Potassium-sensitive loss of muscle force in the setting of reduced inward rectifier Kcurrent: Implications for Andersen-Tawil syndrome.

Abstract

Andersen-Tawil syndrome (ATS) is an ion channelopathy with variable penetrance for the triad of periodic paralysis, arrhythmia, and dysmorphia. Dominant-negative mutations ofencoding the Kir2.1 potassium channel subunit are found in 60% of ATS families. As with most channelopathies, episodic attacks in ATS are frequently triggered by environmental stresses: exercise for periodic paralysis or stress with adrenergic stimulation for arrhythmia. Fluctuations in K, either low or high, are potent triggers for attacks of weakness in other variants of periodic paralysis (hypokalemic periodic paralysis or hyperkalemic periodic paralysis). For ATS, the [K] dependence is less clear; with reports describing weakness in high-Kor low-K. Patient trials with controlled Kchallenges are not possible, due to arrhythmias. We have developed two mouse models (genetic and pharmacologic) with reduced Kir currents, to address the question of K-sensitive loss of force. These animal models and computational simulations both show K-dependent weakness occurs only when Kir current is <30% of wildtype. As the Kir deficit becomes more severe, the phenotype shifts from high-K-induced weakness to a combination where either high-Kor low-Ktriggers weakness. A Kchannel agonist, retigabine, protects muscle from K-sensitive weakness in our mouse models of the skeletal muscle involvement in ATS.