Na<sub>v</sub>1.4 slow‐inactivation: Is it a player in the warm‐up phenomenon of myotonic disorders?

Lossin, Christoph

doi:10.1002/mus.23713

Cited by 8 publications

(8 citation statements)

References 26 publications

(55 reference statements)

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“…8 The relative density of sodium channels opening during the upstroke of the action potential can be estimated by measuring the maximal rate of action potential rise and action potential peak. 32 Thus, if slow inactivation of sodium channels contributes to warm-up, both action potential rate of rise and action potential peak will be reduced.…”

Section: Resultsmentioning

confidence: 99%

“…5, 6 Changes in membrane potential, membrane conductance, and slow inactivation of sodium channels have all been proposed to underlie warm-up. 7, 8 Unfortunately, it has been impossible to directly study the mechanism underlying warm-up because muscle contraction makes it impossible to perform intracellular recording from individual muscle fibers during the stimulation necessary to induce warm-up. Because of this technical challenge, the mechanism underlying warm-up has remained unknown since its original description almost 40 years ago.…”

Section: Introductionmentioning

confidence: 99%

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Sodium channel slow inactivation as a therapeutic target for myotonia congenita

Novak

Norman

Mitchell

et al. 2015

Annals of Neurology

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Objective Patients with myotonia congenita have muscle hyperexcitability due to loss-of-function mutations in the chloride channel in skeletal muscle, which causes spontaneous firing of muscle action potentials (myotonia), producing muscle stiffness. In patients, muscle stiffness lessens with exercise, a change known as the warm-up phenomenon. Our goal was to identify the mechanism underlying warm up and to use this information to guide development of novel therapy. Methods To determine the mechanism underlying warm-up, we used a recently discovered drug to eliminate muscle contraction, thus allowing prolonged intracellular recording from individual muscle fibers during induction of warm-up in a mouse model of myotonia congenita. Results Changes in action potentials suggested slow inactivation of sodium channels as an important contributor to warm-up. These data suggested enhancing slow inactivation of sodium channels might offer effective therapy for myotonia. Lacosamide and ranolazine enhance slow inactivation of sodium channels and are FDA-approved for other uses in patients. We compared the efficacy of both drugs to mexiletine, a sodium channel blocker currently used to treat myotonia. In vitro studies suggested both lacosamide and ranolazine were superior to mexiletine. However, in vivo studies in a mouse model of myotonia congenita suggested side effects could limit the efficacy of lacosamide. Ranolazine produced fewer side effects and was as effective as mexiletine at a dose that produced none of mexiletine’s hypoexcitability side effects. Interpretation We conclude ranolazine has excellent therapeutic potential for treatment of patients with myotonia congenita.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Sodium channel slow inactivation as a therapeutic target for myotonia congenita

Novak

Norman

Mitchell

et al. 2015

Annals of Neurology

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“…We also examined whether slow inactivation of the transient Na + current contributed to resolution of myotonia, as has recently been proposed 21, 29. If the transient Na + channel availability decreases, the AP peak and dV/dt will decrease, and the AP threshold will increase.…”

Section: Resultsmentioning

confidence: 91%

Inhibiting persistent inward sodium currents prevents myotonia

Hawash

Voss

Rich

2017

Annals of Neurology

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ObjectivePatients with myotonia congenita have muscle hyperexcitability due to loss‐of‐function mutations in the ClC‐1 chloride channel in skeletal muscle, which causes involuntary firing of muscle action potentials (myotonia), producing muscle stiffness. The excitatory events that trigger myotonic action potentials in the absence of stabilizing ClC‐1 current are not fully understood. Our goal was to identify currents that trigger spontaneous firing of muscle in the setting of reduced ClC‐1 current.Methods In vitro intracellular current clamp and voltage clamp recordings were performed in muscle from a mouse model of myotonia congenita.ResultsIntracellular recordings revealed a slow afterdepolarization (AfD) that triggers myotonic action potentials. The AfD is well explained by a tetrodotoxin‐sensitive and voltage‐dependent Na+ persistent inward current (NaPIC). Notably, this NaPIC undergoes slow inactivation over seconds, suggesting this may contribute to the end of myotonic runs. Highlighting the significance of this mechanism, we found that ranolazine and elevated serum divalent cations eliminate myotonia by inhibiting AfD and NaPIC.InterpretationThis work significantly changes our understanding of the mechanisms triggering myotonia. Our work suggests that the current focus of treating myotonia, blocking the transient Na+ current underlying action potentials, is an inefficient approach. We show that inhibiting NaPIC is paralleled by elimination of myotonia. We suggest the ideal myotonia therapy would selectively block NaPIC and spare the transient Na+ current. Ann Neurol 2017;82:385–395

