Muscle Na⁺ channelopathies

Abstract

Background: Muscle channelopathies such as paramyotonia, hyperkalemic periodic paralysis, and potassium-aggravated myotonia are caused by gain-of-function Na⁺ channel mutations.

Methods: Implementation of a three-dimensional radial ²³Na magnetic resonance (MR) sequence with ultra-short echo times allowed the authors to quantify changes in the total muscular ²³Na signal intensity. By this technique and T2-weighted ¹H MRI, the authors studied whether the affected muscles take up Na⁺ and water during episodes of myotonic stiffness or of cold- or exercise-induced weakness.

Results: A 22% increase in the ²³Na signal intensity and edema-like changes on T2-weighted ¹H MR images were associated with cold-induced weakness in all 10 paramyotonia patients; signal increase and weakness disappeared within 1 day. A 10% increase in ²³Na, but no increase in the T2-weighted ¹H signal, occurred during cold- or exercise-induced weakness in seven hyperkalemic periodic paralysis patients, and no MR changes were observed in controls or exercise-induced stiffness in six potassium-aggravated myotonia patients. Measurements on native muscle fibers revealed provocation-induced, intracellular Na⁺ accumulation and membrane depolarization by −41 mV for paramyotonia, by −30 mV for hyperkalemic periodic paralysis, and by −20 mV for potassium-aggravated myotonia. The combined in vivo and in vitro approach showed a close correlation between the increase in ²³Na MR signal intensity and the membrane depolarization (r = 0.92).

Conclusions: The increase in the total ²³Na signal intensity reflects intracellular changes, the cold-induced Na⁺ shifts are greatest and osmotically relevant in paramyotonia patients, and even osmotically irrelevant Na⁺ shifts can be detected by the implemented ²³Na MR technique.