Acetylcholinesterase (AChE) expression in fast rat muscles is approximately fourfold higher than in slow muscles. We examined whether different muscle activation patterns are responsible for this difference and whether the calcineurin signaling pathway is involved in AChE regulation. The slow soleus and fast extensor digitorum longus (EDL) muscles were directly or indirectly stimulated by a tonic lowfrequency or a phasic high-frequency pattern of electric impulses. The phasic, but not tonic, stimulation increased the AChE mRNA levels in denervated soleus muscles to those in the normal EDL and maintained high levels of AChE mRNA in denervated EDL muscles. Therefore, muscle activation pattern is the predominant regulator of extrajunctional AChE expression in rat muscles. Indirect phasic stimulation of innervated muscles, imposed on their natural pattern of neural activation, did not increase the AChE transcript levels in the soleus, whereas a 30% reduction was observed in the EDL muscles. A low number of impulses per day is therefore prerequisite for high AChE expression. Treatment by tacrolimus and cyclosporin A, two inhibitors of calcineurin (but not by a related substance rapamycin, which does not inhibit calcineurin), increased the levels of AChE transcripts in the control soleus muscles and in tonically electrically stimulated soleus and EDL muscles, even to reach those in the control EDL muscles. Therefore, tonic muscle activation reduces the extrajunctional levels of AChE transcripts by activating the calcineurin signaling pathway. In denervated soleus and EDL muscles, tacrolimus did not prevent the reduction of AChE mRNA levels, indicating that a calcineurin-independent suppressive mechanism was involved.

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Acetylcholinesterase‐associated collagen Q is expressed also outside of neuromuscular junctions in the slow soleus muscle, but not in fast muscles. We examined the nerve dependence of muscle collagen Q expression and mechanisms responsible for these differences. Denervation decreased extrajunctional collagen Q mRNA levels in the soleus muscles and junctional levels in fast sternomastoid muscles to about one third. Cross‐innervation of denervated soleus muscles by a fast muscle nerve, or electrical stimulation by ‘fast’ impulse pattern, reduced their extrajunctional collagen Q mRNA levels by 70–80%. In contrast, stimulation of fast muscles by ‘slow’ impulse pattern had no effect on collagen Q expression. Calcineurin inhibitors tacrolimus and cyclosporin A decreased collagen Q mRNA levels in the soleus muscles to about 35%, but did not affect collagen Q expression in denervated soleus muscles or the junctional expression in fast muscles. Therefore, high extrajunctional expression of collagen Q in the soleus muscle is maintained by its tonic nerve‐induced activation pattern via the activated Ca2+‐calcineurin signaling pathway. The extrajunctional collagen Q expression in fast muscles is independent of muscle activation pattern and seems irreversibly suppressed. The junctional expression of collagen Q in fast muscles is partly nerve‐dependent, but does not encompass the Ca2+‐calcineurin signaling pathway.