Muscle & nerve · 2026
Efficacy of Retigabine in Treating Weakness in a Mouse Model of Hypokalemic Periodic Paralysis.
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Denman Kirsten, Rich Mark M
Аннотация
INTRODUCTION/AIMS: Hypokalemic periodic paralysis (HypoKPP) is an ion channelopathy causing episodic skeletal muscle weakness triggered by hypokalemia. Reduced inward rectifier K+ (Kir) channel activity contributes to membrane depolarization and paralysis, suggesting that pharmacologic activation of muscle K+ channels may restore excitability. The Kv7 channel agonist retigabine previously mitigated low-K+ weakness in HypoKPP models. Here, we tested whether this effect persists under conditions producing sustained, severe weakness.
METHODS: Extensor digitorum longus (EDL) muscles from mice homozygous for the SCN4A R669H mutation were studied by isometric twitch force recording at 34°C, with or without 20 U/L insulin. Weakness was induced by reducing extracellular K+ to 1.0 mM. Retigabine (10 μM) was applied to the bath, and twitch force was analyzed by paired or unpaired t tests (n = 4-7 per group).
RESULTS: Baseline twitch force in 4.75 mM K+ was ~50% lower in HypoKPP than wild-type muscle (p = 0.01). Force declined further after 1 h in 4.75 mM K+ (p = 0.016) and was completely lost at 1.0 mM K+ with insulin. Retigabine significantly reduced loss of force at both 4.75 and 1.0 mM K+ (p = 0.047 and p = 0.007, respectively).
DISCUSSION: Kv7 channel activation by retigabine preserved contractile force even during sustained depolarization from severe hypokalemia. These findings extend prior work and support development of K+ channel agonists as a therapeutic approach for HypoKPP.
METHODS: Extensor digitorum longus (EDL) muscles from mice homozygous for the SCN4A R669H mutation were studied by isometric twitch force recording at 34°C, with or without 20 U/L insulin. Weakness was induced by reducing extracellular K+ to 1.0 mM. Retigabine (10 μM) was applied to the bath, and twitch force was analyzed by paired or unpaired t tests (n = 4-7 per group).
RESULTS: Baseline twitch force in 4.75 mM K+ was ~50% lower in HypoKPP than wild-type muscle (p = 0.01). Force declined further after 1 h in 4.75 mM K+ (p = 0.016) and was completely lost at 1.0 mM K+ with insulin. Retigabine significantly reduced loss of force at both 4.75 and 1.0 mM K+ (p = 0.047 and p = 0.007, respectively).
DISCUSSION: Kv7 channel activation by retigabine preserved contractile force even during sustained depolarization from severe hypokalemia. These findings extend prior work and support development of K+ channel agonists as a therapeutic approach for HypoKPP.