30-60 min after exercise. Anti-BrdU-positive cells were observed in damaged fibers and at the periphery of undamaged fibers. Changes typical of muscle regeneration were observed; however, the formation of new fibers in the interstitial space was also evident. The mitotic activity also changed and reflected the appearance of anti-BrdU-positive cells and activated satellite cells. Amino acid uptake increased during the first week of exercise, probably reflecting muscle hypertrophy and synthesis of other noncontractile related proteins. The uptake also increased during the second week, probably due to hyperplasia, a finding also supported by electron microscopy. Our results suggest that one bout of weight-lifting exercise in untrained rats induced muscle hyperplasia following regeneration. The process of muscle hyperplasia was activated by muscle fiber damage in our model.