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

Sepsis 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 (NaV), but the exact mechanism is still unknown. The aim of the present study was to check whether tumor necrosis factor (TNF-α), a cytokine released during sepsis, exerts a rapid effect on NaV. Sodium current (INa) was recorded by macropatch clamp in skeletal muscle fibers isolated from rat peroneus longus muscle, in control conditions and after TNF-α 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-α. TNF-α induced a reversible dose- and time-dependent inhibition of INa. A maximum inhibition of 75% of the control current was observed. A shift toward more negative potentials of activation and inactivation curves of INa was also noticed. These effects were prevented by chelerythrin...