Possible role of apamin‐sensitive K⁺ channels in myotonic dystrophy

Abstract

Myotonic muscular dystrophy is a genetic disease characterized mainly by muscle atrophy and myotonia, a repetitive electrical activity of muscle. In the present study, the possible role of apamin-sensitive K+ channels in the genesis of myotonia was investigated. Apamin is a peptide from bee venom that specifically blocks small conductance Ca(2+)-activated K+ channels. The injection of a small amount of apamin (20-30 microliters, 10 mumol/L) into the thenar muscle of myotonic dystrophy patients decreased the basal electrical activity during the electromyogram in the 6 patients studied. Myotonic discharges after muscle percussion were more difficult to trigger and of smaller intensity and duration. In 2 controls and in 2 patients with generalized myotonia, as well as in 1 patient with myotonia congenita (where the defect is in chloride channels), apamin had no effect. These results suggest that apamin-sensitive K+ channels participate in the mechanism that generates myotonia in myotonic dystrophy.

Correction of ClC-1 splicing eliminates chloride channelopathy and myotonia in mouse models of myotonic dystrophy

“…In light of the abnormal calcium homeostasis observed in DM1 cells and model systems (18,19), and the effects of DM1 on alternative splicing of the SERCA1 calcium reuptake pump of the sarcoplasmic reticulum (7,20), it also seems possible that excessive calcium release due to myotonic discharges may aggravate the degeneration of DM1 muscle fibers. Although previous studies have implicated sodium channels or calcium-activated potassium channels in DM1 (12)(13)(14), a second finding of the present study is that DM1-associated myotonia results primarily from a chloride channelopathy.…”

“…However, the mechanism of ClC-1 downregulation and its requirement for myotonia in DM1 are controversial. Effects on sodium or potassium channels have also been implicated in DM1-associated myotonia (12)(13)(14). In addition, evidence that chloride channelopathy in DM1 results from downregulation of ClC-1 transcription, rather than abnormal splicing, has been reported (15).…”

Electrophysiological evaluation in myotonic dystrophy: correlation with CTG length expansion

“…The pathophysiology responsible for the muscle wasting, weakness and for myotonia is not yet completely defined 26,27 . Deficiency in muscle anabolism due to multiple causes 1 , deficiency of MD protein kinase leading to dysregulation of the calcium metabolism in muscle fiber 26 and reduction of type 2 muscle fiber numbers 27 are proposed to explain weakness and wasting.…”

“…Deficiency in muscle anabolism due to multiple causes 1 , deficiency of MD protein kinase leading to dysregulation of the calcium metabolism in muscle fiber 26 and reduction of type 2 muscle fiber numbers 27 are proposed to explain weakness and wasting. Alteration in the function of slow potassium channels can produce myotonia 26 . Recently, evidences based on a transgenic mice, support a possible mechanism of RNA gain of function in the pathogenesis of MD 15 .…”

Potassium currents in human myogenic cells from healthy and congenital myotonic dystrophy foetuses

“…There are now several pieces of experimental evidence suggesting that myotonia could be due to a decrease in the expression of muscle-specific ClC-1 chloride channels [8,10]. Moreover, an increased cytosolic Ca 2+ concentration [11], altered expression of small conductance Ca 2+ -activated K + channels [12] and a gating abnormality of Na + channels [13,14] could also contribute to the modifications in the excitability in DM1 muscle cells. However, the muscle wasting observed during the progression of the disease and the severe impairment of muscle maturation described in the severe congenital form of DM1 [15,16] cannot be explained by these electrophysiological observations.…”