Muscle Na ⁺ channelopathies

Abstract

Abstract-Background:Muscle channelopathies such as paramyotonia, hyperkalemic periodic paralysis, and potassiumaggravated myotonia are caused by gain-of-function Na ϩ channel mutations. Methods: Implementation of a threedimensional radial 23 Na magnetic resonance (MR) sequence with ultra-short echo times allowed the authors to quantify changes in the total muscular 23 Na signal intensity. By this technique and T2-weighted 1 H MRI, the authors studied whether the affected muscles take up Na ϩ and water during episodes of myotonic stiffness or of cold-or exercise-induced weakness. Results: A 22% increase in the 23 Na signal intensity and edema-like changes on T2-weighted 1 H 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 23 Na, but no increase in the T2-weighted 1 H signal, occurred during cold-or exerciseinduced 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 ϩ accumulation and membrane depolarization by Ϫ41 mV for paramyotonia, by Ϫ30 mV for hyperkalemic periodic paralysis, and by Ϫ20 mV for potassium-aggravated myotonia. The combined in vivo and in vitro approach showed a close correlation between the increase in 23 Na MR signal intensity and the membrane depolarization (r ϭ 0.92). Conclusions: The increase in the total 23 Na signal intensity reflects intracellular changes, the coldinduced Na ϩ shifts are greatest and osmotically relevant in paramyotonia patients, and even osmotically irrelevant Na ϩ shifts can be detected by the implemented 23 Na MR technique.

Targeted mutation of mouse skeletal muscle sodium channel produces myotonia and potassium-sensitive weakness

“…The effects of Ca 2+ observed in this study are also consistent with the observation that in normal muscle fibers, increased [Ca 2+ ] o hyperpolarizes the resting membrane potential (36) (16,45). Increased [Na + ] i is an important factor for activation of the Na + /K + pump (50,51), and Na + /K + pump stimulation improves membrane excitability and contractility in normal muscles with reduced Na + and/or K + gradients (52)(53)(54).…”

“…The original "normokalemic" periodic paralysis family described by Poskanzer and Kerr (43) and subsequently shown to harbor the Met1592Val mutation in the Na V 1.4 gene (42), showed a sensitivity to oral ingestion of K + even though the plasma [K + ] remained in the normal range during attacks. The phenotype associated with the Met1592Val mutation can be heterogeneous, though, with other reports indicating attacks of weakness associated with mild hyperkalemia or with cold sensitivity (44,45). We observed that raising [K + ] o from 4 to 8 mM produced only transient weakness in isolated mutant EDL muscle.…”

Genotype-Phenotype Correlation and Therapeutic Rationale in Hyperkalemic Periodic Paralysis

“…However, in vitro and in vivo studies have shown that increased sodium influx and membrane depolarization of cooled PC fibers persist for hours. 24,25,30 This is in agreement with weakness lasting up to 8 h in PC patients, compared with that in hyperkalemic PP, which lasts from 30 min to 2 h. The larger sodium influx and the more pronounced sustained depolarization in PC (by 40 mV) than in hyperkalemic PP (by 30 mV) 24,25,30 may aggravate the T-tubular and myoplasmic disequilibrium and require more time for recovery.…”

“…3), corresponding to a gain-of-function defect. 10,21 As a result, sodium influx is increased, as shown in vitro 24 and in vivo 25 (FIGS. 4 and 5).…”

“…25 In contrast to the cold-induced weakness in PC, hyperkalemic PP muscle regains strength after rewarming.…”