Treatment of myotonia congenita with retigabine in mice

Dupont, Christian; Denman, Kirsten; Hawash, Ahmed; Voss, Andrew A.; Rich, Mark M.

doi:10.1016/j.expneurol.2019.02.002

Cited by 20 publications

(31 citation statements)

References 31 publications

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“…Force measurements were performed as previously reported ( Dupont et al, 2019 ). Mice were anesthetized with isoflurane using a low-flow anesthesia system (SS-01; Kent Scientific), with body temperature maintained at ∼35°C using a heat lamp and temperature probe.…”

Section: Methodsmentioning

confidence: 99%

Depressed neuromuscular transmission causes weakness in mice lacking BK potassium channels

Wang

Burke

Talmadge

et al. 2020

Journal of General Physiology

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Mice lacking functional large-conductance voltage- and Ca2+-activated K+ channels (BK channels) are viable but have motor deficits including ataxia and weakness. The cause of weakness is unknown. In this study, we discovered, in vivo, that skeletal muscle in mice lacking BK channels (BK−/−) was weak in response to nerve stimulation but not to direct muscle stimulation, suggesting a failure of neuromuscular transmission. Voltage-clamp studies of the BK−/− neuromuscular junction (NMJ) revealed a reduction in evoked endplate current amplitude and the frequency of spontaneous vesicle release compared with WT littermates. Responses to 50-Hz stimulation indicated a reduced probability of vesicle release in BK−/− mice, suggestive of lower presynaptic Ca2+ entry. Pharmacological block of BK channels in WT NMJs did not affect NMJ function, surprisingly suggesting that the reduced vesicle release in BK−/− NMJs was not due to loss of BK channel–mediated K+ current. Possible explanations for our data include an effect of BK channels on development of the NMJ, a role for BK channels in regulating presynaptic Ca2+ current or the effectiveness of Ca2+ in triggering release. Consistent with reduced Ca2+ entry or effectiveness of Ca2+ in triggering release, use of 3,4-diaminopyridine to widen action potentials normalized evoked release in BK−/− mice to WT levels. Intraperitoneal application of 3,4-diaminopyridine fully restored in vivo nerve-stimulated muscle force in BK−/− mice. Our work demonstrates that mice lacking BK channels have weakness due to a defect in vesicle release at the NMJ.

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Section: Methodsmentioning

confidence: 99%

Depressed neuromuscular transmission causes weakness in mice lacking BK potassium channels

Wang

Burke

Talmadge

et al. 2020

Journal of General Physiology

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“…To determine whether antagonism of TRPV4 might be effective as therapy, we measured the severity of myotonia using in vivo contractile force recordings of gastrocnemius muscle as described previously. 28 The sciatic nerve was stimulated at 60 Hz while measuring isometric muscle force generation. In wild type muscle, force fused during 60 Hz stimulation and relaxed immediately upon cessation of stimulation ( Fig 5A).…”

Section: Resultsmentioning

confidence: 99%

TRPV4 Antagonism Prevents Mechanically Induced Myotonia

Dupont

Novak

Denman

et al. 2020

Annals of Neurology

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Objective Myotonia is caused by involuntary firing of skeletal muscle action potentials and causes debilitating stiffness. Current treatments are insufficiently efficacious and associated with side effects. Myotonia can be triggered by voluntary movement (electrically induced myotonia) or percussion (mechanically induced myotonia). Whether distinct molecular mechanisms underlie these triggers is unknown. Our goal was to identify ion channels involved in mechanically induced myotonia and to evaluate block of the channels involved as a novel approach to therapy. Methods We developed a novel system to enable study of mechanically induced myotonia using both genetic and pharmacologic mouse models of myotonia congenita. We extended ex vivo studies of excitability to in vivo studies of muscle stiffness. Results As previous work suggests activation of transient receptor potential vanilloid 4 (TRPV4) channels by mechanical stimuli in muscle, we examined the role of this cation channel. Mechanically induced myotonia was markedly suppressed in TRPV4‐null muscles and in muscles treated with TRPV4 small molecule antagonists. The suppression of mechanically induced myotonia occurred without altering intrinsic muscle excitability, such that myotonia triggered by firing of action potentials (electrically induced myotonia) was unaffected. When injected intraperitoneally, TRPV4 antagonists lessened the severity of myotonia in vivo by approximately 80%. Interpretation These data demonstrate that there are distinct molecular mechanisms triggering electrically induced and mechanically induced myotonia. Our data indicates that activation of TRPV4 during muscle contraction plays an important role in triggering myotonia in vivo. Elimination of mechanically induced myotonia by TRPV4 inhibition offers a new approach to treating myotonia. ANN NEUROL 2020;88:297–308.

