{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T16:49:16Z","timestamp":1773420556245,"version":"3.50.1"},"reference-count":47,"publisher":"Rockefeller University Press","issue":"1","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2011,7,1]]},"abstract":"<jats:p>In patients with hyperkalemic periodic paralysis (HyperKPP), attacks of muscle weakness or paralysis are triggered by K+ ingestion or rest after exercise. Force can be restored by muscle work or treatment with \u03b22-adrenoceptor agonists. A missense substitution corresponding to a mutation in the skeletal muscle voltage-gated Na+ channel (Nav1.4, Met1592Val) causing human HyperKPP was targeted into the mouse SCN4A gene (mutants). In soleus muscles prepared from these mutant mice, twitch, tetanic force, and endurance were markedly reduced compared with soleus from wild type (WT), reflecting impaired excitability. In mutant soleus, contractility was considerably more sensitive than WT soleus to inhibition by elevated [K+]o. In resting mutant soleus, tetrodotoxin (TTX)-suppressible 22Na uptake and [Na+]i were increased by 470 and 58%, respectively, and membrane potential was depolarized (by 16 mV, P &amp;lt; 0.0001) and repolarized by TTX. Na+,K+ pump\u2013mediated 86Rb uptake was 83% larger than in WT. Salbutamol stimulated 86Rb uptake and reduced [Na+]i both in mutant and WT soleus. Stimulating Na+,K+ pumps with salbutamol restored force in mutant soleus and extensor digitorum longus (EDL). Increasing [Na+]i with monensin also restored force in soleus. In soleus, EDL, and tibialis anterior muscles of mutant mice, the content of Na+,K+ pumps was 28, 62, and 33% higher than in WT, respectively, possibly reflecting the stimulating effect of elevated [Na+]i on the synthesis of Na+,K+ pumps. The results confirm that the functional disorders of skeletal muscles in HyperKPP are secondary to increased Na+ influx and show that contractility can be restored by acute stimulation of the Na+,K+ pumps. Calcitonin gene-related peptide (CGRP) restored force in mutant soleus but caused no detectable increase in 86Rb uptake. Repeated excitation and capsaicin also restored contractility, possibly because of the release of endogenous CGRP from nerve endings in the isolated muscles. These observations may explain how mild exercise helps locally to prevent severe weakness during an attack of HyperKPP.<\/jats:p>","DOI":"10.1085\/jgp.201010586","type":"journal-article","created":{"date-parts":[[2011,6,28]],"date-time":"2011-06-28T02:50:30Z","timestamp":1309229430000},"page":"117-130","update-policy":"https:\/\/doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":19,"title":["Na+,K+-pump stimulation improves contractility in isolated muscles of mice with hyperkalemic periodic paralysis"],"prefix":"10.1085","volume":"138","author":[{"given":"Torben","family":"Clausen","sequence":"first","affiliation":[{"name":"Department of Physiology and Biophysics, Aarhus University, DK-8000 Aarhus C, Denmark 1"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ole B\u00e6kgaard","family":"Nielsen","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Aarhus University, DK-8000 Aarhus C, Denmark 1"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Johannes D.","family":"Clausen","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Aarhus University, DK-8000 Aarhus C, Denmark 1"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas Holm","family":"Pedersen","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Aarhus University, DK-8000 Aarhus C, Denmark 1"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lawrence J.","family":"Hayward","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655 2"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"291","published-online":{"date-parts":[[2011,6,27]]},"reference":[{"key":"2023072521395664600_bib1","doi-asserted-by":"crossref","first-page":"C419","DOI":"10.1152\/ajpcell.1993.264.2.C419","article-title":"Calcitonin gene-related peptide stimulates active Na+-K+ transport in rat soleus muscle","volume":"264","author":"Andersen","year":"1993","journal-title":"Am. 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Physiol."},{"key":"2023072521395664600_bib41","doi-asserted-by":"crossref","first-page":"783","DOI":"10.2460\/ajvr.1993.54.05.783","article-title":"[3H]ouabain binding in skeletal muscle from horses with hyperkalemic periodic paralysis","volume":"54","author":"Pickar","year":"1993","journal-title":"Am. J. Vet. Res."},{"key":"2023072521395664600_bib42","doi-asserted-by":"publisher","first-page":"883","DOI":"10.1002\/mus.880121103","article-title":"Adynamia episodica hereditaria: what causes the weakness?","volume":"12","author":"Ricker","year":"1989","journal-title":"Muscle Nerve."},{"key":"2023072521395664600_bib43","doi-asserted-by":"publisher","first-page":"8794","DOI":"10.1073\/pnas.89.18.8794","article-title":"Cloning and stable maintenance of 300-kilobase-pair fragments of human DNA in Escherichia coli using an F-factor-based vector","volume":"89","author":"Shizuya","year":"1992","journal-title":"Proc. Natl. Acad. Sci. 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