{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,6]],"date-time":"2026-09-06T08:12:23Z","timestamp":1788682343708,"version":"build-2803163510"},"reference-count":54,"publisher":"Wiley","issue":"22","license":[{"start":{"date-parts":[[2024,10,11]],"date-time":"2024-10-11T00:00:00Z","timestamp":1728604800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["AR074985"],"award-info":[{"award-number":["AR074985"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2024,11]]},"abstract":"<jats:sec><jats:title>Abstract<\/jats:title><jats:p>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\u2010up of K<jats:sup>+<\/jats:sup> in small invaginations of muscle membrane known as t\u2010tubules. We explored differences between diaphragm and EDL that might underlie reduction of K<jats:sup>+<\/jats:sup> build\u2010up in diaphragm t\u2010tubules. Smaller size of diaphragm fibres, which promotes diffusion of K<jats:sup>+<\/jats:sup> out of t\u2010tubules, 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<jats:sup>+<\/jats:sup> build\u2010up whereas increased Kir conductance lessened build\u2010up, although the effect was modest. Our data and computer simulation suggest opening of K<jats:sup>+<\/jats:sup> channels during action potentials has little effect on K<jats:sup>+<\/jats:sup> build\u2010up whereas opening of K<jats:sup>+<\/jats:sup> channels during the interspike interval slightly lessens K<jats:sup>+<\/jats:sup> build\u2010up. We conclude that activation of K<jats:sup>+<\/jats:sup> channels may lessen myotonia by opposing depolarization to action potential threshold without worsening K<jats:sup>+<\/jats:sup> build\u2010up in t\u2010tubules.\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp16347-gra-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>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.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Identifying why the diaphragm is resistant to myotonia may help in developing novel therapy.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>We found the reason the diaphragm has less myotonia is that it is less prone to depolarization caused by K<jats:sup>+<\/jats:sup> build\u2010up in t\u2010tubules during repetitive firing of action potentials.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Smaller fibre size contributes to resistance to K<jats:sup>+<\/jats:sup> build\u2010up with differences in K<jats:sup>+<\/jats:sup> currents playing little role.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Our data suggest drugs that open K<jats:sup>+<\/jats:sup> channels may be effective in treating myotonia as they may lessen excitability without worsening K<jats:sup>+<\/jats:sup> build\u2010up in t\u2010tubules.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1113\/jp286636","type":"journal-article","created":{"date-parts":[[2024,10,11]],"date-time":"2024-10-11T16:25:10Z","timestamp":1728663910000},"page":"6171-6188","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Reduced K<sup>+<\/sup> build\u2010up in t\u2010tubules contributes to resistance of the diaphragm to myotonia"],"prefix":"10.1113","volume":"602","author":[{"given":"Jessica H.","family":"Myers","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Cell Biology and Physiology Wright State University  Dayton Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirsten","family":"Denman","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Cell Biology and Physiology Wright State University  Dayton Ohio 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