Genetic CLC-1 chloride channel deficiency modifies diaphragm muscle isometric contractile properties

Genetic deficiency of the muscle chloride channel CLC-1 leads to myotonia congenita in humans as well as myotonia in mice and goats. The hallmark of myotonia is delayed muscle relaxation due to persistent electrical discharges in the muscle. The present study tested the hypothesis that performance of CLC-1 deficient diaphragm muscle is also altered during the contractile phase of the contraction-relaxation cycle. Diaphragm of CLC-1 deficient and wild type mice underwent in vitro isometric contractility testing. Myotonia was easily demonstrable during contractions elicited by train stimulation, but was not seen during twitch stimulation or during train stimulation preceded by a series of twitch stimulations. Twitch force was reduced from 16.7+/-2.5 N/cm(2) in normal muscle to 7.2+/-1.9 N/cm(2) in CLC-1 deficient muscle (P<0.002). Isometric twitch contraction time was shortened from 19.6+/-0.9 to 15.7+/-1.0 ms (P<0.002). During repetitive 25 Hz stimulation, force/area was lower for diseased than normal muscle, whereas force as a percent of initial values declined at a faster rate for normal than diseased muscle. The latter could be accounted for by a rightward shift in the force-frequency relationship of CLC-1 deficient relative to normal muscle, as use of stimulation frequencies which elicited comparable force levels as a percentage of maximum 100 Hz tetanic force led to similar rates of fatigue. These findings indicate that genetic CLC-1 deficiency not only affects muscle relaxation (myotonia) but also modulates diaphragm performance during the contractile phase of the contraction-relaxation cycle.