Reduced K(+) build-up in t-tubules contributes to resistance of the diaphragm to myotonia.

Patients with myotonia congenita suffer from slowed muscle relaxation caused by hyperexcitability. The diaphragm is only mildly affected in myotonia congenita; discovery of the mechanism underlying its resistance to myotonia could identify novel therapeutic targets. Intracellular recordings from two mouse models of myotonia congenita revealed the diaphragm had less myotonia than either the extensor digitorum longus (EDL) or the soleus muscles. A mechanism contributing to resistance of the diaphragm to myotonia was reduced depolarization of the interspike membrane potential during repetitive firing of action potentials, a process driven by build-up of K(+) in small invaginations of muscle membrane known as t-tubules. We explored differences between diaphragm and EDL that might underlie reduction of K(+) build-up in diaphragm t-tubules. Smaller size of diaphragm fibres, which promotes diffusion of K(+) out of t-tubules, was identified as a contributor. Intracellular recording revealed slower repolarization of action potentials in diaphragm suggesting reduced Kv conductance. Higher resting membrane conductance was identified suggesting increased Kir conductance. Computer simulation found that a reduction of Kv conductance had little effect on K(+) build-up whereas increased Kir conductance lessened build-up, although the effect was modest. Our data and computer simulation suggest opening of K(+) channels during action potentials has little effect on K(+) build-up whereas opening of K(+) channels during the interspike interval slightly lessens K(+) build-up. We conclude that activation of K(+) channels may lessen myotonia by opposing depolarization to action potential threshold without worsening K(+) build-up in t-tubules. KEY POINTS: In mouse models of the muscle disease myotonia congenita, the diaphragm has much less myotonia (muscle stiffness) than the extensor digitorum longus or soleus muscles. Identifying why the diaphragm is resistant to myotonia may help in developing novel therapy. We found the reason the diaphragm has less myotonia is that it is less prone to depolarization caused by K(+) build-up in t-tubules during repetitive firing of action potentials. Smaller fibre size contributes to resistance to K(+) build-up with differences in K(+) currents playing little role. Our data suggest drugs that open K(+) channels may be effective in treating myotonia as they may lessen excitability without worsening K(+) build-up in t-tubules.