title: Tumor Necrosis Factor alpha induced hypoexcitability in rat muscle evidenced in a model of ion currents and action potential.
abstract: Sepsis and Tumor Necrosis Factor alpha (TNFα), a major pro-inflammatory mediator, have previously been shown to induce a decrease in the conductance of voltage-dependent sodium channels (NaV). Moreover, TNFα increased resting membrane potential, leading to hyperpolarization. NaV and resting potential are the two major factors of membrane excitability. Then we hypothesis that TNFα can decrease muscle membrane excitability. To evidence that role of TNFα, 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 TNFα-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 TNFα-containing medium, thus corresponding to a decreased excitability.
authors.affiliation: Université de Brest, Faculté de Médecine et des Sciences de la Santé, Laboratoire de Physiologie, EA 1274 "Mouvement Sport Santé", Brest F-29200, France; Université Européenne de Bretagne, Brest F-29200, France; CHU Brest, Pôle Anesthésie Réanimation, Brest F-29200, France.
authors.forename: Maïté
authors.initials: M
authors.lastname: Guillouët
authors.forename: Fabrice
authors.initials: F
authors.lastname: Rannou
authors.forename: Marie-Agnès
authors.initials: MA
authors.lastname: Giroux-Metges
authors.forename: Mickael
authors.initials: M
authors.lastname: Droguet
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Pennec
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D003198:Computer Simulation; D005260:Female; D007249:Inflammation / Q000378:metabolism; D008564:Membrane Potentials / Q000502:physiology*; D018485:Muscle Fibers, Skeletal / Q000378:metabolism* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D018805:Sepsis / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D061566:Voltage-Gated Sodium Channels / Q000378:metabolism / Q000502:physiology
chemical_list: D014409:Tumor Necrosis Factor-alpha; D061566:Voltage-Gated Sodium Channels; D000254:Sodium-Potassium-Exchanging ATPase
keywords: Action potential; Excitability; Ion currents; Muscle; TNFα