Loss of muscle excitability in acute quadriplegic myopathy

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DESCRIPTION (provided by applicant): Critically ill patients develop paralysis due to loss of skeletal muscle excitability (critical illness myopathy, CIM). In an animal model of CIM, a hyperpolarized shift in the voltage dependence of sodium channel inactivation was found to underlie loss of excitability. During investigation of sodium channel gating defects in CIM, several processes were identified that rapidly modulate the voltage dependence of sodium channel gating (over minutes rather than days as in CIM). One process is a holding potential induced shift in the voltage dependence of sodium channel gating. A second process is a damage-induced, hyperpolarized shift in the voltage dependence of sodium channel gating. The goal of the current proposal is to determine the mechanism and function of both the rapid shifts in the voltage dependence of sodium channel gating as well as the slower shift that develops in CIM. Combined electrophysiologic and biochemical approaches will be used to determine the mechanisms underlying the various shifts in the voltage dependence of sodium channel gating that have been identified. Computer modeling will be employed to explore potential functional consequences of gating changes that have been identified. While the goal of this work is to develop therapy for CIM, the identification of pathways that modulate the voltage dependence of sodium channel gating has implications for treatment of other disorders of excitability such as epilepsy and cardiac arrhythmia.