Tumor Necrosis Factor alpha induced hypoexcitability in rat muscle evidenced in a model of ion currents and action potential

Sepsis and Tumor Necrosis Factor alpha (TNF alpha), a major pro-inflammatory mediator, have previously been shown to induce a decrease in the conductance of voltage-dependent sodium channels (Na-v). Moreover, TNF alpha increased resting membrane potential, leading to hyperpolarization. Na-v and resting potential are the two major factors of membrane excitability. Then we hypothesis that TNF alpha can decrease muscle membrane excitability. To evidence that role of TNF alpha, we carried out a simulation of the sodium and potassium currents and action potential (AP) of isolated muscle fibre. We used a computer model based on Hodgkin and Huxley equations, but also taking into account the sodium-potassium pump current. Our first aim was to optimise this model in control conditions according to our measurements of currents. Then the model was modified to fit the values measured experimentally in TNF alpha-containing medium in order to determine the modifications induced in the currents and hence in AP triggering. Our model provides a very good fit with experimental data on the ion currents. Moreover, it clearly shows that the triggering level of AP is increased in TNF alpha-containing medium, thus corresponding to a decreased excitability. (c) 2013 Elsevier Ltd. All rights reserved.