The actions and receptor for ciliary neurotrophic factor (CNTF) are largely restricted to cells of the nervous system, although one of the CNTF receptor components, CNTFR alpha, is expressed by skeletal muscle. Here we show that the other CNTF receptor components, LIFR beta and gp130, are also expressed by skeletal muscle and that expression of all three CNTF receptor components is greatly increased in denervated muscle. In vivo, administration of CNTF activates these receptors on skeletal muscle by inducing receptor phosphorylation and immediate-early gene responses. Furthermore, CNTF reduces the denervation-induced atrophy of muscle and attenuates the reduced twitch and tetanic tensions that result from muscle denervation. Our findings reveal that, in addition to its known neurotrophic actions, CNTF exerts myotrophic effects by attenuating the morphological and functional changes associated with denervation of rat skeletal muscle.