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“…Ranolazine, an anti-anginal drug, demonstrated antimyotonic properties in both myotonic congenita and paramyotonia congenita model [60][61][62]. In contrast to mexiletine and lamotrigine, which enhance fast inactivation of voltage-gated sodium channels, ranolazine enhances slow inactivation and blocks persistent voltage-dependent sodium inward current [61][62][63][64][65].…”

Section: Ranolazinementioning

confidence: 99%

“… Ranolazine Ranolazine, an anti-anginal drug, demonstrated antimyotonic properties in both myotonic congenita and paramyotonia congenita model [ 60 – 62 ]. In contrast to mexiletine and lamotrigine, which enhance fast inactivation of voltage-gated sodium channels, ranolazine enhances slow inactivation and blocks persistent voltage-dependent sodium inward current [ 61 – 65 ]. An open-label pilot study of thirteen patients with MC treated with ranolazine resulted in significantly improved self-reported severity of stiffness and reduced myotonia duration on electromyography.…”

Section: Treatment Of Myotoniamentioning

confidence: 99%

Treatment Updates for Neuromuscular Channelopathies

Jitpimolmard

Matthews

Fialho

2020

Curr Treat Options Neurol

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Purpose of review This article aims to review the current and upcoming treatment options of primary muscle channelopathies including the non-dystrophic myotonias and periodic paralyses. Recent findings The efficacy of mexiletine in the treatment of myotonia is now supported by two randomised placebo-controlled trials, one of which utilised a novel aggregated n-of-1 design. This has resulted in licencing of the drug via orphan drug status. There is also good evidence that mexiletine is well tolerated and safe in this patient group without the need for intensive monitoring. A range of alternative antimyotonic treatment options include lamotrigine, carbamazepine and ranolazine exist with variable evidence base. In vitro studies have shown insight into reasons for treatment failure of some medications with certain genotypes opening the era of mutation-specific therapy such as use of flecainide. In the periodic paralyses, the ability of MRI to distinguish between reversible oedema and irreversible fatty replacement makes it an increasingly useful tool to guide and assess pharmacological treatment. Unfortunately, the striking efficacy of bumetanide in hypokalaemic periodic paralysis animal models was not replicated in a recent pilot study in humans. Summary The treatment of skeletal muscle channelopathies combines dietary and lifestyle advice together with pharmacological interventions. The rarity of these conditions remains a barrier for clinical studies but the example of the aggregated n-of-1 trial of mexiletine shows that innovative trial design can overcome these hurdles. Further research is required to test efficacy of drugs shown to have promising characteristics in preclinical experiments such as safinamide, riluzule and magnesium for myotonia or bumetanide for hypokalaemic periodic paralysis.

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Na_v1.4 slow‐inactivation: Is it a player in the warm‐up phenomenon of myotonic disorders?

Cited by 8 publications

References 26 publications

Sodium channel slow inactivation as a therapeutic target for myotonia congenita

Sodium channel slow inactivation as a therapeutic target for myotonia congenita

Inhibiting persistent inward sodium currents prevents myotonia

Treatment Updates for Neuromuscular Channelopathies

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Nav1.4 slow‐inactivation: Is it a player in the warm‐up phenomenon of myotonic disorders?

Cited by 8 publications

References 26 publications

Sodium channel slow inactivation as a therapeutic target for myotonia congenita

Sodium channel slow inactivation as a therapeutic target for myotonia congenita

Inhibiting persistent inward sodium currents prevents myotonia

Treatment Updates for Neuromuscular Channelopathies

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Product

Resources

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Na_v1.4 slow‐inactivation: Is it a player in the warm‐up phenomenon of myotonic disorders?