Neurotrophic regulation of two properties of skeletal muscle by impulse- dependent and spontaneous acetylcholine transmission

Abstract

Listen

Translate article

In this study, we have evaluated the role of impulse-dependent and spontaneous acetylcholine (ACh) transmission in the neural regulation of two muscle properties: the resting membrane potential (RMP) and the number of extrajunctional ACh receptors. Complete blockade of ACh transmission was produced by infusion of a-bungarotoxin (a-BuTx) into the soleus muscles of rats in viuo via implanted osmotic pumps. Blockade of nerve impulse conduction was induced by prolonged treatment of the sciatic nerves of rats with tetrodotoxin (TTX). Control studies demonstrated that the pharmacological actions of cw-BuTx and TTX were highly specific, with no significant impairment of fast axonal transport or alterations in the morphology or physiology of the treated nerves. ACh blockade using a-BuTx produced a fall in the RMP that was identical to the effect of surgical denervation with respect to the time of onset, rate of development, and extent of change. Blockade of nerve impulses using TTX produced a similar but partial change in the RMP that began later and progressed more slowly than that of denervation. Similarly, the increase of extrajunctional ACh receptors following cY-BuTx-induced blockade of ACh transmission was identical to that of surgical denervation. By contrast, the effect of nerve impulse block using TTX was less pronounced at equivalent time points. Our findings indicate that specific pharmacological blockade of ACh transmission produces changes in the RMP and extrajunctional ACh receptors of skeletal muscle that are quantitatively equivalent to those of denervation. This suggests that ACh transmission itself mediates the nerve’s trophic regulation of these muscle properties. Impulse-related ACh release and/or the muscle usage that it triggers account for only part of the regulatory effect; spontaneous ACh transmission (quanta1 and/or nonquantal) contributes the remainder. We suggest that nonquantal ACh release may represent the neurotrophic influence not fully accounted for in previous studies. Motor innervation plays an important role in the regsupply “trophic” influences that normally prevent these ulation of many properties of skeletal muscle. Eliminadenervation changes. The question of how these inflution of the influence of the nerve by surgical denervation ences of the nerve are mediated has been a matter of results in a variety of changes in the physiological, biocontinuing controversy. Although ACh transmission and chemical, and structural properties of muscle fibers the muscle usage that it produces have been shown to (Guth, 1968; Drachman, 1974; Gutmann, 305; Vrbova et play an important role (reviewed by Drachman et al., al., 1978). Conversely, the motor nerve is thought to 1981; Thesleff and Sellin, 1980), it also has been suggested I We would like to thank Dr. P. Talalay and Dr. J. J. Bray for that unrelated factors (for example, materials carried by reading the manuscript, R. N. Adams, K. 4. Fahnestock, M. J. Peper, axonal transport) may participate as well (Fernandez and and C. Choy for technical assistance, and C. F. Barlow for help in Ramirez, 1974; Ochs, 1974; Guth and Albuquerque, 1978; preparation of the manuscript. This work was supported by National Guth et al., 1981). Institutes of Health Grants 5 PO1 NS10920 and 5 ROl HD04817. In the present study, we have attempted to define the ’ To whom correspondence should be addressed at Department of neural influences that regulate two such properties of Neurology, Johns Hopkins School of Medicine, 1721 E. Madison Street, skeletal muscle, the resting membrane potential (RMP) Baltimore, MD 21205. and the distribution of extrajunctional acetylcholine