The Role of Muscle Activation Pattern and Calcineurin in Acetylcholinesterase Regulation in Rat Skeletal Muscles

Abstract

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.

Three-dimensional co-culture of C2C12/PC12 cells improves skeletal muscle tissue formation and function

“…However, the distribution and expression of the different AChE isoforms in muscles depend on the muscle fibre types, the motor nerve contact and the contractile activity (Rubin et al , ; Tsim et al , ). When electrical stimulation is used, the AChE mRNA expression level depends on the electrical pattern stimulation applied to the muscle cells and is different in fast and slow muscle fibres (Pregelj et al , ). The enhancement of the AChE mRNA expression level observed in our study (Figure ) results from an increase in cell activity due to electrical stimulation.…”

Fiber Types in Mammalian Skeletal Muscles

“…electrical activity and load (623). It has been hypothesized that specific neural impulse patterns in fast or slow muscles are responsible for different AChE activities.…”

Regulation of acetylcholinesterase activity by nitric oxide in rat neuromuscular junction via N‐methyl‐d‐aspartate receptor activation

“…It is known that the density of AChE in the synaptic cleft is not constant and can adapt to changes in synaptic activity (Rotundo, ; Rotundo et al ., ). The rate of AChE synthesis and therefore the amount of the enzyme in the cleft may depend on the pattern of neuronal firing (Pregelj et al ., ). However, all established mechanisms of AChE regulation require dozens of hours, as synthesis, secretion, and anchoring of the enzyme are required for activity.…”