Fatigue-inducing stimulation resolves myotonia in a drug-induced model

Abstract

BackgroundSlowed muscle relaxation is the contractile hallmark of myotonia congenita, a disease caused by genetic CLC-1 chloride channel deficiency, which improves with antecedent brief contractions ("warm-up phenomenon"). It is unclear to what extent the myotonia continues to dissipate during continued repetitive contractions and how this relates temporally to muscle fatigue. Diaphragm, EDL, and soleus muscles were examined in vitro during repetitive 20 Hz and 50 Hz train stimulation in a drug-induced (9-AC) rat myotonia model.ResultsAt the onset of stimulation, 9-AC treated diaphragm and EDL muscle had markedly prolonged half relaxation and late relaxation times (range 147 to 884 ms, 894 to 1324 ms). Half relaxation and late relaxation times reached near-normal values over the 5-10 and 10-40 subsequent contractions, respectively. In both muscles myotonia declined faster during repetitive 50 Hz than 20 Hz stimulation, and much faster than the rate of force loss during fatigue at both frequencies. Soleus muscle was resistant to the myotonic effects of 9-AC.ConclusionsIn a drug-induced model of mechanical myotonia, fatigue-inducing stimulation resolves the myotonia, which furthermore appears to be independent from the development of muscle fatigue.

Sodium channel slow inactivation as a therapeutic target for myotonia congenita

“…ClCn1 adr-mto2J mice (ClC adr mice) that are homozygous for the null mutation in the ClC-1 gene have severe muscle stiffness that manifests as impaired ability to run 29 , a stiff gait, and an inability to rapidly right after being placed in a supine position. When ClC adr mice were placed in a supine position they initially took 3.5 ± 1.0 seconds (n = 10 mice) to right themselves.…”

“…Warm-up has been shown to occur ex vivo in wild type muscle made acutely myotonic by block of muscle chloride channels. 29 To study action potential and passive membrane properties associated with warm-up it is necessary to record from individual muscle fibers before and after repeated activation of the fiber. The recent discovery of N-benzyl-p-toluenesulfonamide (BTS) has made this possible.…”

Novel Insights into the Pathomechanisms of Skeletal Muscle Channelopathies

“…The mechanism of the warm-up phenomenon remains uncertain. In vitro, rat diaphragm and extensor digitorum longus muscle made myotonic by pharmacologic block of ClC1 warms up on a much shorter time scale (within a minute) than fatigue (loss of force) develops [33], so fatigue and warm-up appear to be quite separate. This fits with the clinical observation that in patients with transient weakness, warm-up causes increased strength-quite the opposite of fatigue.…”

“…Regulation of ClC1 expression at transcriptional and post-transcriptional levels helps to match the properties of a muscle cell to the demands of its motor neuron [32]. Fast muscle expresses more ClC1 than slow muscle and is more prone to myotonia when its chloride conductance is impaired [33].…”

In vivo evaluation of antimyotonic efficacy of β-adrenergic drugs in a rat model of myotonia

“…Up today, the study of potential countermeasures against myotonia induced by 9-AC has been performed only in vitro (Dengler and Rudel, 1979; van Lunteren et al., 2011; Su et al., 2012). Therefore one important novelty of the model described here is that drugs are tested in vivo in conscious animals.…”