Search

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. [ABSTRACT FROM AUTHOR]

In addition to the hallmark muscle stiffness, patients with recessive myotonia congenita (Becker disease) experience debilitating bouts of transient weakness that remain poorly understood despite years of study. We performed intracellular recordings from muscle of both genetic and pharmacologic mouse models of Becker disease to identify the mechanism underlying transient weakness. Our recordings reveal transient depolarizations (plateau potentials) of the membrane potential to 25 to 35 mV in the genetic and pharmacologic models of Becker disease. Both Na+ and Ca2+ currents contribute to plateau potentials. Na+ persistent inward current (NaPIC) through NaV1.4 channels is the key trigger of plateau potentials and current through CaV1.1 Ca2+ channels contributes to the duration of the plateau. Inhibiting NaPIC with ranolazine prevents the development of plateau potentials and eliminates transient weakness in vivo. These data suggest that targeting NaPIC may be an effective treatment to prevent transient weakness in myotonia congenit [ABSTRACT FROM AUTHOR]

Objective: Myotonia is caused by involuntary firing of skeletal muscle action potentials and causes debilitating stiffness. Current treatments are insufficiently efficacious and associated with side effects. Myotonia can be triggered by voluntary movement (electrically induced myotonia) or percussion (mechanically induced myotonia). Whether distinct molecular mechanisms underlie these triggers is unknown. Our goal was to identify ion channels involved in mechanically induced myotonia and to evaluate block of the channels involved as a novel approach to therapy.Methods: We developed a novel system to enable study of mechanically induced myotonia using both genetic and pharmacologic mouse models of myotonia congenita. We extended ex vivo studies of excitability to in vivo studies of muscle stiffness.Results: As previous work suggests activation of transient receptor potential vanilloid 4 (TRPV4) channels by mechanical stimuli in muscle, we examined the role of this cation channel. Mechanically induced myotonia was markedly suppressed in TRPV4-null muscles and in muscles treated with TRPV4 small molecule antagonists. The suppression of mechanically induced myotonia occurred without altering intrinsic muscle excitability, such that myotonia triggered by firing of action potentials (electrically induced myotonia) was unaffected. When injected intraperitoneally, TRPV4 antagonists lessened the severity of myotonia in vivo by approximately 80%.Interpretation: These data demonstrate that there are distinct molecular mechanisms triggering electrically induced and mechanically induced myotonia. Our data indicates that activation of TRPV4 during muscle contraction plays an important role in triggering myotonia in vivo. Elimination of mechanically induced myotonia by TRPV4 inhibition offers a new approach to treating myotonia. ANN NEUROL 2020;88:297-308. [ABSTRACT FROM AUTHOR]

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., (© 2024 The Author(s). The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)