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 Ϯ 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.Key words: sprouting; motor unit; motoneuron disease; neuromuscular activity; partial denervation; poliomyelitis Poliomyelitis, the early stages of amyotrophic lateral sclerosis (ALS), spinal cord trauma, and motoneuron destruction associated with cancer are only some of the neuromuscular conditions resulting in compensatory axonal sprouting and, in turn, MU enlargement (Brown et al., 1981;Halstead and Wiechers, 1987). MU enlargement is unfortunately restricted to a limit of five-to eightfold such that sprouting compensates for up to 85% loss of muscle units (MUs) (Thompson and Jansen, 1977;Brown and Ironton, 1978;Yang et al., 1990;Rafuse et al., 1992). Thus when Ͻ20% of intact MUs remain and sprouting cannot reinnervate all denervated muscle fibers, muscle weakness becomes evident (Luff et al., 1988;Rafuse et al., 1992; Rafuse and Gordon, 1996a,b).The strong association of exercise with muscle strength and endurance has led naturally to attempts to optimize muscle function with exercise. However, the effects of neuromuscular activity on sprouting are both unclear and controversial because of the conflicting findings of previous studies of these effects. Some studies have shown that activity can promote sprouting or reinnervation (Ribchester, 1988;Einsiedel and Luff, 1994) or that it has no effect at all (Gardiner and Faltus, ...