Targeted mutation of mouse skeletal muscle sodium channel produces myotonia and potassium-sensitive weakness

Abstract

Hyperkalemic periodic paralysis (HyperKPP) produces myotonia and attacks of muscle weakness triggered by rest after exercise or by K + ingestion. We introduced a missense substitution corresponding to a human familial HyperKPP mutation (Met1592Val) into the mouse gene encoding the skeletal muscle voltage-gated Na + channel Na V 1.4. Mice heterozygous for this mutation exhibited prominent myotonia at rest and muscle fibertype switching to a more oxidative phenotype compared with controls. Isolated mutant extensor digitorum longus muscles were abnormally sensitive to the Na + /K + pump inhibitor ouabain and exhibited age-dependent changes, including delayed relaxation and altered generation of tetanic force. Moreover, rapid and sustained weakness of isolated mutant muscles was induced when the extracellular K + concentration was increased from 4 mM to 10 mM, a level observed in the muscle interstitium of humans during exercise. Mutant muscle recovered from stimulation-induced fatigue more slowly than did control muscle, and the extent of recovery was decreased in the presence of high extracellular K + levels. These findings demonstrate that expression of the Met1592Val Na + channel in mouse muscle is sufficient to produce important features of HyperKPP, including myotonia, K + -sensitive paralysis, and susceptibility to delayed weakness during recovery from fatigue.

The non-dystrophic myotonias: molecular pathogenesis, diagnosis and treatment

“…These changes were present before any spontaneous episodes of paralysis had been observed. Furthermore, they were shown to increase with age in the heterozygotes while muscle force generation declined (Hayward et al, 2008). These findings support the clinical observations that myopathy increases with age (Links et al, 1990;Plassart et al, 1994) and that it may be independent of paralytic attacks in the periodic paralyses (Buruma et al, 1978;Links et al, 1990).…”

“…Recently, a mouse model of hyperkalaemic periodic paralysis has been engineered by introducing the murine equivalent of the SCN4A mis-sense mutation M1592V (Hayward et al, 2008). This mutation causes both myotonia and paralysis in humans (Rojas et al, 1991;Kelly et al, 1997) and was demonstrated to produce the same symptoms in the mouse indicating the validity of the model.…”

“…A single point mutation has been identified in the equine skeletal muscle sodium channel gene that substitutes a phenylalanine for a leucine in the DIV/S3 segment of the protein (Rudolph et al, 1992). Recently a mouse model of hyperkalaemic periodic paralysis was successfully engineered by introducing the equivalent of the common human M1592V mutation into the murine SCN4A gene (Hayward et al, 2008). The mouse was shown to display similar clinical and biopsy findings to those seen in human cases of hyperkalaemic periodic paralysis validating it as a reasonable animal model.…”

“…The mouse was shown to display similar clinical and biopsy findings to those seen in human cases of hyperkalaemic periodic paralysis validating it as a reasonable animal model. New insights into the beneficial effects of elevated extracellular calcium levels and detrimental effects of impairing the sodium/potassium pump in the pathophysiology of hyperkalaemic periodic paralysis have already been determined (Hayward et al, 2008). This knock-in mouse offers potential for developing an increased understanding of the pathophysiology of hyperkalaemic periodic paralysis and possibly the development of future therapies.…”

A sodium channel knockin mutant (NaV1.4-R669H) mouse model of hypokalemic periodic paralysis

“…Importantly, these data also show that R669H +/m mice do not have an increased susceptibility to force reduction in high K + . This distinction is notable because other disease-associated mutations in Na V 1.4 with gain-of-function alterations in channel activity will predispose muscle to attacks of hyperkalemic periodic paralysis (HyperPP), often accompanied with myotonia (22). R669H m/m muscle was more susceptible to a severe loss of force, in either low or high K + .…”