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“…In myotonia, repetitive firing of myofibers causes an accumulation of K + in the transverse tubular system, which depolarizes the membrane sufficiently to initiate self-sustaining AP that results in prolonged (myotonic) contraction (Adrian and Bryant, 1974;Clausen, 2013). This depolarization might trigger an activation of slow persistent inward current (NaPIC), which results in repetitive firing (Tricarico et al, 2005;Dupont et al, 2019). Another recently published treatment option includes retigabine, a KCNQ 5 channel activator, which appears to improve myotonia via activation of K + current during action potential trains (Dupont et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

“…This depolarization might trigger an activation of slow persistent inward current (NaPIC), which results in repetitive firing (Tricarico et al, 2005;Dupont et al, 2019). Another recently published treatment option includes retigabine, a KCNQ 5 channel activator, which appears to improve myotonia via activation of K + current during action potential trains (Dupont et al, 2019). However, to date, these beneficial effects have only been detected under in vitro conditions.…”

Section: Introductionmentioning

confidence: 99%

“…However, to date, these beneficial effects have only been detected under in vitro conditions. This might either be explained by administration of an insufficient dose or due to differential sensitivity to retigabine's effects on different muscle groups (Dupont et al, 2019). However, retigabine is designed to treat epilepsy and therefore shows high penetrance into the central nervous system and depressant effects.…”

Section: Introductionmentioning

confidence: 99%

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Paxilline Prevents the Onset of Myotonic Stiffness in Pharmacologically Induced Myotonia: A Preclinical Investigation

et al. 2020

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Reduced Cl− conductance causes inhibited muscle relaxation after forceful voluntary contraction due to muscle membrane hyperexcitability. This represents the pathomechanism of myotonia congenita. Due to the prevailing data suggesting that an increased potassium level is a main contributor, we studied the effect of a modulator of a big conductance Ca2+- and voltage-activated K+ channels (BK) modulator on contraction and relaxation of slow- and high-twitch muscle specimen before and after the pharmacological induction of myotonia. Human and murine muscle specimens (wild-type and BK−/−) were exposed to anthracene-9-carboxylic acid (9-AC) to inhibit CLC-1 chloride channels and to induce myotonia in-vitro. Functional effects of BK-channel activation and blockade were investigated by exposing slow-twitch (soleus) and fast-twitch (extensor digitorum longus) murine muscle specimens or human musculus vastus lateralis to an activator (NS1608) and a blocker (Paxilline), respectively. Muscle-twitch force and relaxation times (T90/10) were monitored. Compared to wild type, fast-twitch muscle specimen of BK−/− mice resulted in a significantly decreased T90/10 in presence of 9-AC. Paxilline significantly shortened T90/10 of murine slow- and fast-twitch muscles as well as human vastus lateralis muscle. Moreover, twitch force was significantly reduced after application of Paxilline in myotonic muscle. NS1608 had opposite effects to Paxilline and aggravated the onset of myotonic activity by prolongation of T90/10. The currently used standard therapy for myotonia is, in some individuals, not very effective. This in vitro study demonstrated that a BK channel blocker lowers myotonic stiffness and thus highlights its potential therapeutic option in myotonia congenital (MC).

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Treatment of myotonia congenita with retigabine in mice

Cited by 20 publications

References 31 publications

Depressed neuromuscular transmission causes weakness in mice lacking BK potassium channels

Depressed neuromuscular transmission causes weakness in mice lacking BK potassium channels

TRPV4 Antagonism Prevents Mechanically Induced Myotonia

Paxilline Prevents the Onset of Myotonic Stiffness in Pharmacologically Induced Myotonia: A Preclinical Investigation

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