Inhibition of denervation changes in skeletal muscle by blockers of protein synthesis

1. A study was made of the effects of inhibitors of protein synthesis (actinomycin D, chloramphenicol and cycloheximide) on the in vivo development of extrajunctional cholinergic receptors, tetrodotoxin-resistant action potentials, slowing of the time course of the action potential, and on the fall in the resting membrane potential in denervated mouse skeletal muscle. 2. Actinomycin D (0·5 mg/kg, I.P. ) reduced the incorporation of uridine into skeletal muscle by 50-60% for 4-5 days. There was no simultaneous reduction in L -leucine incorporation. 3. Actinomycin D (0·5 mg/kg I.P. , 1 day after denervation) inhibited the development of extrajunctional cholinergic receptors, tetrodotoxin-resistant action potentials and the fall in resting membrane potential for approximately 4 days. 4. The post-denervation fall in the maximum rate of rise and in the amplitude of the overshoot of the muscle fibre action potential was unaffected by actinomycin D treatment. 5. Actinomycin D failed to inhibit the appearance of the membrane changes if given later than 2 days after denervation. 6. Chloramphenicol (6 g/kg in divided doses) and cycloheximide (40 g/kg every 12 hr) were also able to inhibit the appearance of the membrane changes. 7. It is concluded that some denervation induced changes in the muscle fibre membrane depend on the synthesis of new proteins. The results imply that the motor nerve cell normally exerts a regulatory influence on the genome of the muscle cell.