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

At 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.In 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.Slowed muscle relaxation due to persistent electrical discharges is the hallmark of myotonia [1-4]. Myotonia occurs naturally in several species (humans, goats, mice) as a result of genetic deficiency of the skeletal muscle CLC-1 channel, a disease which in humans is termed myotonia congenita [1-13]. It can also be produced experimentally by blocking muscle Cl- channels of normal muscle, for example with 9-anthracene carboxylic acid (9-AC), p-chloro-phenoxy-propionic acid, or 2,4-dichlorphenoxyacetate [4,14-16]. Muscle from humans and animals with myotonia congenita has physiological, structural and biochemical alterations which transcend the loss of CLC-1 channels, including hypertrophy (goats, most humans) or atrophy (mice), alterations in fiber type composition (in particular loss of type IIB fibers, seen in most species with myotonia congenita), and altered amounts of parvalbumin [1,5,7,9,11-13,17,18]. These downstream changes may contribute to the complex abnormalities in contractile performance found in CLC-1 deficient muscle, in particular changes that occur during the contractile phase of the contraction-relaxation cycle, such as impaired force production and alterations in rate of fatigue during isometric contractions [19].Humans with myotonia experience l