PMC

Clinical features of non-dystrophic myotonia. Patient 17 (myotonia congenita): (A,B) show muscle stiffness and hypertrophy; (C,D) show grip myotonia; (E,F) show percussion myotonia. Patient 20 (paramyotonia congenita); (G) shows muscle stiffness and hypertrophy; (H) shows facial stiffness and eye closure myotonia; (I,J) show grip myotonia; (K,L) show percussion myotonia.

Distinct mechanisms underlying electrically- and mechanically-induced myotonia. Electrically-induced myotonia (top two rows): in wild type muscle Cl^- current plays a central role in controlling resting potential both at rest and during firing of action potentials during voluntary movement. Because of the stabilizing influence of Cl^- current, K⁺ build-up in t-tubules does not cause sufficient depolarization to trigger myotonia following voluntary activation of muscle. In myotonia congenita, muscle Cl^- current is reduced such that K⁺ build-up causes depolarization large enough to trigger myotonia. Mechanically-induced myotonia (bottom two rows): mechanical stimulation of wild type muscle activates TRPV4 channels, which depolarizes muscle. This depolarization is opposed by Cl^- current such that myotonia is not triggered. Activation of TRPV4 channels during mechanical stimulation of muscle with reduced Cl^- current causes depolarization sufficient to trigger myotonia.

Treatment with small molecule inhibitors of TRPV4 greatly reduces mechanically-induced myotonia in ClC^adr muscle. A) Mechanically-induced myotonia was present in 28/28 vehicle-treated fibers from 4 mice, and 0/28 fibers treated with 1 μM HC-067047 from 4 mice. At the times indicated by vertical arrows, a blunt electrode was manually advanced to mechanically stimulate the fiber being studied. B) Electrically-induced myotonia was present in 33/33 vehicle-treated fibers from 5 mice and 48/48 HC-067047-treated fibers from 5 mice. C) Following application of vehicle 19/20 fibers from 3 mice had mechanically-induced myotonia. After application of GSK2193874, 3/20 fibers from 3 mice had mechanically-induced myotonia. D) Electrically-induced myotonia was present in 21/21 vehicle-treated fibers from 3 mice and 19/19 fibers treated with 1 μM GSK2193874 from 3 mice.

Exemplary prolonged intracellular recordings of plateau potentials from 9-AC treated muscle fibers (n = 5 fibers). There is no consistent relationship between duration of myotonia and development of plateau potentials. The horizontal lines under each trace mark 200 ms injections of depolarizing current.