BIOGENESIS OF ACETYLCHOLINESTERASE IS IMPAIRED, ALTHOUGH ITS MESSENGER-RNA LEVEL REMAINS NORMAL, IN THE GLUCOCORTICOID-TREATED RAT SKELETAL-MUSCLE

Acetylcholinesterase (AChE) is responsible for the hydrolysis of acety lcholine in the neuromuscular junction and other cholinergic synapses. Insight into the mechanisms controlling AChE expression in skeletal m uscle is important for understanding formation, plasticity, and variou s dysfunctions of the neuromuscular junction. We have investigated the mechanisms responsible for the decreased AChE activity in the fast ra t sternomastoideus muscle after chronic glucocorticoid treatment. Unde r such conditions fast skeletal muscles become atrophic and loose 30-4 0% of their AChE activity, In order to establish at which level synthe sis of AChE is affected by glucocorticoids, we studied the effects of chronic dexamethasone treatment at both AChE mRNA and mature enzyme le vels. Reduced rate of AChE recovery after subtotal irreversible AChE i nhibition was observed during the first week of dexamethasone treatmen t, but not later. Statistical analyses of four independent northern bl ots revealed unchanged AChE mRNA levels. At the same time, we observed more than 60% decrease in the (G(1)+G(2))/A(12) ratio of molecular fo rms at the expense of G forms. It has been generally accepted that glo bular G(1) and G(2) molecular forms are synthesized in the rough endop lasmic reticulum as precursors of asymmetric (A) AChE forms, assembled in the Golgi apparatus. Reduced levels of G(1) and G(2) AChE forms. i n combination with unchanged AChE mRNA, are therefore consistent with the reports demonstrating that glucocorticoids downregulate muscle pro tein synthesis at the translational level. Our findings support but no t entirely prove the concept that impaired translation and/or posttran slational control are the primary cause of decreased AChE activity in the glucocorticoid-treated muscle.