Potassium-sensitive loss of muscle force in the setting of reduced inward rectifier K ⁺ current: Implications for Andersen–Tawil syndrome

Andersen-Tawil syndrome (ATS) is an ion channelopathy with variable penetrance for the triad of periodic paralysis, arrhythmia, and dysmorphia. Dominant-negative mutations of <i>KCNJ2</i> encoding 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-K⁺ or low-K⁺. Patient trials with controlled K⁺ challenges 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-K⁺ or low-K⁺ triggers weakness. A K⁺ channel agonist, retigabine, protects muscle from K⁺-sensitive weakness in our mouse models of the skeletal muscle involvement in ATS.