Sustained contractile activity of skeletal muscle promotes angiogenesis, as well as transformation of contractile protein isoforms and mitochondrial proliferation within myofibers. Since the products of immediate early genes such as c-fos, c-jun, and egr-1 function in many signaling pathways governing cellular responses to external stimuli, we sought to determine whether sustained contractile activity induces their expression in skeletal muscle. Low voltage electrical stimulation was applied to the motor nerve innervating rabbit tibialis anterior muscles for periods ranging from 45 min to 21 d. Northern and Western analysis demonstrated marked but transient inductions of c-fos, c-jun, and egr-1 mRNA and protein within the first 24 h. Longer durations of stimulation were associated with a secondary and sustained rise in the abundance of c-fos, c-jun, and p88egr-1 protein that, surprisingly, was not accompanied by detectable changes in mRNA. Immunohistochemistry demonstrated c-fos immunoreactivity within myofiber and vascular cell nuclei during both early and late phases of this response. These findings reveal a complex pattern of c-fos, c-jun, and egr-1 expression in response to nerve stimulation and suggest that these proteins could function in regulatory pathways that modify muscle phenotype.