CILIARY NEUROTROPHIC FACTOR - REGULATION OF ACETYLCHOLINESTERASE IN SKELETAL-MUSCLE AND DISTRIBUTION OF MESSENGER-RNA ENCODING ITS RECEPTORIN SYNAPTIC VERSUS EXTRASYNAPTIC COMPARTMENTS

Several recent studies have shown that the ciliary neurotrophic factor exerts myotrophic effects in addition to its well-characterized neuro trophic actions on various neuronal populations. Since expression of a cetylcholinesterase in skeletal muscle has been shown to be regulated by putative yet unknown nerve-derived trophic factors, we tested the h ypothesis that the ciliary neurotrophic factor is a neurotrophic agent capable of influencing expression of acetylcholinesterase in adult ra t skeletal muscle in vivo. To this end, we first determined the impact of daily ciliary neurotrophic factor administration on expression of acetylcholinesterase in both intact and denervated rat soleus muscles. The results of our experiments indicate that although chronic adminis tration of ciliary neurotrophic factor partially counteracted the atro phic response of soleus muscles to surgical denervation, thus confirmi ng its myotrophic effects, it failed to either increase acetylcholines terase expression in intact muscles or prevent the decrease normally o ccurring in seven-day denervated muscles. In fact, acetylcholinesteras e messenger RNA and enzyme levels were further reduced by ciliary neur otrophic factor treatment in denervated muscles without significant mo difications in the pattern of acetylcholinesterase molecular forms. Co nversely, transcript levels of the epsilon subunit of the acetylcholin e receptor in intact and denervated soleus muscles treated with the ci liary neurotrophic factor were similar to those observed in their resp ective counterparts from vehicle-treated animals. In addition, we also determined whether transcripts encoding the receptor for the ciliary neurotrophic factor selectively accumulate in junctional domains of ra t skeletal muscle fibres. In contrast to the preferential localization of transcripts encoding acetylcholinesterase and the epsilon subunit of the acetylcholine receptor within the postsynaptic sarcoplasm, mess enger RNAs for the ciliary neurotrophic factor receptor appeared homog eneously distributed between junctional and extrajunctional compartmen ts of both diaphragm and extensor digitorum longus muscle fibres, with no compelling evidence for a selective accumulation within the postsy naptic sarcoplasm. These data show that the ciliary neurotrophic facto r exerts an inhibitory influence on expression of acetylcholinesterase in muscle fibres. Furthermore, the lack of an effect on expression of the epsilon acetylcholine receptor transcripts indicates that treatme nt with ciliary neurotrophic factor does not lead to general adaptatio ns in the expression of all synaptic proteins. Given the distribution of transcripts encoding the ciliary neurotrophic factor receptor along multinucleated muscle fibres, we propose a model whereby the ciliary neurotrophic factor, or a related unknown molecule that also utilizes the receptor for the ciliary neurotrophic factor, contributes to the m aintenance of low levels of enzyme activity in extrajunctional regions of muscle fibres by acting as a repressor of acetylcholinesterase exp ression that functions directly or indirectly via a pretranslational r egulatory mechanism. Accordingly, these results further highlight the complexity of the regulatory mechanisms presiding over acetylcholinest erase expression in vivo. Copyright (C) 1996 IBRO.