The effects of increasing neural activity on sprouting remain unclear and controversial. In a rat model of partial denervation of skeletal muscles, we investigated the effect of neuromuscular activity on sprouting. Rat hindlimb muscles were partially denervated by avulsion of either L4 or L5 spinal root. Immediately after partial denervation, the rats were divided into three groups: (1) normal caged activity, (2) running exercise on wheels, 8 hr daily, and (3) functional electrical stimulation (FES) of sciatic nerves, 20 Hz for 8 hr daily. At 1 month, muscle unit (MU) enlargement was quantitated electrophysiologically and histochemically. MU twitch force was increased by four- to fivefold by partial denervation in extensively denervated tibialis anterior (TA) and medial gastrocnemius (MG) and by approximately twofold in moderately denervated plantaris (PL) and soleus (SOL). For the extensively denervated TA and MG muscles, MU enlargement, measured electrophysiologically, declined significantly after an average of 1757 +/- 310 m/d running exercise and daily FES for 1 month. The detrimental effects on MU enlargement were much less but significant in the moderately denervated PL and did not reach statistical significance in the moderately denervated SOL muscle. Histochemical evaluation of sprouting showed a reduction in the number of sprouts in the extensively denervated TA muscle, but not the moderately denervated PL and SOL muscles, by increased neuromuscular activity. Thus, increased neuromuscular activity is detrimental primarily in muscles that are extensively denervated, and the MUs are smaller than under conditions in which the muscles experience normal physiological levels of activation.