Tumor Necrosis Factor alpha induced hypoexcitability in rat muscle evidenced in a model of ion currents and action potential Maïté Guillouët a,b,c , Fabrice Rannou a,b , Marie-Agnès Giroux-Metges a,b , Mickael Droguet a,b , Jean-Pierre Pennec a,b,⇑ a Université de Brest, Faculté de Médecine et des Sciences de la Santé, Laboratoire de Physiologie, EA 1274 ‘‘Mouvement Sport Santé’’, Brest F-29200, France b Université Européenne de Bretagne, Brest F-29200, France c CHU Brest, Pôle Anesthésie Réanimation, Brest F-29200, France article info Article history: Received 28 January 2013 Received in revised form 14 June 2013 Accepted 2 July 2013 Available online xxxx Keywords: TNFa Muscle Excitability Ion currents Action potential abstract Sepsis and Tumor Necrosis Factor alpha (TNFa), a major pro-inflammatory mediator, have previously been shown to induce a decrease in the conductance of voltage-dependent sodium channels (Na V ). More- over, TNFa increased resting membrane potential, leading to hyperpolarization. Na V and resting potential are the two major factors of membrane excitability. Then we hypothesis that TNFa can decrease muscle membrane excitability. To evidence that role of TNFa, 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 TNFa-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 TNFa-containing medium, thus corresponding to a decreased excitability. Ó 2013 Published by Elsevier Ltd. 1. Introduction The excitability of a muscle corresponds to its ability to respond rapidly to stimulation by generating an action potential (AP), which in turn triggers the contraction. It requires that inward membrane currents exceed outward currents and thereby depola- rise the fibres to the threshold corresponding to AP generation. Therefore, excitability is linked to voltage-gated sodium channels (Na V ), which are responsible for the initiation and propagation of the action potential and resting potential which determines AP threshold. In addition, the amplitude of the AP can condition the excitation–contraction coupling mechanism and hence the effi- ciency of the muscle contraction. Sepsis and pro-inflammatory mediators appear to be major risk factors of neuromuscular hypo-excitability like in critical illness polyneuromyopathy (CIP) [1]. In vivo acute or chronic models of sepsis have been developed in rat allowing studying its effects on the neuromuscular excitability. In a previous study using a model of chronic sepsis induced by caecal ligation and puncture (CLP) in rat, we demonstrated that sepsis increased the latency of the excitation–contraction coupling [2]. In parallel, in an acute model of sepsis, Cankayali et al. [3] ob- served electro-physiological abnormalities in the first hour of sep- sis corresponding to an increased latency and a decreased action potential amplitude. In septic rat, Novak et al. [4] showed that a reduced excitability was due to an increased Na V inactivation, as a consequence of a shift toward hyperpolarised voltages of the voltage dependence of the channels inactivation. In a CLP model of sepsis, we also ob- served a decrease of sodium current in isolated rat flexor digitorum brevis fibres related to a decreased conductance as well as a shift in the activation and inactivation curves Rossignol et al. [5]. In addi- tion, in steroid denervated rat muscle, which is another model of CIP, it was shown that muscle inexcitability was related to a shift in the voltage dependence of Na V 1.4 fast inactivation associated with an upregulation of the Na V 1.5 isoform expression [6,7]. In the early phase of sepsis, TNFa is one of the major pro- inflammatory factors released, and could be involved in the elec- trophysiological alterations observed. We have recently shown in isolated fibres from rat peroneus longus that TNFa decreased Na V current and shifted both activation and inactivation voltage curves 1043-4666/$ - see front matter Ó 2013 Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.cyto.2013.07.007 ⇑ Corresponding author at: Université de Brest, Faculté de Médecine et des Sciences de la Santé, Laboratoire de Physiologie, EA 1274 ‘‘Mouvement Sport Santé’’, Brest F-29200, France. Tel.: +33 2 98 01 64 62. E-mail address: jpennec@univ-brest.fr (J.-P. Pennec). Cytokine xxx (2013) xxx–xxx Contents lists available at SciVerse ScienceDirect Cytokine journal homepage: www.journals.elsevier.com/cytokine Please cite this article in press as: Guillouët M et al. Tumor Necrosis Factor alpha induced hypoexcitability in rat muscle evidenced in a model of ion cur- rents and action potential. Cytokine (2013), http://dx.doi.org/10.1016/j.cyto.2013.07.007