The present study was designed to test the hypothesis that increasing physical activity by running exercise could favor the recovery of muscle mass after extensive injury and to determine the main molecular mechanisms involved. Left soleus muscles of female Wistar rats were degenerated by notexin injection before animals were assigned to either a sedentary or an exercised group. Both regenerating and contralateral intact muscles from active and sedentary rats were removed 5, 7, 14, 21, 28 and 42 days after injury (n=8/group). Increasing contractile activity through running exercise during muscle regeneration ensured the full recovery of muscle mass and muscle cross-sectional area as soon as 21 days after injury, whereas muscle weight remained lower even 42 days post-injury in sedentary rats. The Proliferator-Cell-Nuclear-Antigen and MyoD protein expression went on longer in active than in sedentary rats. Myogenin protein expression was higher in active than in sedentary animals 21 days post-injury. The Akt-mTOR pathway was activated early during the regeneration process, with further increase of mTOR phosphorylation and its downstream effectors, 4E-BP1 and p70s6k in active compared with sedentary rats (days 7-14). The exercise-induced increase in mTOR phosphorylation, independently of Akt, was associated with decreased levels of phosphorylated AMPK. Taken together, results provided evidence that increasing contractile activity during muscle regeneration ensured early and full recovery of muscle mass, and suggested that these beneficial effects may be due to a longer proliferative step of myogenic cells and activation of mTOR signaling, independently of Akt, during the maturation step of muscle regeneration.