Alteration of muscle membrane excitability in sepsis: possible involvement of ciliary nervous trophic factor (CNTF).

International audienceOne of the main factor involved neuromyopathy acquired in intensive care unit (ICU) appears to be sepsis. It induces the release of many pro- and anti-inflammatory factors which can directly modulate the muscle excitability. We have studied the effects of one of them: the ciliary nervous trophic factor (CNTF) which is a cytokine released in the early phase of sepsis. CNTF induces a decrease in the sodium current and an increase in resting potential as in sodium inversion potential. These effects could participate to the hypo-excitability observed during sepsis and could be involved in the ICU acquired neuromyopathy. As for TNF?, this early effect is mainly mediated by protein kinase C (PKC) activation and appears to be a reversible post-transcriptional effect

Tumor necrosis factor-? downregulates sodium current in skeletal muscle by protein kinase C activation: involvement in critical illness polyneuromyopathy.

International audienceSepsis is involved in the decrease of membrane excitability of skeletal muscle, leading to polyneuromyopathy. This effect is mediated by alterations of the properties of voltage-gated sodium channels (Na(V)), but the exact mechanism is still unknown. The aim of the present study was to check whether tumor necrosis factor (TNF-?), a cytokine released during sepsis, exerts a rapid effect on Na(V). Sodium current (I(Na)) was recorded by macropatch clamp in skeletal muscle fibers isolated from rat peroneus longus muscle, in control conditions and after TNF-? addition. Analyses of dose-effect and time-effect relationships were carried out. Effect of chelerythrine, a PKC inhibitor, was also studied to determine the way of action of TNF-?. TNF-? induced a reversible dose- and time-dependent inhibition of I(Na). A maximum inhibition of 75% of the control current was observed. A shift toward more negative potentials of activation and inactivation curves of I(Na) was also noticed. These effects were prevented by chelerythrine pretreatment. TNF-? is a cytokine released in the early stages of sepsis. Besides a possible transcriptional role, i.e., modification of the channel type and/or number, we demonstrated the existence of a rapid, posttranscriptional inhibition of Na(V) by TNF-?. The downregulation of the sodium current could be mediated by a PKC-induced phosphorylation of the sodium channel, thus leading to a significant decrease in muscle excitability