Extracellular magnesium and calcium reduce myotonia in ClC-1 inhibited rat muscle

Skov, Martin; Riisager, Anders; Fraser, James A.; Nielsen, Ole Bækgaard; Pedersen, Thomas Klit

doi:10.1016/j.nmd.2013.03.009

Cited by 23 publications

(46 citation statements)

References 34 publications

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“…With no exposure to ranolazine, myotonia was detected in 100% of ClC EDL fibers (n = 217 fibers, 28 mice); in the presence of 50μM ranolazine, 0% of ClC EDL fibers exhibited myotonia (n = 35 fibers, 4 mice). The second treatment we studied was elevated extracellular Ca 2+ and Mg 2+ , which has been shown to prevent myotonia 13, 30. We recorded from ClC EDL muscle in the presence of physiological (1.5mM Ca 2+ and 1.4mM Mg 2+ ) and elevated (5mM Ca 2+ and 2mM Mg 2+ ) extracellular divalent cation concentrations.…”

Section: Resultsmentioning

confidence: 99%

“…However, it has remained unclear what excitatory events trigger myotonic APs in the absence of the stabilizing ClC‐1 current. Prior to this study, the only excitatory factor implicated in the generation of involuntary APs in myotonia congenita was a steady membrane depolarization from K + buildup in t‐tubules8, 9, 10, 11 that activated the transient Na + channels responsible for APs 12, 13. It was posited >4 decades ago that some additional factor was necessary to account for the spontaneous firing of APs during myotonia9; however, until now, no such factor had been identified.…”

Section: Discussionmentioning

confidence: 96%

“…As we had not yet identified NaPIC, we proposed that ranolazine was eliminating myotonia by enhancing slow inactivation of transient Na + currents 21. Elevation of extracellular divalent cations was suggested to eliminate myotonia by a rightward shift in the voltage dependence of transient Na + activation, such that the AP threshold shifted to more depolarized potentials 13, 30. In the current study, we found that the elimination of myotonia by both ranolazine and elevated divalent cations coincided with NaPIC inhibition and a parallel reduction in the slope of AfD such that the threshold for triggering myotonic APs was not reached.…”

Section: Discussionmentioning

confidence: 99%

“…T‐tubules are narrow invaginations of the surface membrane that are needed to conduct APs into the middle of muscle fibers 7. The resulting K + buildup depolarizes the resting membrane potential8, 9, 10, 11 and is thought to open voltage‐gated Na + channels that trigger the involuntary APs causing myotonia 12, 13. Normally, ClC‐1‐mediated chloride currents, which account for 70 to 80% of resting muscle membrane conductance, offset the depolarizing influence of K + accumulation and prevent myotonia 6, 8, 14, 15…”

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confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Inhibiting persistent inward sodium currents prevents myotonia

Hawash

Voss

Rich

2017

Annals of Neurology

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“…Other studies have found that mutations in both the CLCN1 and CNBP coexist in individuals with MD (Sun et al, 2011), indicating that there is a need for further understanding of the mechanism of Mc. Studies suggested that decreased calcium release or increased uptake may protect Myotonic goat muscle from destructive changes of calcium overload, which has been proposed to be a common factor for dystrophic change (Atkinson, Swift, & Lequire, 1981;Millay et al, 2009;Skov et al, 2014;Skov, Riisager, Fraser, Nielsen, & Pedersen, 2013;Swift, Atkinson, & LeQuire, 1979). It has been shown that disruption in calcium influx causes malfunction in muscle contraction (Allen, Gervasio, Yeung, & Whitehead, 2010).…”

Section: Significance Of the Problemmentioning

confidence: 99%

Characterization of the TRPC3 Gene in Myotonic Goats: Further Insight Into Myotonia congenita and Muscular Dystrophy

Corley¹,

Caviness²

2014

JMBR

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Myotonia congenita (Mc) is a muscle disorder seen in both Myotonic goats and humans, caused by mutations in the chloride ion channel gene (CLCN1). Calcium signaling has been coupled to the function of the CLCN1, but this interaction is not well understood, as individuals with Mc do not experience muscular dystrophy (MD). Over expression of the Transient Receptor Cation Channel 3 (TRPC3), a protein responsible for calcium influx and muscle contraction causes an elevation in calcium which results in a phenotype of MD. Evaluation of the TRPC3 gene in Myotonic goats has not been conducted. Therefore the objective of this experiment was to evaluate gene expression of the TRPC3 gene in Myotonic vs. Spanish goats (control). Total RNA was isolated from whole blood samples. Cross species primers were designed from the human, bovine, and mouse TRPC3 cDNA alignments. The goat partial TRPC3 gene showed 98%, 92% and 91%, and 100%, 98%, and 98% nucleotide and amino acid sequence homology to the bovine, human and mouse TRPC3 genes respectively. Quantitative Real Time PCR showed that gene expression of TRPC3 was 77% higher (P<0.05) in Myotonic than Non-Myotonic (Spanish) goats. Male Myotonic goats expressed 67% higher levels (P<0.05) of TRPC3 than females. The TRPC3 gene expression was 90% higher (P<0.05) in Myotonic goats older than 4 years of age. These data indicate that the TRPC3 gene is a potential biomarker to further study Myotonia congenita in Myotonic goats and the interrelationship of the mechanism of calcium signaling in human Mc and MD.

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Channelopathies of Skeletal Muscle Excitability

Cannon

2015

Comprehensive Physiology

173

176

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Familial disorders of skeletal muscle excitability were initially described early in the last century and are now known to be caused by mutations of voltage-gated ion channels. The clinical manifestations are often striking, with an inability to relax after voluntary contraction (myotonia) or transient attacks of severe weakness (periodic paralysis). An essential feature of these disorders is fluctuation of symptoms that are strongly impacted by environmental triggers such as exercise, temperature, or serum K+ levels. These phenomena have intrigued physiologists for decades, and in the past 25 years the molecular lesions underlying these disorders have been identified and mechanistic studies are providing insights for therapeutic strategies of disease modification. These familial disorders of muscle fiber excitability are “channelopathies” caused by mutations of a chloride channel (ClC-1), sodium channel (NaV1.4), calcium channel (CaV1.1) and several potassium channels (Kir2.1, Kir2.6, Kir3.4). This review provides a synthesis of the mechanistic connections between functional defects of mutant ion channels, their impact on muscle excitability, how these changes cause clinical phenotypes, and approaches toward therapeutics.

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Extracellular magnesium and calcium reduce myotonia in ClC-1 inhibited rat muscle

Cited by 23 publications

References 34 publications

Inhibiting persistent inward sodium currents prevents myotonia

Inhibiting persistent inward sodium currents prevents myotonia

Characterization of the TRPC3 Gene in Myotonic Goats: Further Insight Into Myotonia congenita and Muscular Dystrophy

Channelopathies of Skeletal Muscle Excitability

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